Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1>C(O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:20]1[CH:19]=[C:18]([Cl:23])[N:17]=[C:16]([Cl:15])[N:21]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 27.8 g. (0.2 mole) of glycine ethyl ester hydrochloride and 42.4 g. (0.4 mole) of sodium carbonate in 300 ml. of ethanol was added 36.6 g. (0.2 mole) of 2,4,6-trichloropyrimidine. After stirring at room temperature for 2 hours the mixture was filtered. The filtrate was diluted with 300 ml. of water and the precipitate thus formed was collected, dried, and triturated with 600 ml. of boiling petroleum ether. The insoluble material was filtered off and recrystallized from ethanol-petroleum ether to afford 4.7 g. of product, m.p. 89°-91°C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:23]1>COCCO.C(N(CC)CC)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1[N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:31])=[O:32])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCNC2)cc1
Solvent: CCN(CC)CC
Solvent: COCCO
Product: Cc1ccc(S(=O)(=O)NC2CCCCN(c3nc4c(c(=O)n(C)c(=O)n4C)n3Cc3ccccc3)C2)cc1

Procedure:
7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (1.03 g, 3.40 mmol) and N-(azepan-3-yl)-4-methylbenzenesulfonamide (6B) (1.00 g, 3.73 mmol) were dissolved in 2-methoxyethanol (30 ml) and triethylamine (2.4 ml), and the mixture was heated to 120° C. for 2 days. The solvents were evaporated and the crude product was dissolved in 100 ml of EtOAc and 100 ml of water. The aqueous phase was acidified with 1M potassium hydrogen sulphate until pH=2. The organic layer was separated and extracted with 50 ml of 1M aqueous potassium hydrogen sulphate, and 50 ml of brine, and dried over sodium sulphate. The solvent was evaporated and the crude product was purified by column chromatography on silica gel using EtOAc:heptane (1:1) as the eluent. Evaporation of the solvent gave compound (6C) as a white foam.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:28][C@H:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[C:12]([CH:27]=1)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:14])#[N:7].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN1CCN(C)C1=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:28][C@H:29]2[CH2:33][CH2:32][N:31]([C:2]([O:4][CH3:5])=[O:3])[CH2:30]2)=[C:12]([CH:27]=1)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:14])#[N:7]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@H]2CCNC2)cc1OC
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: COC(=O)N1CC[C@H](Nc2ccc(C#N)cc2C(=O)NCc2ccc(OC)c(OC)c2)C1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of methyl chloroformate (26 mg) in chloroform (2 mL) was added dropwise to a mixture of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (80 mg) and triethylamine (43 mg) in a mixture of chloroform (2 mL) and 1,3-dimethyl-2-imidazolidinone (1 mL) under cooling on an ice bath. The reaction mixture was stirred for 2 hours at same temperature and the reaction was quenched by addition of 3-(N,N-dimethylamino)propylamine (0.1 mL). The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with 70% ethyl acetate in hexane. The obtained crystals were recrystallized from a mixture of 2-propanol and diisopropyl ether to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidin-3-ylamino]benzamide (55 mg) as white crystals.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH3:18]N(C)C=O.CI>O>[CH3:18][N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11]
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)c2cscc2Nc2ccccc21
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 0.84 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 0.18 g. of 55% sodium hydride-mineral oil dispersion in 25 ml. of dimethylformamide is added 0.3 ml. of methyl iodide. The reaction mixture is stirred for 2.5 hours, cooled, diluted with water and filtered. The solid product is recrystallized from methanol-water to give pale yellow crystals, m.p. 195°-198° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:5][C:4]([C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:2]=1[CH3:1])=[O:7])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: Cc1ccc(C(=O)CCl)c(C)c1
Product: CC(=O)OCC(=O)c1ccc(C)cc1C

Procedure:
Following the procedure of Example 1,5 grams of 2,4-dimethylphenacyl chloride are reacted with 5 grams of acetic acid to obtain 2,4-dimethylphenacyl acetate, m.p. 43°-45° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:16][N:15]=[CH:14]2.CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>CN(C)C=O>[CH:40]1([NH:41][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([CH:21]([CH3:26])[C:22]([F:23])([F:24])[F:25])=[N:16][N:15]=[CH:14]4)[CH:4]=2)[CH2:38][CH2:39]1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C(F)(F)F)nncc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C(C)C(F)(F)F)nncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoic acid (86 mg, 239 μmol) in N,N-dimethylformamide (1000 μl) were added HATU (136 mg, 358 μmol) and cyclopropylamine (8 μl, 2387 μmol). The resulting mixture was stirred at RT for 20 h, during which LC-MS indicated conversion to the desired product. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Preparative HPLC purification (Shimadzu) afforded the title compound as a white amorphous solid. MS (ES+): 400.4 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[NH:7][C:8](=[O:12])[N:9]([CH3:11])[CH:10]=1)=[O:4].[H-].[Na+].[CH3:23]I.[OH-].[Na+]>CN(C=O)C.CO.CCCCCC.CCOC(C)=O.C1COCC1>[F:20][C:15]1[CH:14]=[C:13]([CH:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]([CH3:11])[C:8](=[O:12])[N:7]2[CH3:23])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: COC(=O)C1=CN(C)C(=O)NC1c1ccc(F)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1C=C(C(=O)O)C(c2ccc(F)c(F)c2)N(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.36 g (1.3 mmol) (−)-4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (the product of Example 10, Step C) in 3 ml DMF was added 0.068 g (2.8 mmol) sodium hydride. After the gas evolution had ceased (5 min), 0.10 ml (1.6 mmol) methyl iodide was added and the reaction mixture was stirred 2 hours at room temperature then poured into 100 ml EtOAc and washed 100 ml 5% aqueous KHSO4 solution, 100 ml water, and 100 ml brine; then dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 5 ml MeOH and to this was added 0.2 ml (0.5 mmol, 2.5M solution in water) NaOH, 2 ml THF, and 0.8 ml (2 mmol, 2.5M solution in water) NaOH. The initially heterogeneous reaction mixture slowly became homogeneous, and after 6 hours, the reaction was poured into 75 ml EtOAc and extracted 2×75 ml H2O. The aqueous layer was acidified to pH=1 with concentrated HCl solution, solid NaCl was added and the mixture extracted 3×50 ml ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered and concentrated in vacuo. Toluene (50 ml) was added and removed in vacuo two times, and the residue was dissolved in 1 ml CH2Cl2 and 0.33 g of essentially pure solid was obtained by adding hexane. α25=−150° C.=0.37 MeOH. 1H NMR (300 MHz, CD3OD) d 7.45 (s, 1H); 7.28-7.12 (m, 3H); 5.25 (s, 1H); 3.21 (s, 3H); 2.82 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:17]3[C:18](N)=[N:19][O:20][N:21]=3)[CH3:16])=[CH:11][CH:10]=2)[S:6][CH:7]=1.N([O-])=[O:26].[Na+].OS(O)(=O)=O>CC(O)=O.Cl.O>[F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:17]3[C:18]([OH:26])=[N:19][O:20][N:21]=3)[CH3:16])=[CH:11][CH:10]=2)[S:6][CH:7]=1
Reactant: O=N[O-]
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nonc1N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nonc1O
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a cooled solution of 4-[(1R)-1-{4-[(4-(trifluoromethyl)-1,3-thiazol-2-yl)amino]phenyl}ethyl]-1,2,5-oxadiazol-3-amine (0.2 g, 0.56 mmol) in AcOH (5 ml) and 37% HCl (3 ml), a solution of sodium nitrite (44 mg, 0.845 mmol) in water (3 ml) was added dropwise. The resulting reaction mixture was stirred for 30 min, then conc. H2SO4 (0.5 ml) was added and the reaction quenched with a saturated solution of NH4Cl (10 ml); the resulting mixture was extracted with Et2O (3×10 ml) and the collected organic extracts were evaporated under vacuum; the crude was purified by flash chromatography to afford pure 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1,2,5-oxadiazol-3-ol (13) (0.17 g, 0.48 mmol) as a white solid (85%). [α]D=−51 (c=1; CH3OH); 1H-NMR (DMSO-d6): δ 8.25 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.05 (s, 1H), 3.90 (q, 1H, J=7 Hz), 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: [N:1]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][CH2:39][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([O:30]C(C1C=CC=CC=1)=O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]>[Pd].C(O)C.CO>[N:1]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][CH2:39][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 95 %

Procedure:
A mixture of palladium on carbon (10%, 4.0 g.) in ethanol (20 ml.) was added to a solution of BocPro-DTrp-PheOBz (70.44 mmole.) in methanol (100 ml.). The mixture was diluted to 200 ml. with methanol, hydrogenated under pressure for three hours and filtered. The filtrate was stripped of volatiles. After unsuccessful attempts to crystallize the residue from ether-hexane and methanol-water it was twice dissolved in, and stripped of, chloroform and dried under high vacuum, affording BocPro-DTrp-PheOH in 95% yield as a foam (36.6 g.).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11]CC)=O)[CH:4]=1)[CH3:2].[OH-].[NH4+:15]>>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([NH2:15])=[O:11])[CH:4]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(CC)n(C)n1
Agent: [OH-]
Product: CCc1cc(C(N)=O)nn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (5.03 g, 27.6 mmol) and ammonium hydroxide (28 mL of 30%) was stirred for 18 hours at ambient temperature. A precipitate formed, was isolated by filtration, and washed with cold hexanes to provide 2.60 g of 5-ethyl-1-methyl-1H-pyrazole-3-carboxamide as a white solid, mp 170-172° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:17][N:16]([C:18](=[O:39])[C@H:19]([NH:29][C:30](=[O:38])[CH2:31][CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:15]1)C1C=CC=CC=1.C>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:15][N:16]([C:18](=[O:39])[C@H:19]([NH:29][C:30](=[O:38])[CH2:31][CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:17]1
Reactant: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)N2CC(OCCCCOCc3ccccc3)(c3ccccc3C)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)N2CC(OCCCCO)(c3ccccc3C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
900 mg (1.44 mmol) of N-[(R)-2-[3-(4-benzyloxybutoxy)-3-o-tolylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are dissolved in 100 ml of acetic acid. 90 mg of 20% palladium hydroxide dispersed on active charcoal are added and the mixture is placed under a dihydrogen atmosphere and stirred for 1 hour at room temperature. The reaction medium is filtered through a layer of Celite and then concentrated to dryness. The crude residue obtained is purified by chromatography on silica gel eluted with an 85/15 dichloromethane/methanol mixture. 440 mg of N-[(R)-2-[3-(4-hydroxybutoxy)-3-o-tolylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white solid, in a yield of 67%.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:16]([O:18]CC)=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[OH-].[Na+].CCO.O>>[C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:16]([OH:18])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1c(N2CCOC(CF)C2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Yield: 100.3 %

Procedure:
A mixture of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylate (300 mg, 0.00054 mol), Sodium hydroxide (0.12 g, 0.0030 mol) in EtOH (10.0 mL, 0.171 mol) and water (3.0 mL, 0.17 mol) was stirred at it until completion by LCMS. The mixture was concentrated and the residue was acidified by 1NHCl. The precipitate was collected and dried in air and vacuum to afford 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylic acid (225 mg, 99%). LCMS: (FA) ES+ 415, ES− 413.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([CH:19]=O)[CH2:18][CH2:17]1.C([BH3-])#N.[Na+].Cl>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][CH:16]2[CH2:18][CH2:17]2)[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=CC1CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(CC1CC1)C1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
18.9 g of 1-benzyl-4-methylaminopiperidine as the oil prepared according to a) are taken up in 250 ml of methanol and combined with 8.3 g of cyclopropanecarboxaldehyde and 11.3 g of sodium cyanoborohydride. The mixture is stirred for 5 hours at 40-50° C., then for about another 16 hours at ambient temperature. It is then acidified with 2 N hydrochloric acid, evaporated to dryness in vacuo and the residue is taken up in water. It is washed with ether, made alkaline with concentrated sodium hydroxide solution and extracted with ether/ethyl acetate. The organic extract is dried over sodium sulphate and freed from the solvents in vacuo. 22.7 g 1-benzyl-4-(cyclopropylmethyl-methyl-amino)-piperidine are obtained as a yellowish oil.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].N1CCCCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Temperature: 35 °C
Yield: 88.4 %

Procedure:
To a toluene (40 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidine-3-carboxylate (2.0 g, 4.6 mmols) is added ethynyltrimethylsilane (451 mg, 4.6 mmols), copper (I)iodide (88 mg, 0.46 mmols, 0.1 equivs), Bis(triphenylphosphine)palladium(II)dichloride (165 mg, 0.23 mmols, 0.05 equivs) and piperidine (782 mg, 9.2 mmols, 2 equivs). The mixture is heated in an atmosphere of nitrogen at 35° C. for six hours. The mixture is filtered through a pad of Celite. The pad of Celite is washed with ethylacetate (2×15 ml). The combined organic filtrates were concentrated using rotary evaporation at reduced pressure to give a crude viscous oil. The oil is purified by flash column chromatography (grading from 100% hexanes to 15% EtOAc) to give the title compound (1.65 g): m/z (Cl) 306 ([M+H]+-Boc).
Reaction SMILES: C([C:3](CC)([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17](=[O:33])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:10][C:9]=1[O:34][CH2:35][C:36]([O-:38])=[O:37])[C:4]([O-:6])=[O:5])C.[OH-].[Na+]>>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][C:17]([NH:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])=[C:9]([O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:10]=2)=[O:33])[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCC(CC)(Oc1ccc(CCNC(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)NCCc2ccc(OCC(=O)O)c(OCC(=O)O)c2)CC1
Yield: 89.2 %

Procedure:
The compound obtained in the above process (a) (150 mg) was hydrolyzed with 1.3 ml of 1N sodium hydroxide to give 121 mg of the title compound.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 50 °C
Yield: 84.1 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) and lithium tert-butoxide (0.10 g, 1.3 mmol) were added under nitrogen atmosphere to 10 mL of tetrahydrofuran and the mixture was stirred at room temperature for 2 hours (Solution 1). (S)-1-chloro-3-(dibenzylamino)propan-2-ol (0.32 g, 1.1 mmol) and lithium tert-butoxide were added to 10 mL tetrahydrofuran and stirred at room temperature for 2 hours (Solution 2). Solution 2 was added to Solution 1 and the material liquid was heated to 50° C. and reacted for 5 hours. Saturated ammonium chloride solution, and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 0.40 g of off-white solid in 84% yield.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:17]([CH:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[OH:20])=[CH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:19](=[O:20])[C:17]([C:11]1[CH:12]=[CH:13][C:14]([CH3:1])=[CH:15][CH:16]=1)=[CH2:18]
Reactant: C=C(c1ccccc1)C(O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To oxalyl chloride (1.01 g) in dichloromethane (10 ml) at -70° C. was added dimethylsulphoxide (1.23 g) in dichloromethane (6 ml). To the resulting mixture was dropwise added a solution of α-(1-phenylethenyl)-2,4-dichlorobenzenemethanol (2.07 g) in dichloromethane (6 ml). Triethylamine (2.17 g) was added to the reaction mixture and the resulting mixture was stirred for an additional 20 minutes and then allowed to warm to room temperature. The reaction mixture was washed with water and the organic phase separated and concentrated under reduced pressure. The resulting residue was redissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulphate. The solvent removed under reduced pressure to yield 1-(2,4-dichlorophenyl)-2-(4-methylphenyl)propen-1-one (δ (CDCl3), 5.92 (1H,s) 6.16 (1H,s) and 7.1-7.3 (10H,m) p.p.m.) as an oil having the formula: ##STR19##
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:14]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([NH:27][C@H:11]([CH2:10][CH2:9][OH:8])[CH2:12][N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:14]2)(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)Cc1cn(C[C@@H](CCO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc(F)cc2)c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: COC(=O)Cc1cn(C[C@@H](CCO)NS(=O)(=O)c2ccc(F)cc2)c2ncccc12
Yield: 88.6 %

Procedure:
To a solution of methyl [1-((2R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[(4-fluorophenyl)sulfonyl]amino}butyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]acetate (1.2 g, 2.2 mmol) in dichloromethane (40 mL) was added 1 M TBAF (4.8 mL, 2.2 equiv.). After a period of 0.5 h the reaction mixture was quenched with 25% aqueous ammonium acetate, the organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on combiflash (20% ethyl acetate in hexane to 100% ethyl acetate) to provide 849 mg of the title compound.