Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:15])[N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Cl:16][C:17]([SH:20])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:16][C:17]1[S:20][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[N:15]=1
Reactant: CCOC(=O)C1CCN(C(=N)N)CC1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of ethyl 1-[amino(imino)methyl]piperidine-4-carboxylate hydrochloride (1.50 g, 6.36 mmol) and perchloromethyl mercaptan (1.37 ml, 12.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.04 g, 50.9 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.10 g (62.9%) of the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1>>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[C:15]3[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: COC(=O)c1ccc(Cl)nc1
Product: CCc1cc2c(=O)n3cc(C(=O)OC)ccc3nc2s1

Procedure:
A mixture of 10 g (0.05 mol) of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) and 8.61 g (0.05 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in a wax bath at 178°-188° C. for three hours under nitrogen. The distillate is collected in a Dean-Stark trap attached to the reaction flask. The mixture is cooled, dissolved in hot methanol, cooled and 5.5 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 151°-152° C. after recrystallization from methanol.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[OH:32][CH:30]1[CH2:31][N:28]([C:23]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[O:25])[CH2:29]1
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(O)C1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Dissolve 1-Benzhydryl-azetidin-3-ol (250 mg, 1.04 mmoL) in methanol (3.0 mL) and add to Pd(OH)2 (50 mg) under nitrogen. Degas reaction vessel and purge with 60 psi H2 (g). Repeat degass/H2 purge cycle again. Allow to stir under 60 psi H2 for 15 h. Release reaction and filter through celite with additional methanol. Evaporate methanol to yield azetidin-3-ol as a liquid which is used without further purification. Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol) and azetidin-3-ol (50 mg, 0.68 mmol, excess) in dichloromethane (1.0 mL) and triethylamine (0.500 mL, 3.58 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (300 mg, 0.66 mmol, excess) at room temperature. Stir for 30 minutes, load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 167 mg of (3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam (73%). LRMS: MH+ 432.97.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:22](Cl)[O:23][CH2:24][CH2:25][O:26][CH3:27]>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-hydroxyphenylacetate (200 mg, 1.20 mmol) in DCM (5 ml) is added DIPEA (0.315 ml, 1.81 mmol), and then MEMCl (0.204 ml, 1.81 mmol), and the resulting reaction mixture is stirred for 2 hours at room temperature. An additional portion of MEMCl (0.102 ml, 1 mmol) and of DIPEA (0.158 ml, 1 mmol) are added, and the reaction mixture is stirred for a further 16 hours. An additional portion of MEMCl (0.102 ml, 1 mmol) and of DIPEA (0.158 ml, 1 mmol) are added and the reaction mixture is stirred for 3 hours. The reaction mixture is diluted with DCM and washed with 0.5 M HCl, 1 M NaOH and then 0.5 M HCl, dried (MgSO4) and concentrated in vacuo to afford [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid methyl ester
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[OH:12]>C(O)C.[C].[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[OH:12])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(O)c1ccccn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1C(O)c1ccccn1
Yield: 57.7 %

Procedure:
(2-methyl-4-nitrophenyl)(pyridin-2-yl)methanol (0.83 g) was dissolved in ethanol (50 ml), and the solution was reduced by catalytic hydrogenation overnight with 10% palladium-carbon of 50% hydration (50 mg). The catalyst was removed, and the solvent of the filtrate was distilled off and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give (4-amino-2-methylphenyl)(pyridin-2-yl)methanol (0.42 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 40 mg, 1.0 mmol) in 2.0 mL of DMF at room temperature was added 1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3 portions. After 30 minutes of stirring at room temperature, 2,4-dichloropyrimidine (0.15 g, 1.0 mmol) was added as a solution in 1.0 mL DMF. The reaction mixture stirred for 3 h at room temperature. The reaction was quenched with saturated sodium bicarbonate solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-30% ethyl acetate:heptane) to afford the desired compound as an off-white solid (53 mg, 17% yield). MS/ES+: m/z=312.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:3]1.[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[N:21]=[N:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([NH:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=3)=[O:8])[CH2:3]2)=[O:28])[N:21]=[N:20]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Reaction time: 2 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 3-aminopyrrolidine-1-carboxylate (1 equiv), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (1 equiv.), HATU (1.5 equiv.) and triethylamine (5 equiv.) in dimethylformamide was stirred at RT for 18 hours. Another 1 equivalent of 4-(1H-1,2,3-triazol-4-yl)butanoic acid was added to the reaction mixture and stirring continued for a further 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dry loaded using silica onto a 12 g ISCO column, eluting with 0-15% MeOH in DCM. The product fractions were combined and concentrated under reduced pressure. Further purification was carried our using preparative LC-MS. The product fractions were concentrated under reduced pressure to give an aqueous solution and extracted with EtOAc to afford the title compound;
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[NH2:9][CH:10]([CH3:13])[CH2:11][OH:12]>C(O)C>[C:1]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])(=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CC(N)CO
Reactant: CCOC(=O)C(C)O
Solvent: CCO
Product: CC(CO)NC(=O)C(C)O
Temperature: 112.5 °C

Procedure:
3.7 g ethyl lactate and 2.1 g 2-amino-1-propanol were mixed and subsequently heated to 110-115° C. for 2.5 hours. During the reaction, the ethanol formed was distilled off. After the reaction the excess of ethyl lactate was removed by vacuum distillation (bottom temperature: 150° C., 1 mbar), using a 20 cm vigreux column. 3.9 g of residual N-lactoyl 2-amino-1-propanol (brown viscous liquid) was collected, the purity of which was confirmed by NMR analysis. The yield of the reaction was 95%
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCOc1cccc(O)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(OCCCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 7.3 g of 60% NaH in 190 ml of anhydrous dimethylformamide is cooled in an ice bath. To this mixture is added 22.0 g of 3-pentyloxyphenol dissolved in 50 ml of anhydrous dimethylformamide. This mixture is then stirred at room temperature for 45 minutes; 23.2 ml of ethyl 4-bromobutyrate are added; and the resultant mixture is stirred at 60° C. for 17 hours. The solvent is removed under vacuum and the residue worked up as above. The residue is flash chromatographed on normal phase silica gel using a gradient from hexane to a 4:1 ratio of hexane:ether to yield ethyl 4-(3-pentyloxyphenoxy)butyrate as a clear oil.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][SH:5].F[C:15]1[C:16]([C:21]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:13][C:2]([F:1])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][S:5][C:15]1[C:16]([C:21]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)CCNC(=O)c1ncccc1F
Reactant: Fc1ccc(C(F)(F)CCS)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1ncccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
To a solution of 3,3-difluoro-3-(4-fluorophenyl)-propane-1-thiol (0.19 g, 0.92 mmol) in DMF (5 ml) in sealed tube are added 3-fluoro-N-(3-methyl-butyl)-pyridine-2-carboxylic acid amide (0.19 g, 0.92 mmol) and cesium carbonate (1.50 g, 4.60 mmol). The reaction mixture is heated at 90° C. for 2 h. After completion of the reaction, the reaction mixture is poured onto ice-water, extracted with EtOAc (3×30 ml). The combined organic layers are washed with brine (50 ml), water (30 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 30% EtOAc/hexane) affording 3-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-pyridine-2-carboxylic acid amide (example 3) (0.15 g, 0.37 mmol, 41%). [M+H]+ 397.1.
Reaction SMILES: [C:1]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.NN.[OH-].[K+].C(O)COCCO>O>[CH2:1]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCc1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 80.2 %

Procedure:
In a 200 ml-three-necked flask, 6.00 g (20.5 mM) of 2-octanoylfluorene, 3.06 ml (50.4 mM) of hydrazine hydrate (80% aqueous solution), 4.20 g (63.6 mM) of potassium hydroxide and 60 ml of diethyleneglycol were placed, followed by heating to about 130° C. to dissolve the mixture. Then, the mixture was gradually heated to 210°-217° C., followed by stirring for 3 hours and 40 minutes under heating. After the reaction, the reaction mixture was cooled and poured into 250 ml of water to precipitate a crystal. The crystal was recovered by filtration and dissolved in toluene, followed by washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/2) to obtain 4.58 g of 2-octylfluorene.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[N:24]O)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C.O1CCCC1>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]([NH2:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc12
Yield: 70.5 %

Procedure:
The procedure used in Example 6 is followed, but starting from 4 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 0.7 g of Raney nickel in 100 ml of ethanol and 100 ml of tetrahydrofuran for 10 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, and then purification by formation of a paste in diisopropyl ether, in this way we obtain 2.7 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder which is used as it is in the following stage.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[C:9][C:10]2[N:11]=[N:12][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1>C(OCC)(=O)C.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[N:12][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)[O:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(C#CCCn4ccnn4)nn3)co2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)nn3)co2)cc1

Procedure:
3-(4-[1,2,3]Triazol-1-yl-but-1-ynyl)-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine (0.047 g, 0.1 mmol) is dissolved in ethyl acetate (3 ml) and hydrogenated for 3 h at r.t. in the presence of palladium on charcoal (10%, 20 mg). After filtration and concentration in vacuo the residue is purified by flash column chromatography (ethyl acetate/methanol 19:1) yielding 3-(4-[1,2,3]triazol-1-yl-butyl)-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine as an off-white solid.
Reaction SMILES: [CH2:1]([C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)=[O:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CS(C)=O>[CH2:1]([C:9]([C@@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)=[O:10])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@H]2C(=O)CCc1ccccc1

Procedure:
Into a 250 mL 3-neck round bottom flask is placed 17β-(phenethylcarbonyl)-androsta-3,5-diene-3-carboxylic acid and an excess of sodium hydroxide. To the flask is added dimethyl sulfoxide as a solvent. The mixture is heated to reflux for 3 hours. Standard workup followed by isolation by preparative HPLC yields title compound.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]([NH:20][CH:21]2[C:45](=[O:46])[N:23]3[C:24]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:25]([OH:28])[CH2:26][S:27][C@H:22]23)=[O:19])=[CH:12][CH:11]=1.FS(OC)(=O)=O>CN(P(N(C)C)(N(C)C)=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]([NH:20][CH:21]2[C:45](=[O:46])[N:23]3[C:24]([C:29]([O:31][CH:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:25]([O:28][CH3:1])[CH2:26][S:27][C@H:22]23)=[O:19])=[CH:12][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(CSc1ccc(Cl)cc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: COS(=O)(=O)F
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)CSc3ccc(Cl)cc3)[C@H]2SC1
Reaction time: 0.02 h

Procedure:
A solution of 60 mg. of lithium diisopropylamide in 10 cc. of HMPA is cooled to 0° C. and 260 mg. of diphenylmethyl 7-(4-chlorophenylthio)acetamido-3-hydroxy-3-cephem-4-carboxylate is added in one portion. After stirring the reaction mixture for 1 minute, 70 mg. of methyl fluorosulfonate is added, and stirring is continued for 30 minutes. The reaction mixture is poured into 50 cc. of ethyl acetate, washed with water, and dried. Removal of the solvent under reduced pressure provides diphenylmethyl 7-(4-chlorophenylthio)acetamido-3-methoxy-3-cephem-4-carboxylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[N:16]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:32])[N:20]=1)[CH2:17][CH3:18]>>[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=1[N:16]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)([OH:31])[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:32])[N:20]=1)[CH2:17][CH3:18]
Reactant: c1ccsc1
Reactant: CCN(c1nc(C)cc(N2CCC(=O)CC2)n1)c1ccc(C(C)C)cc1Br
Product: CCN(c1nc(C)cc(N2CCC(O)(c3cccs3)CC2)n1)c1ccc(C(C)C)cc1Br
Yield: 44.2 %

Procedure:
The operation of Example 4-(1) was followed using 168 mg of thiophene and 432 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-6-methyl-4-(4-oxopiperidin-1-yl)pyrimidine to give 228 mg of 2-(N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(thiophen-2-yl)-4-hydroxypiperidin-l-yl]-6-methylpyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1Cl)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 73.3 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55 mmol) with 2-chlorobenzene-1-sulfonyl chloride (382.2 mg, 1.555 mmol) was carried out according to a similar to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as base. 1-[(2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 73.3% yield (481.8 mg) as white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][N:19]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:41]4[CH2:40][CH2:39][CH2:38][CH2:36]4)=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)O)ccc3n2CC2CC2)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)N4CCCC4)ccc3n2CC2CC2)nc1
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
Following the general procedure 20E, 1-(cyclopropylmethyl)-2-[(5-ethoxy-2-pyridinyl)methyl]-1H-benzimidazole-5-carboxylic acid (80 mg, 0.228 mmol) was dissolved in DMF (2 mL) and HATU (104 mg, 0.274 mmol) was added followed by DIPEA (48 μl, 0.274 mmol), After being stirred for 10 min, pyrrolidine was added and the resulting mixture was stirred overnight. The crude residue obtained after work-up was purified using reverse phase preparative HPLC to give a TFA salt as white solids (42 mg, 37%). 1H NMR (400 MHz, CD3OD): δ 8.18 (d, J=2.8 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.87 (s, 1H), 7.72 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.2 Hz, J=2.8 Hz, 1H), 4.89 (s, 2H), 4.43 (d, J=6.8 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.60 (t, J=7.6 Hz, 2H), 3.44 (t, J=7.6 Hz, 2H), 2.02–1.94 (m, 2H), 1.92–1.86 (m, 2H), 1.37 (t, J=7.2 Hz, 3H), 1.30–1.22 (m, 1H), 0.64–0.58 (m, 2H), 0.48–0.44 (m, 2H). MS (ESI) (M+H)+=405. Anal. Calcd for C24H28N4O2.0.8TFA.0.2H2O: C, 55.32; H, 5.12; N, 9.49. Found: C, 55.30; H, 4.91; N, 9.23.