Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][C:22](=[O:24])[CH3:23])[CH:3]=1.[BH4-]>C(O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][CH:22]([OH:24])[CH3:23])[CH:3]=1
Reactant: CC(=O)COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Agent: [BH4-]
Solvent: CCO
Product: CC(O)COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2

Procedure:
The product from Example 75 is treated with sodum borohydride in absolute ethanol at reflux to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1)[CH2:3]O.C(N(CC)CC)C.C1(C)C=CC(S([Cl:41])(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:41][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reaction time: 8 h
Yield: 19705.9 %

Procedure:
A mixture of 2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-1-propanol (991 mg, 2.9 mol), triethylamine (0.4 mL, 2.9 mmol), p-toluenesulfonyl chloride (678 mg, 3.4 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol) and methylene chloride (15 mL) was stirred 8 hours at 20° to 25° C. The reaction mixture then was filtered and concentrated and the residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (95:5) to give 1-chloro-2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (238 mg, 0.67 mol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH3:8])[N:3]=1.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=1[C:12](Cl)=[O:13].C([O-])(O)=O.[Na+].C(OC(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:8][N:4]1[C:5]([CH3:7])=[CH:6][C:2]([NH:1][C:12](=[O:13])[C:11]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:10]=2[CH3:9])=[N:3]1
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: Cc1cc(N)nn1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(=O)Nc1cc(C)n(C)n1
Reaction time: 18 h
Yield: 38.2 %

Procedure:
To a cooled (0°-5° C.) solution of 3-amino-1,5-dimethyl pyrazole (95%, 32.7 g, 0.28M) in anhydrous CH2Cl2 (200 ml) was added a CH2Cl2 (100 ml) solution of the 2,6 dimethyl benzoyl chloride (23.6 g, 0.14M). The reaction mixture was allowed to room temperature for 18 hours and then CH2Cl2 was concentrated to give an oily mixture which was diluted in AcOEt. This suspension was then treated with saturated NaHCO3. After usual work-up, the crude material was cristallized with diisopropyloxide to give 13 g of the desired amide (38% : yield based on the 2,6-dimethyl benzoyl chloride).
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].O=C1CCC([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])CC1.O>O1CCCC1>[CH2:8]=[C:15]1[CH2:16][CH2:17][CH:18]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of tetrahydrofuran, potassium tert-butoxide (16.8 g, 0.15 mol) was added at −20° C., reacted for 0.5 h after the temperature was raised to 0° C. Then, tert-butyl 4-oxo-cyclohexylcarbamate (Compound 7-1) (21.3 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise into the flask under nitrogen. After 3 hours of reaction at room temperature, a small amount of water was added to dissolve the solids. The mixture was rotary evaporated to remove THF, extracted with anhydrous diethyl ether, and dried, concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 7-2 as a colorless liquid (19.5 g, 92.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:24].CO>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1.[ClH:24]
Reactant: COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(OC2CCNCC2)c(F)c1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 8.54 mmol) in dioxane (21.36 mL) was treated with HCl (4 M in dioxane, 21.36 mL, 85 mmol) at room temperature and the resulting reaction mixture stirred overnight. Flash silica gel chromatography using a gradient of 5% to 30% MeOH in DCM gave the title compound as its HCl salt (1.7 g, 76%) as a white solid. ESI-MS m/z [M+H]+ 226.20.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH2:18])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]1[CH2:24][CH2:23][S:22][CH2:21][C:20]1=[O:25]>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH:18][C:20](=[O:25])[CH2:21][S:22][CH2:23][CH2:24][OH:19])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCC2)ccn1
Reactant: O=C1CSCCO1
Product: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCC2)ccn1

Procedure:
Following a procedure similar to that described in Example 68, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, N-{4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}-2-(2-hydroxyethylthio)acetamide was obtained. This product was reacted with acetic anhydride in the same manner and same relative proportions as described in Example 67(c), to give the title compound in a 42% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[O:6]
Reactant: CCOP(OCC)OCC
Reactant: O=Cc1ccccc1CCl
Product: CCOP(=O)(Cc1ccccc1C=O)OCC

Procedure:
47.9 g (0.31 mol) of 2-chloromethylbenzaldehyde were heated to 160° C. together with 51.5 g (0.31 mol) of triethyl phosphite. Ethyl chloride distilled off during the course of this. The product was purified by fractional distillation.
Reaction SMILES: [OH:1][C@H:2]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[OH:1][C@H:2]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[N+:23]([O-:35])[CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2cccnc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc[n+]([O-])c2)s1
Reaction time: 0.67 h

Procedure:
To a solution of (4R,5R)-5-{(1S)-hydroxy[5-(3-pyridinyl)-2-thienyl]methyl}-1-methyl-4-phenyl-2-pyrrolidinone (Example 3b, 0.20 g, 0.55 mmol) in CHCl3 (10 mL) was added mCPBA (0.35 g, 1.4 mmol). The reaction mixture was stirred for 40 min, then was treated with a saturated NaHCO3 solution (10 mL). The organic layer was dried (Na2SO4) and was allowed to stand overnight. The white precipitate was filtered off, the filtrate was concentrated under reduced pressure. The crude product was triturated (Et2O/CH2Cl2) to give (4R,5R)-5-{(S)-hydroxy[5-(1-oxido-3-pyridinyl)-2-thienyl]methyl}-1-methyl-4-phenyl 2-pyrrolidinone: mp 138-140° C.; TLC (10% MeOH/CH2Cl2) Rf 0.20; ES-LRMS m/z 381 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[Cl-].[Na+]>O>[NH2:19][C:18]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: N#C[O-]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NC(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To about 0.15 mole of α-amino-4-hydroxybenzeneacetic acid dissolved in 700 ml of water and 0.2 mole of glacial acetic acid is added about 0.2 mole of potassium cyanate. The resulting mixture is stirred at room temperature for about 30 minutes. The reaction mixture is saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate is washed with water, dried over magnesium sulfate, filtered and evaporated to give α-(aminocarbonyl)amino-4-hydroxybenzeneacetic acid
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:22][CH2:23][CH3:24])[CH:6]2[CH2:17][C:16]3[CH:15]=[C:14]4[C:10]([C:11]([C:18](=O)[CH2:19][CH3:20])=[CH:12][NH:13]4)=[CH:9][C:8]=3[CH2:7]2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:1]1([CH2:4][N:5]([CH2:22][CH2:23][CH3:24])[CH:6]2[CH2:17][C:16]3[CH:15]=[C:14]4[C:10]([C:11]([CH2:18][CH2:19][CH3:20])=[CH:12][NH:13]4)=[CH:9][C:8]=3[CH2:7]2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)C1Cc2cc3[nH]cc(C(=O)CC)c3cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCc1c[nH]c2cc3c(cc12)CC(N(CCC)CC1CC1)C3
Yield: 50.1 %

Procedure:
To a stirred solution of 1-[6-(cyclopropylmethyl-propyl-amino)-1,5,6,7-tetrahydro-1-aza-s-indacen-3-yl]-propan-1-one (12h, Chart 2) (58 mg, 0.18 mmol) in dry diethyl ether (4 mL) was added in small portions lithium aluminum hydride (40 mg, 1.06 mmol). The reaction mixture was stirred over night and then quenched by the consecutive addition of water (40 μL), 15% sodium hydroxide (40 μL) and water (120 μL). After stirring for 15 min., the solid material was filtered off and the solvent removed in vacuo to yield a residue of 28 mg (50%) of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[N:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(O)(=O)C>[CH2:28]([O:27][C:23]1[CH:22]=[N:21][N:20]([CH2:19][CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][N:8]([CH3:6])[CH2:9]3)=[CH:14][CH:13]=2)[C:25](=[O:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccccc4)cc3=O)cc2C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCc2ccc(CCn3ncc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 90 mg (0.25 mmol) 5-benzyloxy-2-[2-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-one (example 25.1) in 2.0 mL THF is added 28 μL (0.37 mmol) aqueous 37% formaldehyde solution. The mixture is acidified with 2 drops of acetic acid and then 79 mg (0.37 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred 2 h at RT and is poured into aqueous 10% Na2CO3-solution, the layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is dissolved in DMF and is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH2:13](Cl)Cl>>[CH:12]([N:8]([CH3:9])[C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2])([CH3:11])[CH3:13]
Reactant: ClCCl
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC(C)N(C)C(=O)n1ccnc1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a 50 mL round-bottomed flask was added 1,1′-carbonyldiimidazole (1.663 g, 10.25 mmol), (Fluka Chemie) DCM (25 mL). The solution was stirred at 0° C. using a water bath and treated in one portion with n-isopropylmethylamine (0.5 mL, 6.84 mmol) (Aldrich). The water bath was removed, and the solution was stirred at room temperature. After 2 hours all starting material was consumed. The reaction mixture was diluted with DCM (10 mL) and quenched with water. The organic layer was separated, dried over sodium sulfate and concentrated to afford N-isopropyl-N-methyl-1H-imidazole-1-carboxamide (0.920 g, 5.50 mmol, 80% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.P(=O)(O)(O)O>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:13](=[CH:12][CH:11]=[C:10]([F:9])[CH:15]=2)[NH:16][CH:6]=1
Reactant: O=CCCCCCl
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2[nH]cc(CCCCl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-chloropentan-1-ol (16.2 mL) was dissolved in cold 5 mM 2,2,6,6-tetramethylpiperidine-1-yloxy (tempo) in dichloromethane (240 mL) and cooled down to 0° C. with an ice bath. Potassium bromide (0.5 M in water, 24 mL) was added, and this was followed by the addition (in one portion at 5° C. under vigorous stirring) of a solution of sodium hydrogencarbonate (24 g) in aqueous sodium hypochlorite (0.3 M, 500 mL). The resulting mixture was stirred at 5° C. for 20 min, and the phases were separated. The water phase was extracted with dichloromethane (200 mL), and the combined organic phases were evaporated in vacuo giving 5-chloropentanal as a clear oil (16 g). Subsequently, 5-chloropentanal was suspended in water (100 mL) followed by addition of 4-fluorophenylhydrazine hydrochloride (19.5 g) and toluene (800 mL), and the mixture was stirred at room temperature for 15 min. Phosphoric acid (85%, 100 mL) was added and the mixture was boiled under reflux for 2 h. The mixture was cooled to room temperature and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogencarbonate, dried (MgSO4) and evaporated in vacuo to yield an orange oil. The crude product was purified by flash chromatography on silicagel (eluent:ethylacetate/heptane 1:4) to give the title compound as an orange oil (14 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([S:18]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CO>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:4]2[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: N#Cc1nccnc1Cl
Solvent: CO
Product: CN1CCN(c2nccnc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 3-cyano-2-chloropyrazine (0.45 g, 3.2 mmol) in methanol (10 mL) was added N-methylpiperazine (0.75 mL, 6.4 mmol) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, then the residue was dissolved in ethyl acetate. The precipitate was filtered off and the filtrate was concentrated under reduce pressure. The residue was then purified by flash chromatography on silica gel (dichloromethane/methanol 95:5) to give the title compound as a yellow oil (0.59 g).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2c(F)cccc2Cl)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1c(F)cccc1Cl)N1CC[C@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-chloro-6-fluorophenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[F:27][C:28]([F:43])([F:42])[S:29]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[NH:32][S:29]([C:28]([F:43])([F:27])[F:42])(=[O:31])=[O:30])=[CH:16][CH:17]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: CCCCc1cccc(=O)n1Cc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1cccc(=O)n1Cc1ccc(NC(=O)c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
A mixture of 2.56 g of 6-butyl-1-p-aminobenzyl-1,2-dihydro-2-oxopyridine, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5° and a solution of 2.88 g of o-trifluoromethanesulfonamidobenzoyl chloride in 20 ml of CH2Cl2 is added dropwise. The mixture is stirred for a further 16 hours at 20°, evaporated and worked up in conventional manner to give 6-butyl-1-[4-(o-trifluoromethanesulfonamidobenzamido)benzyl]-1,2-dihydro-2-oxopyridine.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21]>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[CH3:16])[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Reactant: CN(C)CCCN
Solvent: CN(C)C=O
Product: CN(C)CCCNc1nc(C(C)(C)C)cn2c(=O)[nH]nc12
Reaction time: 16 h

Procedure:
A solution of 23 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 41 mg of 3-(dimethylamino)propylamine in DMF (0.5 mL) was heated to 80° C. After 16 h, the product was purified on a Shimadzu reverse-phase HPLC (Shimadzu LC-8A Preparatory LC; Waters Symmetry 30×50 mm column; solvent gradient=15-100% acetontrile/1% aqueous formic acid; flow rate=40 mL/min.) to provide the title compound as a white solid. MS (M+H+)=293.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](Cl)=[O:35]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C:33]2[CH:32]=[C:31]([Cl:30])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NC(=O)c3cc(Cl)cc(Cl)c3)CN2Cc2ccccc2)CC1
Yield: 11.5 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3,5-dichloro-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (8.3 mg, 11.5%) as light yellow oil. MS m/e=562.2 [M+H]+.
Reaction SMILES: [Si]([N:5]=[C:6]=[S:7])(C)(C)C.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1>O1CCCC1.C(OCC)(=O)C>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[S:7])[NH2:5]
Reactant: CCOC(=O)C1CCNCC1
Reactant: C[Si](C)(C)N=C=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C(N)=S)CC1
Yield: 20.3 %

Procedure:
A solution of TMS-isothiocyanate (5.4 mL, 38 mmol) and ethyl piperidine-4-carboxylate (5.9 ml, 38 mmol) in tetrahydrofuran (127 ml) was stirred at room temperature for 3 days. The mixture was then diluted with 500 mL ethyl acetate and washed with 500 mL water and 500 mL brine. The aqueous fractions were further extracted with 500 mL ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by CombiFlash (40-100% ethyl acetate/hexanes) to provide 1.85 g (7.7 mmol, 20%) of ethyl 1-carbamothioylpiperidine-4-carboxylate as a white solid.
Reaction SMILES: C([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([OH:18])=[O:17])(=O)C1C=CC=CC=1>Cl>[NH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([OH:18])=[O:17]
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Agent: Cl
Product: N[C@@H]1CCCC[C@@H]1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of (+)-(1S,2R)-2-benzamidocyclohexanecarboxylic acid (4.0 g, 16.2 mmol, TCI chemical company) and 6 M hydrochloric acid (200 mL) was heated at reflux for 48 h. The reaction mixture was cooled to room temperature and extracted with diethyl ether (2×200 mL). The aqueous portion was concentrated in vacuo to afford (1S,2R)-2-aminocyclohexanecarboxylic acid as a white solid. The crude product was used in the next step without purification or characterization.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][C:15](=[O:29])[C:16]4[CH:17]=[C:18](CC([O-])=O)[CH:19]=[CH:20][C:21]=43)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2.C1C[O:33]CC1>>[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH:15]([OH:29])[C:16]4[CH:17]=[C:18]([OH:33])[CH:19]=[CH:20][C:21]=43)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2
Reactant: C1CCOC1
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CC(=O)c3cc(CC(=O)[O-])ccc3[C@H]1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(O)c3cc(O)ccc3[C@H]1CC2

Procedure:
To a suspension of lithium aluminum hydride (LAH, 95%, 46.9 mg, 1.17 mmol) in 5 mL of anhydrous THF was added estra-1,3,5(10),16-tetraen-6-one-3-yl-acetate (6) (422.9 mg, 1.360 mmol) in 5 mL of anhydrous THF dropwise, with stirring. The reaction was stirred 50 min., after which further LAH (46.5 mg, 1.16 mmol) was added and the reaction stirred 22 h. After refluxing 4 h TLC still showed starting material. The reaction was quenched with 0.5 mL of water +0.5 mL of 20% (w/w) sulfuric acid and concentrated under reduced pressure. The residue was extracted four times with 10 mL portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice by flash chromatography to give solid product. (0.05 g, 0.2 mmol, 10%), m.p. 150-157° C.