Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[CH3:24].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[N:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[N:35]=[C:34]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[N:33]=1>>[CH3:24][C@@H:5]1[CH2:6][C@@H:7]2[C@:21]([CH3:22])([CH2:20][CH:19]=[C:18]3[C@H:8]2[CH2:9][CH2:10][C:11]2[C@:16]3([CH3:17])[CH:15]=[CH:14][C:13](=[O:23])[CH:12]=2)[C@H:4]1[C:3](=[O:25])[CH2:2][N:47]1[CH2:48][CH2:49][N:44]([C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:37]=[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[N:33]=2)[CH2:45][CH2:46]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Reactant: c1ccc(-c2nc(-c3ccccn3)nc(N3CCNCC3)n2)nc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2nc(-c3ccccn3)nc(-c3ccccn3)n2)CC1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83 and 126, and making non-critical variations but starting with 21-iodo-16α-methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22) and 4-[4,6-bis(2-pyridinyl)-1,3,5-triazin-2-yl]piperazine (PREPARATION A-49) the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]OS(C)(=O)=O)[C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.CO.[NH3:22]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:14][NH:22][CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: N
Reactant: CS(=O)(=O)OCc1cc(Br)cnc1COS(C)(=O)=O
Solvent: CO
Product: Brc1cnc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 58 (1 g, crude) in MeOH (5 mL) was added MeOH—NH3 (5 mL) at 0° C. and stirred at rt for overnight. The reaction mixture was evaporated to obtain the desired compound (600 mg, crude) as a brown liquid. Rf: 0.2 (10% MeOH/CHCl3). The crude compound was used in the next step without further purification; (m/z): 199, 201 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH:21]([Mg]Br)([CH3:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)([OH:14])[CH:21]([CH3:23])[CH3:22])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Br
Reactant: O=C(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a stirred solution of (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone (0.1 g, 0.352 mmol) in THF (10 mL) was added isopropyl magnesium bromide (0.1 g, 0.704 mmol) at 0° C. The reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was quenched with ammonium chloride (5 mL) at 0° C., extracted with ethyl acetate (2×20 mL), washed with water followed by brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude was purifying by the preparative TLC (Mobile phase: 10% MeOH in DCM) to obtain pure 1-(2-(4-fluorophenyl)thiazol-5-yl)-2-methyl-1-(pyridin-4-yl)propan-1-ol (0.023 g, 20% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, 2H), 7.92 (t, 3H), 7.56 (d, 2H), 7.27 (t, 2H), 6.22 (s, 1H), 2.79 (t, 1H), 0.98 (d, 3H), 0.71 (d, 3H); LC-MS m/z calculated for [M+H]+ 329.10. found 329.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:12]1(NN)[CH:17]=CC=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:17]=[CH:12][C:13]([CH3:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccccc1
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3,4-dichlorophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+: calc. 501.055493; found 501.053920.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[N:11]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:7][C:8]1[N:9]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(C2CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1nc(C2CC2)nc(N2CCOCC2)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of 2.61 g (0.03 mole) of morpholine in 20 ml of chloroform is added in the course of 30 minutes to a solution of 5.7 g (0.03 mole) of 2,4-dichloro-6-cyclopropyl-1,3,5-triazine in 50 ml of chloroform, cooled to between 3° and 5° C. The temperature of the mixture is allowed to return to about 10° C., then the mixture is cooled again to 5° C. and a solution of 4.14 g (0.03 mole) of potassium carbonate in 15 ml of water is added dropwise. The mixture is then stirred at room temperature for two hours. 30 ml of water are added and the organic phase is separated off. The solution is washed with water and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent: 96.5:3.5 (v/v) dichloromethane-ethylacetate) and then recrystallized from hexane. 5.5 g of 2-chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine are thus obtained. Yield: 76.2%. M.P.: 99°-100° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CSc1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.6 g, 9.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]yridine, 7a, (2.5 g, 6.0 mmol) and Na2CO3 (1.9 g, 18.0 mmol) were dissolved in DME (37.5 mL) and water (7.5 mL). The mixture was purged with nitrogen for 20 minutes, treated with Pd(PPh3)4, purged with nitrogen for another 20 minutes and heated to reflux overnight. After cooling to room temperature, water (35 mL) was added and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and acetonitrile and dried overnight at 50° C., affording 2.3 g (88.5%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.70-8.57 (m, 2H), 8.55-8.42 (m, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(c3ccc([N+](=O)[O-])cc3)CCC2c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Temperature: 145 °C
Reaction time: 1.5 h
Yield: 31.3 %

Procedure:
The product from Example 179C (13.2 g, 27.5 mmol) and 4-methoxybenzylamine (18 mL, 139 mmol) were combined and stirred at 145° C. for 1.5 h. The mixture was cooled to rt, and CH2Cl2 was added. The resulting precipitate was filtered off, and the filtrate was washed successively with 1N aq. HCl and saturated aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (5.0 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.Cl[CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Na]>C(O)C.C(OCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CCOC(=O)C(F)Cl
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(F)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Yield: 35.3 %

Procedure:
To a stirred mixture of 2.0 g (0.0065 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.91 g (0.0065 mole) of ethyl chlorofluoroacetate in 50 mL of ethanol was added a solution of 0.15 g (0.0065 mole) of sodium in 5 mL of ethanol. The reaction mixture was heated at reflux for 34 hours. The mixture was cooled, and the solvent was removed by evaporation under reduced pressure, leaving a residue. This residue was dissolved in diethyl ether, and the solution was washed first with water, followed by an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate, then filtered. The filtrate was evaporated under reduced pressure to yield 0.95 g of ethyl [2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]fluroacetate as an oil, Compound 51.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:16])[CH2:4][CH:5]2[CH2:11][CH2:10][S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12.BrBr.O>C(O)(=O)C>[N:1]1[NH:2][C:3](=[O:16])[CH:4]=[C:5]2[CH2:11][CH2:10][S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12
Reactant: O=C1CC2CCSc3ccccc3C2=NN1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc2c(n[nH]1)-c1ccccc1SCC2
Yield: 93.2 %

Procedure:
To a mixture of 92 g of 4,4a,5,6-tetrahydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one in 920 ml of acetic acid is added 64 g of bromine dropwise at 50°-60° C., and the mixture is kept at the same temperature for an hour and poured into a large quantity of water. The precipitated crystals are collected by filtration, and washed with warm water and then with ethanol. The crystals are dried to give 85 g of 5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 311°-313° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:30])[NH:4][CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C.O>[CH3:34][N:4]1[CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([CH3:1])[C:3]1=[O:30]
Reactant: CI
Reactant: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn(C)c1=O
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 3-methyl-5-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyridin-2-one (0.184 mmol) in 1 mL DMF was added NaH (0.221 mmol; 60% suspension in oil) in several portions. After 1 hour, iodomethane (0.20 mmol) was added. After 1 hour, the mixture was diluted with water and the solid was collected by filtration, washed with water and dried. The residue was purified with flash silica gel chromatography using 25% hexanes in ethyl acetate. The product-rich fractions were concentrated in vacuo to provide the title compound (0.051 mmol), m.p.>200° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:35])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH2:12][NH:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[O:35])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CSC(CN[C@@H](C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.45 g., 1.07 mmole), L-alanyl-L-proline, 1,1-dimethylethyl ester (0.78 g., 3.21 mmole), and crushed 3A° molecular sieves (2 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After 2.5 hours, sodium cyanoborohydride (0.20 g., 3 eq.) is added and stirring continued for 15 hours. The reaction mixture is filtered to remove the sieves and the filtrate is diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed to give the desired product, as a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone, 4:1) isomer A at Rf =0.30 and isomer B at Rf =0.13. Flash chromatography (silica gel LPS-1; benzene:acetone, 7:3) affords impure product (isomer A). Repeated flash chromatography (silica gel LPS-1; ethyl acetate:benzene, 6:4) gives 0.20 g. of 1-[N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-L-alanyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a nearly colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:12]([O-])([OH:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Fc1ccc2ncccc2c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(F)cc2cccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-fluoroquinoline (2 g, 13.6 mmol) and fuming HNO3 (15 mL) in a round bottom flask equipped with a cooling condenser was refluxed for 100 hours, the resulting mixture was cooled to r.t., poured slowly into crushed ice/H2O, and then the mixture was extracted with DCM (200 mL×3). The combined organic layers were dried over Na2SO4, and concentrated. The residue was passed through a short pad of silica gel to give 1.6 g of title compound. 1H NMR (CHLOROFORM-d) δ: 9.08 (dd, J=4.1, 1.5 Hz, 1H), 8.25 (dd, J=8.5, 1.5 Hz, 1H), 7.89 (dd, J=7.5, 2.8 Hz, 1H), 7.72 (dd, J=8.1, 2.8 Hz, 1H), 7.62 (dd, J=8.4, 4.3 Hz, 1H). LC-MS: m/z 466.6 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>>[B:14]([OH:19])([OH:15])[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccc(Cl)nc1
Yield: 60 %

Procedure:
5-Bromo-2-chloropyridine was treated with n-BuLi (1.6 M in hexanes, 12.0 mL, 19.1 mmol), triisopropyl borate (4.8 mL, 20.9 mmol) and HCl(aq) (2.7 N, 16.8 mL) as for 1 to give the title compound 4 (1.7 g, 60% yield) as a pink solid: 1H NMR (CD3OD) δ 8.58 (br s, 1H), 7.95 (br d, J=6.7 Hz, 1H), 7.95 (d, J=8 Hz, 1H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.O>CS(C)=O>[O:20]1[CH2:4][CH:19]1[CH:16]1[CH2:17][CH2:18][C:13]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:14][CH2:15]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1COC2(CCC(C3CO3)CC2)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 60% strength dispersion of sodium hydride in mineral oil (1.78 g, 44.59 mmol) was taken up in dimethylsulfoxide (25 ml), and trimethylsulfoxonium iodide (9.80 g, 44.6 mmol) was added. The mixture was stirred at room temperature for 45 min. A solution of 1,4-dioxaspiro[4,5]decane-8-carbaldehyde (7.59 g, 44.6 mmol) in dimethylsulfoxide (20 ml) was then added to the mixture. The reaction mixture was stirred at 60° C. for 18 h. After cooling, the mixture was poured into water (100 ml) and extracted with diethyl ether (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The crude product (4.64 g) was purified by flash chromatography with cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=[C:10](I)[C:3]=12.[Li][C:23](C)(C)[CH3:24].C(I)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=[C:10]([CH2:23][CH3:24])[C:3]=12
Reactant: [Li]C(C)(C)C
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(Cl)ccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cn([Si](C(C)C)(C(C)C)C(C)C)c2nccc(Cl)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
The 4-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (27.0 g, 62.1 mmol) in THF (300 mL) was cooled to about −75° C. then t-BuLi (1.7 M in pentane, 73.1 mL, 124 mmol) was added over about 30 min keeping the internal temperature below about −70° C. After complete addition, EtI (15.0 mL, 186 mmol) was added. The mixture was warmed slowly to about −40° C. then the mixture was allowed to warm to rt. Saturated aqueous NaHCO3 (50 mL) was added and the mixture was stirred for about 30 min. The mixture was filtered and the solids washed with EtOAc (3×50 mL). The solvents were removed under reduced pressure then the material was partitioned between EtOAc (200 mL) and water (50 mL). The layers were separated then the organic layer was washed with saturated aqueous NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting material was treated with MeOH (80 mL) then warmed to about 60° C. The mixture was cooled to rt and the resulting slurry stirred overnight at rt. The solids were collected by filtration then washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure then purified by silica gel chromatography using a 120 g silica gel column and eluting with heptane. The material was stirred with MeOH (15 mL) overnight then the solid was collected by filtration and washed with MeOH (2 mL). The solid material was combined with the first crop of solids and dried under reduced pressure to give 4-chloro-3-ethyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (17.4 g, 83%): LC/MS (Table 2, Method g) Rt=3.21 min; MS m/z 337 (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[CH:12][CH:11]=1.CC(N=NC(C#N)(C)C)(C#N)C.CCCCCC>CCOC(C)=O>[Br:8][CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[N:15]=1
Reactant: Cc1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1cccc(CBr)n1
Temperature: 65 °C

Procedure:
Add NBS (35.6 g, 0.20 mole) to a solution of 6-fluoro-2-methylpyridine (20 mL, 0.19 mole) in EtOAc (400 mL) at room temperature. When the temperature reaches 45° C., add AIBN (400 mg, 2.4 mmol). Heat the mixture at 65° C. for 6 h, then cool to room temperature and add hexane (1 L). Remove the white precipitate by filtration and wash the solid with hexane/EtOAc (1:1). Wash the filtrate with small amounts of aqueous Na2S2O3, NaHCO3, and brine. Dry the organics (Na2SO4), filter, then remove most of the solvent under vacuum at room temperature. Transfer the remaining solution to a distillation set-up. Remove the remaining solvent by distilling at atmospheric pressure, followed by the unreacted starting material at 80 mm (bp ca 70° C.; 11.2 g) and then the title product at 1 mm (bp ca 75° C.; 12.1 g, 32%). NMR (300 MHz; CDCl3): 7.82 (1H; dd); 7.35 (1H; dd); 6.90 (1H; dd); 4.50 (2H; s).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:10]=[CH:9]2)([CH3:5])[CH2:3][OH:4].C(=O)=O>CO>[NH2:1][C@@:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([O:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][CH2:22]1)[CH:10]=[CH:9]2)([CH3:5])[CH2:3][OH:4]
Reactant: CC(N)(CO)c1ccc2nc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3n2)CC1

Procedure:
SFC separation of the above 2-amino-2-[2-(4-trans-tert-butyl-cyclohexyloxy)-quinolin-6-yl]-propan-1-ol (Example 78) (100 mg, 0.3 mmol) with Whelk-01 (R,R) (3×15 cm) 08-10149 in 15% MeOH(0.1% DEA)/CO2, 100 bar, 85 mL/min, 220 nm gave 62 mg of peak 1 (>99% ee) and 12 mg of peak 2 (>99% ee). Peak 1 was subjected to chromatography purification with CH2Cl2/MeOH(20-50%) give (R)-2-amino-2-(2-(trans-4-tert-butylcyclohexyloxy)quinolin-6-yl)propan-1-ol as a foamy solid (39.4 mg). LCMS 1.42 min 357.30 ([M+1], 100%). 1H NMR (400 MHz, MeOD) δ=8.10 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 2H), 6.87 (d, J=8.8 Hz, 1H), 5.20-5.09 (m, 1H), 3.75 (d, J=11.0 Hz, 1H), 3.70 (d, J=11.0 Hz, 1H), 2.29 (d, J=8.0 Hz, 2H), 1.93 (d, J=14.5 Hz, 2H), 1.55 (s, 3H), 1.52-1.38 (m, 2H), 1.38-1.23 (m, 2H), 1.20-1.07 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:9]([F:22])[CH:8]=1.[C:23](=[O:25])=[O:24].Cl>C1COCC1>[F:22][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:13][C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: CCCCCC[C@@H](C)Oc1ccc(Br)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)Oc1ccc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium (2.5 M, 17.2 ml, 0.043 mol) in hexanes was added, dropwise, to a cooled (−78° C.), stirred solution of compound 35 (10.00 g, 0.033 mol) in dry THF (100 ml) under a dry nitrogen atmosphere and left to stir for 20 min. The resultant solution was poured into a slush of solid carbon dioxide and dry THF. This was left overnight at room temperature and then acidified with dilute hydrochloric acid. The THF/water azetrope was evaporated off in vacuo and the residue was dissolved in diethyl ether, washed with water and then extracted with 5% sodium hydroxide solution which was acidified with dilute hydrochloric acid. The product was extracted with diethyl ether and the ethereal solution was washed with water until acid-free, dried (MgSO4) and evaporated in vacuo to leave an off-white, semi-solid.