Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH:22]=O)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNCc1ccccc1
Reaction time: 0.33 h

Procedure:
Benzylamine (49.7 mmol) is added to a solution of (1R,35,45)-3-formyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (49.7 mmol) in DCM (200 mL). The mixture is treated with sodium triacetoxyborohydride (69.6 mmol), stirred for additional 20 min, poured into water (200 mL) and stirred vigorously for 10 min. The layers are separated and the aq. layer is extracted twice with DCM (2×100 mL). The combined organic layers are washed with sat. NaHCO3 solution (100 mL), water (100 mL) and brine (150 mL), dried over MgSO4 and treated with activated charcoal (5 g). The mixture is filtered through celite and the filtrate is concentrated in vacuo to give the desired benzylamine which is used without further purification. LC-MS (basic): tR=1.00 min; [M+H]+=317.3.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:16](=[O:25])[O:15][C:14]([CH3:27])([CH3:26])[C:13]=3[CH:28]=2)=[CH:5][CH:4]=1)#[N:2].[Br:29]N1C(=O)CCC1=O.N1C=CC=CC=1.O>C1COCC1>[Br:29][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[N:7]([CH3:8])[C:6]=1[C:9]1[CH:10]=[CH:11][C:12]2[N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:16](=[O:25])[O:15][C:14]([CH3:27])([CH3:26])[C:13]=2[CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C

Procedure:
To a solution of tert-butyl 6-(5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate (1 eq, 1.94 g, 5.10 mmol) in THF (150 mL) at −78° C. was added N-bromosuccinimide (1.1 eq, 1.0 g, 5.61 mmol). The solution was allowed to warm and stir for 16 hours Pyridine (1 mL) was added and the mixture was poured into water (150 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, tert-butyl 6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate was obtained by crystallization from 20% ethyl acetate/hexane as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) δ 1.56 (s, 9H), 1.71 (s, 6H), 3.65 (s, 3H), 7.30 (s, 1H), 7.44 (d, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.55 (s, 1H). M/z (ESI (+)) 461 (M+H)+. Anal. calcd for C21H22N3O4, C, 54.8,H, 4.82, N, 9.13. Found, C, 54.9, H, 4.86, N, 9.1.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1.[CH3:33][C:34]([CH3:36])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:34]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1)([CH3:36])[CH3:33]
Reactant: CC(C)=O
Reactant: CC(Nc1cc(-c2cc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1cc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 60 mg (0.14 mmol) {4-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.15 mL (2mmol) acetone, 120 mg (2 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as a yellow solid. MS (ES+): 464 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[C:4]([I:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:25][C:26]([Cl:30])=[CH:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=2)=[C:4]([I:9])[CH:5]=[C:6]([O:8][CH2:28][CH:27]=[C:26]([Cl:30])[Cl:25])[CH:7]=1
Reactant: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(I)c1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2I)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.23 g of 3-chloro-5-hydroxy-1-iodo-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]-benzene were dissolved in 22 ml of acetone, and 0.79 g of 1,1,3-trichloropropene, 1.3 g of potassium carbonate and 0.27 g of sodium iodide were added. The mixture was stirred at room temperature for 20 hours (monitored by TLC). The reaction mixture was then concentrated using a rotary evaporator, and the resulting crude product was subjected to chromatographic purification. Yield: 2.62 g (95%)
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].CN(CCN(C)C)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>CO.CN(C)C=O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[C:23]([N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 4.8 %

Procedure:
To a solution of uracil (8.9 g), copper(II) acetate (9.6 g), N,N,N,N-tetramethylethylenediamine (10.2 ml) in methanol/dimethy formamide/water (500/100/100 ml) was added 3-trifluoromethylphenyl boronic acid (10.0 g) and the resulting mixture was stirred at room temperature for twelve hours. The reaction mixture was concentrated under reduced pressure so as to remove methanol and thereto was added water (100 ml). The resulting mixture was extracted with ethyl acetate (100 ml×3) and the organic layer was washed with water (100 ml×2) and saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (650.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].ClC(OCC(C)C)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37]>C1COCC1.CN1CCOCC1.CN(C=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12](=[O:14])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37])=[O:5])[CH3:2]
Reactant: C=C1C[C@H](C(=O)O)[C@@H](C(=O)OCC)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=C1C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)[C@@H](C(=O)OCC)C1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1.0 g of 41b in 10 ml of THF and 0.61 ml of N-methylmorpholine was added at −12° C. 0.72 ml of isobutyl chloroformate and stirring was continued at −15° C. for 30 min and at 20° C. for 1 h. The suspension obtained was added to a hot (60° C.) solution of 1.13 g of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 8 ml of DMF and stirring was continued at 60° C. for 1 h. The reaction mixture was evaporated and the residue partitioned between 1 N HCl and AcOEt, the organic layer was washed with HCl and brine, dried and evaporated. The residue was chromatographed on silica using heptane/AcOEt (1:2) to give 1.28 g of the title compound 54a. MS: 385.0 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]#[N:4].[C:5]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:8])([CH3:7])[CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>O.C(O)C>[C:5]([N:9]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:2][CH2:3][NH2:4])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)NC1CCCCC1
Reactant: N#CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)N(CCN)C1CCCCC1
Temperature: 25 °C

Procedure:
Hydroxyacetonitrile (5.3 ml of of a 70% w/w solution in water, 32 mmol) was added to a stirred solution of N-(tert-butyl)cyclohexanamine (5.3 ml, 32 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was heated under reflux for 16 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The crude residue was dissolved in tetrahydrofuran (30 ml) and a solution of lithium aluminium hydride in tetrahydrofuran (1M, 55 ml, 55 mmol) was slowly added. The reaction mixture was heated under reflux for 2 hours. An aqueous solution of sodium hydroxide (2M, 6 ml) was then carefully added. The suspension was filtered and the liquid was concentrated under reduced pressure to give the title compound (3 g) as an oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:22])[C:12]([CH3:21])([S:14][CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:22])[C:12]([SH:14]([CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[S:33]([CH3:32])(=[O:35])=[O:34])([CH3:13])[CH3:21])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(SCC1CCNC1)C(=O)Nc1cc(C(C)(C)C)on1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)[SH](CC2CCNC2)S(C)(=O)=O)no1
Temperature: 90 °C
Yield: 79.7 %

Procedure:
To a solution of 172 mg (0.52 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(pyrrolidin-3-ylmethylsulfanyl)-propionamide (prepared according to Method I, step 1) and 0.18 mL (1.04 mmol) of N,N-diisopropylethylamine in THF were added 0.16 mL (2.11 mmol) of methanesulfonyl chloride. The reaction was heated within a microwave to 90° C. for 0.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford 168 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(1-methanesulfonyl-pyrrolidin-3-ylmethylsulfanyl)-2-methyl-propionamide, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13](=[O:24])[N:14]2C(OC(C)(C)C)=O)=[CH:9][CH:8]=1.Cl.O1CCOCC1.CC(O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13](=[O:24])[NH:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2N(C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Temperature: 25 °C

Procedure:
To crude tert-butyl 7-((3-chlorobenzyl)oxy)-3-(2-ethoxy-2-oxoethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (115.7 g, 244.1 mmol) was added a 4.0 M 1,4-dioxane hydrochloride solution (200 mL, 0.8 mol) in an ice bath. After addition, the ice bath was removed and the reaction was warmed to ambient temperature. The reaction was concentrated to a yellow oil and azeotroped with toluene (2×250 mL) to furnish a brown oil. The oil was diluted in toluene (400 mL) followed by 2-propanol (400 mL). The resulting white ppt that was formed was filtered and washed with 2-propanol to furnish the desired product as a white solid. The mother liquor was concentrated to a brown solid that was triturated with 2-propanol (400 mL), filtered and washed with 2-propanol to furnish a second crop of product (38.3 g). The two crops were combined to give (50.3 g, 55%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.43 (s, 1H), 7.35-7.29 (m, 3H), 7.06 (d, J=8.3 Hz, 1H), 6.59 (dd, J=8.3, 2.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 5.02 (s, 2H), 4.23-4.15 (m, 2H), 3.12-2.92 (m, 3H), 2.92-2.77 (m, 1H), 2.48 (dd, J=16.2, 7.5 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H). [M+H]=374.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:43]1([NH:50][C:51]2[O:52][CH2:53][C:54]3[CH:60]=[C:59]([NH2:61])[CH:58]=[CH:57][C:55]=3[N:56]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>ClCCl.CN(C)C=O.O>[CH:43]1([NH:50][C:51]2[O:52][CH2:53][C:54]3[CH:60]=[C:59]([NH:61][C:9](=[O:11])[CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:58]=[CH:57][C:55]=3[N:56]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2CCCCCC2)=N3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
(4-Methyl-piperazin-1-yl)-acetic acid (167 mg, 1.1 mmol), N,N-diisopropyl ethyl amine (398 mg, 3.1 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (452 mg, 1.4 mmol) were dissolved in dichloromethane 25 mL) and dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. N2-Cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (228 mg, 0.88 mmol) was added and stirring was continued overnight. The reaction mixture was diluted with water and thrice extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol/ammonia 100:0:0−>110:10:1). The title compound (144 mg, 41%) was obtained as an off-white foam; MS: m/e=400.5 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.C([O-])([O-])=[O:27].[Na+].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:27])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: O=C([O-])[O-]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2 g of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 4.1 g of Na2CO3 in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.74 g H2O2 (50% aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes-while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Pantoprazole with a yield of about 85% (LC purity>95%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][O:8][CH:9]=1)=O.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[C:39]([F:41])[C:38]([Cl:42])=[CH:37][C:36]=2[C:43]([NH:45][NH2:46])=O)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(NC(C)C)(C)C>O1CCOCC1.CC#N>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[C:39]([F:41])[C:38]([Cl:42])=[CH:37][C:36]=2[C:43]2[N:2]([CH3:1])[C:3]([C:5]3[N:6]=[CH:7][O:8][CH:9]=3)=[N:46][N:45]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CNC(=O)c1cocn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)NN)cc1
Solvent: c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: Cn1c(-c2cocn2)nnc1-c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A 25 mL scintillation vial was charged with oxazole-4-carboxylic acid methylamide (132 mg, 1.0 mmol), POCl3 (0.27 mL, 3 mmol), pyridine (0.48 mL, 6 mmol) and CH3CN (10 mL). The vial was sealed, heated to 40° C., and stirred for four hours. The volatiles were then evacuated in vacuo and to the residue was added 4-tert-butyl-N-(4-chloro-5-fluoro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (400 mg, 1.0 mmol), diisopropylamine (2.0 mL), and dioxane (2.0 mL). The vial was sealed, heated to 130° C., and stirred for two hours. The volatiles were then removed in vacuo, and the residue was purified via automated silica gel chromatography and then HPLC to afford 4-tert-butyl-N-[4-chloro-5-fluoro-2-(4-methyl-5-oxazol-4-yl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide as a white powder: 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.48 (d, 1H), 8.04 (d, 1H), 7.67 (d, 1H), 7.50 (d, 2H), 7.33 (d, 1H), 7.3 (d, 2H), 3.59 (s, 3H), 1.23 (s, 9H), MS (ES) M+H expected 490.1, found 490.0.
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+].Cl.[H][H]>O>[SH:4][CH:5]([CH2:1][CH2:2][SH:3])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCCCC1CCSS1
Reactant: [H][H]
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Product: O=C(O)CCCCC(S)CCS
Reaction time: 0.5 h

Procedure:
α-Lipoic acid (5.15 g, 25.0 mmol) was suspended in water (125 mL), and sodium bicarbonate (2.1 g, 25.0 mmol) was added. The mixture was stirred to produce a clear solution. The resulting pale yellow solution was cooled in an ice bath, and solid sodium borohydride (1.90 g, 50.0 mmol) was added, with stirring, in small portions over 20 min. The solution was stirred in an ice bath for another 30 min and then at room temperature for 30 min. The cloudy solution was cooled in an ice bath, and the pH was adjusted to 1 by slow addition of 2M hydrochloric acid. A vigorous evolution of hydrogen occurred as the excess sodium borohydride decomposed, and an oily liquid was seen to separate. The mixture was extracted with chloroform (3×50 mL). The combined chloroform extracts were dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure at room temperature. The remaining oil was further dried under vacuum to remove traces of solvent. 6,8-Bismercaptooctanoic acid was isolated as a colorless oil: 5.2 g (100%). The product was stored at −20° C. under nitrogen. 1H-NMR (CDCl3): δ 2.89 (m, 1H, S—C—H). 2.67 (m, 2H, S—CH2), 2.34 (t, J=7.1 Hz, 2H, CH2C(O)), 1.4-1.92 (m, 8H, (CH2)2), 1.33 (t, J=8.0 Hz, 1H, S—H), 1.30 (t, J=7.6 Hz, 1H, S—H).
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:10][C:4]=2[O:3]1.C[O-].[Na+].C[O-].[C:21](O)(=[O:23])C>CO>[F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([O:23][CH3:21])=[CH:10][C:4]=2[O:3]1
Reactant: O=[N+]([O-])c1cc2c(cc1F)OC(F)(F)O2
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])OC(F)(F)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2,2,5-Trifluoro-6-nitrobenzo[d][1,3]dioxole (2.5 g, 11 mmol) was dissolved in dry methanol (20 mL), treated with 30% sodium methoxide solution (3.1 g, 17 mmol), and stirred at 20° C. for 1 h. After excess methoxide was neutralized by addition of acetic acid, the volatiles were removed by rotary evaporation. The residue was taken up in ethyl acetate (50 mL), washed with saturated NaHCO3 (10 mL), saturated NaCl (10 mL), dried (Na2SO4) and evaporated. The material was purified by chromatography on silica with a 0-30% ethyl acetate-hexane gradient to give the title compound as a white solid (1.8 g, 70%): mp 84-85° C. 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.90 (s); EIMS m/z 233.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C@:13]1(O)[C:18](=[CH2:19])[CH2:17][C@H:16]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:14]12[CH3:15])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH:26]=[CH:27]1)[CH2:22][CH2:21]3)(=[O:12])[CH3:11].P([O-])([O-])([O-])=O>C(Cl)Cl.C(N(CC)CC)C>[C:1]1([S:7]([CH2:19][C:18]2[CH2:17][C@@H:16]3[C@:14]([CH3:15])([CH2:32][CH:31]=[C:30]4[C@H:20]3[CH2:21][CH2:22][C:23]3[C@:28]4([CH3:29])[CH:27]=[CH:26][C:25](=[O:33])[CH:24]=3)[C:13]=2[C:10](=[O:12])[CH3:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Reactant: O=S(Cl)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C

Procedure:
Phenylsulfinyl chloride in methylene chloride (2.5N, 2.4 ml) was added to a mixture of 17α-acetyl-17β-hydroxy-16-methyleneandrost-1,4,9(11)-trien-3-one (VB, Example 17, 1 g) in methylene chloride (10 ml) and triethylamine (0.82 ml) previously cooled to -30° over a period of 2 hrs. The reaction is plunged into phosphate buffer (pH 7, 10 ml); the phases are separated; the aqueous phase is extracted with methylene chloride; the organic phases are combined and dried over sodium sulfate and concentrated under reduced presure to an isomeric mixture of the title compound. The isomers are separated by chromatography on silica gel (50 g), eluting with acetone/hexane: 5/95 to give the title compound, NMR (CDCl3) 0.89, 1.42, 2.10, 4.03, 5.5, 6.0, 6.27, 7.20 δ.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[OH:21])[C:7]=2[C:6]=1[CH3:23])=[O:4].Br[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:23])=[O:4]
Reactant: BrC1CCCC1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCCC3)c2c1C

Procedure:
Prepared analogously to example 243.2 from 4-(4-fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (67 mg) and bromocyclopentane (60 mg).