Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:21]=[CH:20][S:19][C:8]2=[N:9][C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].C(O)=O.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:21]=[CH:20][S:19][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc2ccsc2nc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2sccc2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
6-Trifluoromethanesulfonyloxy-thieno[2,3-b]pyridine-5-carboxylic acid methyl ester described in Preparation Example T-9 (10 mg, 29 μmol), tetrakis(triphenylphosphine)palladium(0) (3.4 mg, 2.9 μmol), formic acid (1.7 μl, 44 μmol) and N,N-diisopropylethylamine (15 μl, 87 μmol) were dissolved in 1-methyl-2-pyrrolidone (0.5 mL), and the mixture was stirred for 1.5 hours at 100° C. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (7 mg, quantitatively) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH:29]=[O:30])=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCn1c(-c2ccccc2)nc(C(OC)OC)c1C=O

Procedure:
To a solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74 g, 10 mmol) in anhydrous TH-F under nitrogen at −78° C., n-BuLi (1.6 M in hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture is continued stirring at this temperature for 30 ran. After anhydrous DMF (4 mL) is added, the mixture is stirred at room temperature for 16 h. Saturated ammonium chloride and ethyl acetate were added at 0° C. and the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.60-7.56 (m, 2H), 7.51-7.46 (m, 3H), 5.63 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73-1.63 (m, 2H), 1.28-1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[N:11]1([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nccc2sccc12
Reactant: C1CNCCN1
Solvent: CCO
Product: c1cc2sccc2c(N2CCNCC2)n1
Yield: 56.1 %

Procedure:
A mixture of 4-chlorothieno[3,2-c]pyridine (22.7 g, 0.13 mole) and piperazine (57.7 g, 0.67 mole) were heated in a bomb with a minimum amount of ethanol (50 mL) at 120° for 24 hours. The reaction was cooled, partitioned between dichloromethane and water, and the organic layer was isolated, dried (MgSO4), filtered, and concentrated in vacuo to an oil. Flash chromatography (methylene chloride-10% methanol-1% ammonium hydroxide) of this material gave 16 g (54%) of a golden oil. Treatment of an ethanol solution of the oil with ethanolic HCl followed by recrystallization from ethanol gave the hydrochloride salt as off-white crystals, m.p. 275°-283°.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:17]([O-])=O.C(NS(C1C(Cl)=C([N+]([O-])=O)C=C(C=1)C(O)=O)(=O)=O)CCC.N[C:42]1[CH:43]=[C:44]([CH:48]=[C:49](S(=O)(=O)NC)[C:50]=1[O:51]C1C=CC=CC=1)C(O)=O.CNC.C(N)CCC.NC1CC(S(=O)(=O)NCCCC)(OC2C=CC=CC=2)C=C(C(O)=O)C=1>>[NH2:17][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])[C:2]=1[O:51][C:50]1[CH:49]=[CH:48][CH:44]=[CH:43][CH:42]=1)[C:6]([OH:8])=[O:7]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CNS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Agent: CCCCNS(=O)(=O)C1(Oc2ccccc2)C=C(C(=O)O)C=C(N)C1
Agent: CCCCNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: CNC
Solvent: CCCCN
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1

Procedure:
The starting materials, 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid and 5-n-butylsulphamyl-4-chloro-3-nitro-benzoic acid, were new and were obtained as described for the starting material of Example 2 by substituting aqueous dimethylamine (3.6 g containing 1.5 g of dimethylamine) and n-butylamine (2.2 g), respectively, for the aqueous methylamine, and had melting points of 233°-235°C, and 196°-198°C, respectively.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:20])=[C:7]([CH2:15][CH2:16][C:17](O)=[O:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6]([OH:20])=[C:7]([CH2:15][CH2:16][C:17]([Cl:23])=[O:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CCC(=O)O)c(O)c(C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)Cl)c(O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Operating under a nitrogen current, 29.8 g of methyl 3-(3',5'-di-tert-butylhydroxyphenyl)propionate, 80 mL of ethanol, and 6 g of sodium hydroxide were introduced in a 0.5-L four-neck flask equipped with a stirrer, addition funnel, and thermometer and were stirred for 1 hour while heating under reflux. After completion of the stirring period, the ethanol was removed by distillation and the reaction mass was then neutralized by the gradual addition of concentrated hydrochloric acid. 150 mL of a 1:1 liquid mixture of toluene and ethyl acetate was added followed by washing twice with water. The solvent was subsequently distilled from the washed organic layer to give 27.2 g of 3-(3',5'-di-text-butylhydroxyphenyl)propionic acid in crystalline form. Then, while operating under a nitrogen current, 8.0 g of this 3-(3',5'-di-tert-butylhydroxyphenyl)propionic acid and 50 mL of dry toluene were introduced into a 0.2-L four-neck flask equipped with a stirrer, addition funnel, and thermometer and were stirred. After completion of stirring, 4 g of thionyl chloride was added dropwise at room temperature from the addition funnel. The reaction solution was then heated to 70° C. and a reaction was run for 4 hours with stirring. After completion of the reaction, the by-products were distilled under reduced pressure from the reaction solution to give 8.1 g of 3-(3',5'-di-tert-butylhydroxyphenyl)propionyl chloride in crystalline form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:17])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To the solution of 4,5-dichloro-benzene-1,2-diamine (25 g, 0.14 mol) in dry DMF (200 mL), was added CDI (23 g, 0.14 mol) as the solid. The reaction solution was stirred at room temperature for 1 hour, then water (500 mL) was added. The precipitated solid was collected by filtration, washed with water, dried thoroughly to afford the titled compound (26.0 g, 90%). The crude product was used in the following reaction without further purification.
Reaction SMILES: [Ca].[OH2:2].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[OH:3][CH2:4][C:5]([C@H:7]([C@H:7]([C@@H:5]([CH2:4][OH:3])[OH:6])[OH:2])[OH:8])=[O:6]
Reactant: O
Reactant: OCC(O)CO
Agent: [Ca]
Product: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
passing the isomerized reactor mixture to a second SMB zone comprising a plurality of adsorbent columns containing a strong acid cation calcium exchange resin stationary phase and operating in a 2-3-2-2 SMB cycle with water as a desorbent to provide a second extract stream comprising substantially pure d-tagatose, water, and glycerol and a second raffinate stream comprising substantially pure d-galactose, water, salts and a minor portion of d-tagatose;
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:14])([CH2:8][CH2:9][C:10](Cl)([CH3:12])[CH3:11])[CH3:7].[C:15]1([CH3:22])[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[CH3:22][C:15]1[C:16]([CH3:21])=[CH:17][C:18]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:6]([CH3:14])([CH3:7])[C:19]=2[CH:20]=1
Reactant: Cc1ccccc1C
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
7 g of aluminum chloride was added by portions to 200 ml solution of 50 g 2,5-dichloro-2,5-dimethylhexane in orthoxylene at 0° C. under stirring. After the mixture was stirred at the same temperature for 15 minutes, it was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated to give 60 g of 2,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene as a brown oil.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>C(O)(=O)C.O.CS(C)=O.CO>[CH:25]1([NH:28][CH2:2][CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=4[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: NC(=O)c1cccc2[nH]c(-c3cccc(CC4OCCO4)c3)nc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1cccc2[nH]c(-c3cccc(CCNC4CC4)c3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 10A (300 mg, 0.88 mmol) in acetic acid (10 mL) and water (20 mL) was heated at 70° C. for 20 hours. After cooling, the solution was concentrated to give a light yellow solid. To a solution of the crude aldehyde (80 mg) in dimethyl sulfoxide (2 mL) and methanol (3 mL) was added cyclopropylamine (60 μL) and the mixture stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (54 mg, 0.86 mmol) was added and the mixture heated at 55° C. overnight. Volatiles were removed and the residue purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100% gradient) to provide 8.8 mg of the title compound as a trifluoroacetate salt. To a solution of this salt in 1:1 methanol/dichloromethane (1 mL) was added 1M HCl in ether (3 mL). Concentration afforded the title compound as a hydrochloride salt. 1H NMR (CD3OD): δ 0.91-1.03 (m, 4H), 2.83-2.89 (m, 1H), 3.23-3.29 (m, 2H), 3.49-3.55 (m, 2H), 7.70-7.79 (m, 3H), 8.03-8.13 (m, 3 H), 8.20 (s, 1H),
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]4[CH2:25][CH:26]5[NH:30][CH:29]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38]>CO.C(OCC)C>[ClH:38].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH2:25][CH:26]4[NH:30][CH:29]([C:13]3=2)[CH2:28][CH2:27]4)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2-c2ccccc2)CC2CCC1N2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)c1c(n2-c2ccccc2)CC2CCC1N2
Reaction time: 2 h

Procedure:
To a solution of the product of step D (70 mg, 0.13 mmol) in methanol was added 2M HCl in diethylether (4 mL). After stirring for 2 h, the solution was concentrated in vacuo, triturated with ethyl acetate, and lyophilized from water to give 2-phenylsulfonyl-5-phenyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (50 mg, 57%, AUC HPLC >99%) as a white solid: mp 195-200° C.; 1H NMR (CD3OD, 300 MHz) δ 8.38 (d, J=1.8 Hz, 1H), 7.95-7.99 (m, 2H), 7.72 (dd, J=8.8, 1.5 Hz, 1H), 7.51-7.64 (m, 6H), 7.39-7.42 (m, 2H), 7.32 (d, J=9.0 Hz, 1H), 5.39-5.40 (m, 1H), 4.49 (br s, 1H), 3.39 (dd, J=8.7, 4.5 Hz, 1H), 2.81 (d, J=17.7 Hz, 1H), 2.37-2.46 (m, 3H), 1.98-2.08 (m, 1H); ESI, m/z 415 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:44][O:45][CH2:46][C:47]([O:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:14])[CH3:15])[NH:8][C:9]([O:11][CH3:12])=[O:10])=[O:48]
Reactant: COCC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COCC(=O)O[C@@H](CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 105, 200 mg (0.33 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in 2.6 ml of dioxane and 0.4 ml of pyridine are reacted with 50 μl (0.495 mmol) of methoxyacetic acid chloride and 2 mg (0.017 mmol) of DMAP. To complete the reaction a further 0.5 equivalents of methoxyacetic acid chloride and a few granules of DMAP are added and the mixture is stirred. Extraction and digestion from DIPE/hexane in an ultrasound bath yields the pure title compound: TLC Rf (O)=0.48; tRet (V)=15.6 min; FAB-MS (M+H)+ =678.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=O)[C:12]2[N:13]([N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=2)[CH:14]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:11]1[C:12]2[N:13]([N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=1
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc2c(Cl)nc(-c3ccc(Cl)cc3Cl)cn2n1

Procedure:
6.86 g (19.5 mmol) of ethyl 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate (Example 11A) were dissolved in 50 ml of phosphoryl chloride and stirred at reflux for 12 h. The reaction mixture was poured into 1.25 l of saturated sodium bicarbonate solution, and solid sodium bicarbonate was added until a pH of 7 had been reached. The solid was filtered off and dissolved in dichloromethane and chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 6.34 g (85% of theory) of the product as a solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH:35]=[O:36])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCC1>C1COCC1>[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([C@H:35]([C:15]3[C:14]([Cl:16])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:9])[OH:36])[CH2:24]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1[C@@H](O)c1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.51 mL, 7.02 mmol) was added to 3,5-dichloropyridine (820 mg, 5.54 mmol) dissolved in THF (15 mL) cooled at −78° C. and stirred at this temperature for 1 h. (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (1.04 g, 3.70 mmol) and its epimer at C2 of the pyrrolidine in THF (11 mL) was added and the solution was removed from the cooling bath and allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated ammonium chloride, the aqueous layer was extracted with EtOAc (2×50 mL) and the organic layer washed with brine (30 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-80% EtOAc in heptane) affording (2S,4S)-tert-butyl 4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 2.79 mmol, 76% yield) as a mixture of epimers. MS (ESI) 451.1, 453.1 [M+Na]+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:19]=[O:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[CH2:1]([C:8]1[C:9]([CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nc2cc(Cl)ccc2cc1Cc1ccccc1
Reactant: CC(C)[Mg]Cl
Solvent: ClCCl
Product: CC(C)C(O)c1nc2cc(Cl)ccc2cc1Cc1ccccc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a solution of 3-benzyl-7-chloroquinoline-2-carbaldehyde (1.23 g, 4.4 mmol) in anhydrous DCM (12 ml) at −78° C., was added isopropylmagnesium chloride (6.6 m, 13.2 mmol). The resulting solution was allowed to warm to ambient temperature over one hour. The reaction mixture was then quenched with saturated NH4Cl and extracted with DCM (3×). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The crude product was subjected to flash column chromatography using an ISCO purification system. Elution in hexanes with a gradient of ethyl acetate (0-100%) yielded 1-(3-benzyl-7-chloroquinolin-2-yl)-2-methylpropan-1-ol 25 (0.44 g, 1.3 mmol, 30%) as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[C:59]=2[F:65])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[C:59]=2[F:65])[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2F)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.1 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-2-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 23 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 78 mg white solid (46%). MS (ISP) 499.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[CH3:10][C@@H:11]1[N:34]([CH3:35])[CH2:33][C@:16]23[CH2:17][CH2:18][C@@H:19]4[C@@:24]5([CH3:32])[CH2:25][CH2:26][C@H:27]([N:29](C)[CH3:30])[CH2:28][C:23]5=[CH:22][CH2:21][C@H:20]4[C@@H:15]2[CH2:14][CH2:13][C@H:12]13>C1C=CC=CC=1>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[N:29]([CH3:30])[CH:27]1[CH2:28][C:23]2[C:24]([CH3:32])([CH:19]3[CH:20]([CH2:21][CH:22]=2)[CH:15]2[CH2:14][CH2:13][CH:12]4[CH:11]([CH3:10])[N:34]([CH3:35])[CH2:33][C:16]24[CH2:17][CH2:18]3)[CH2:25][CH2:26]1
Reactant: C[C@H]1[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](N(C)C)CC[C@]5(C)[C@H]4CC[C@]23CN1C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCC(Cl)(Cl)Cl)CCC5(C)C4CCC32CN1C
Temperature: 90 °C
Yield: 60.7 %

Procedure:
2,2,2-Trichloroethylchloroformate (5.94 g, 28 mmol) was added dropwise to a stirred solution of conessine (10 g, 28 mmol) in 200 mL benzene. Very thick gel resulted. The mixture was heated at reflux for 4 h (oil bath temperature 90° C.), then cooled down to room temperature, quenched with water, the pH adjusted with 25 mL saturated sodium bicarbonate, and extracted with dichloromethane 3×. Organic layers were dried over Na2SO4, filtered, and evaporated to give crude product, which was purified by flash chromatography to give desired product (8.8 g, 61% yield).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]=O)[N:18]=3)[N:15]=2)[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:43][C:44]1([F:48])[CH2:47][NH:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:46]4[CH2:47][C:44]([F:48])([F:43])[CH2:45]4)[N:18]=3)[N:15]=2)[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC=O)c4ccc(OC(F)F)cc34)nc12
Reactant: FC1(F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34 mg, 58.0 μmol) in dichloroethane (6 mL) was added 3,3-difluoroazetidine hydrochloride (9.76 mg, 75.3 μmol.30). The mixture was stirred at 25° C. for 15 min, then sodium triacetoxyborohydride (18.4 mg, 86.9 μmol0) was added and stirring was continued for 18 h. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with dichloromethane (5×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(1-(3-(3,3-difluoroazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 57.2 μmol, 98.8%) as an off-white solid. MS (M+Na)+=686; 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.36 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=74.0 Hz, 1H), 5.75 (s, 2H), 4.61 (t, J=6.6 Hz, 2H), 3.53-3.72 (m, 6H), 2.64 (t, J=6.0 Hz, 2H), 2.14 (dq, J=6.8, 5.7 Hz, 2H), 1.64 (s, 9H), 0.91-1.08 (m, 2H), 0.00 (s, 9H).