Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:4]=2[C:3]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][CH2:8][C:2]3[S:17][C:16]([NH2:18])=[N:15][C:3]=3[C:4]=2[CH:12]=1
Reactant: NC(N)=S
Reactant: O=C1c2cc(F)ccc2CCCC1Br
Solvent: CCO
Product: Nc1nc2c(s1)CCCc1ccc(F)cc1-2

Procedure:
6-Bromo-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (1.0 g, 3.89 mmole) was mixed with thiourea (355 mg, 4.66 mmole) in 20 ml of ethanol and heated at reflux temperature for 16 hours. The reaction mixture was cooled and filtered to give a solid (m.p. 270° C.). The filtrate was concentrated and then partitioned between ethyl acetate and saturated sodium carbonate solution. The organic extract was concentrated and chromatographed (silica, ethyl acetate/hexanes) to give the desired product as a yellow solid (m.p. 142-144° C., 34%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[CH:9]=[C:4]2[CH:3]=[N:2]1.[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=[C:29]([C:35]([F:38])([F:37])[F:36])[N:28]=2)[CH2:23][CH2:22]1>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:20][CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:32]([CH2:33][NH:34][C:11]([NH:10][C:8]3[CH:9]=[C:4]4[CH:3]=[N:2][NH:1][C:5]4=[N:6][CH:7]=3)=[O:19])=[CH:31][CH:30]=[C:29]([C:35]([F:38])([F:36])[F:37])[N:28]=2)[CH2:25][CH2:26]1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Reactant: O=C(Nc1cnc2[nH]ncc2c1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cnc3[nH]ncc3c2)CC1
Temperature: 50 °C
Yield: 71.5 %

Procedure:
To a solution of phenyl 1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (C) (84 mg, 0.329 mmol) in acetonitrile was added DMAP (40 mg, 0.329 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (D) (90 mg, 0.329 mmol) at room temperature. The reaction mixture was heated to 50° C. for 15 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)urea (example compound 5) (102 mg, 71%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11].C([O-])(=O)C.[NH4+]>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1cccs1
Temperature: 100 °C

Procedure:
A mixture of thiophene-2-carbaldehyde (Compound 66a) (1.20 g, 0.0107 mol), malonic acid (1.11 g, 0.0107 mol) and ammonium acetate (0.825 g, 0.0107 mol) in DMF (8.5 mL) was heated to 100° C. for 3 h. The system was diluted with ethyl acetate and washed with water and dried over MgSO4. The solvent was removed in vacuo and the title compound was purified by silica gel column chromatography using 3:1 Hexanes:ethyl acetate as the eluent.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1(=[O:26])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([OH:15])=[O:14])[C:10](=[O:21])[C:9]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:8]12.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:10]1(=[O:21])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([O:15][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])[C:7](=[O:26])[C:8]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:9]12
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of cesium carbonate (3.819 g, 11.7 mmol.) and (S)-2-phthalimido-6-hydroxyhexanoic acid (6.00 g, 21.6 mmol.) in dimethylformamide (60 ml.) was treated with benzyl bromide (3.30 ml., 4.75 g., 27.7 mmol.). After stirring at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic extract was washed with water (twice) and brine, then dried (sodium sulfate), filtered and stripped to give an oil. The oil was flash chromatographed (Merck silica gel, 6/4-ethyl acetate/hexane) to give essentially pure product as a solid. Recrystallization from ethyl acetate/hexane gave 7.173 g. (1st crop) and 394 (2nd crop) for a total of 7.567 g. of pure title product; m.p. 106°-108.5° C.; [α]D =-27.5° (c=1.5, methanol). TLC (75/25 ethyl acetate/hexanes) Rf =0.43.
Reaction SMILES: Cl.Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]3[C:18]=2[C:19]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]4[O:37][CH2:38][O:39][C:31]=24)=[N:20][CH:21]=[N:22]3)[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:35]1[C:30]([NH:29][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:17]=3[O:16][CH:13]3[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]3)[N:22]=[CH:21][N:20]=2)=[C:31]2[O:39][CH2:38][O:37][C:32]2=[CH:33][CH:34]=1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A mixture of 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxyquinazoline dihydrochloride (2.39 g), trifluoroacetic acid (10 ml) and methylene chloride (35 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a 1N aqueous sodium hydroxide solution. The organic layer was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (1.44 g); NMR Spectrum: (CDCl3) 1.8-2.0 (m, 2H), 2.15-2.3 (m, 2H), 2.75-2.9 (m, 2H), 3.1-3.2 (m, 2H), 3.9 (s, 3H), 4.65 (m, 1H), 6.0 (s, 2H), 6.46 (d, 1H), 6.72 (d, 1H), 6.8 (d, 1H), 6.91 (d, 1H), 8.5 (s, 1H), 9.21 (s, 1H); Mass Spectrum: M+H+ 429 and 431.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16]>O.CCOC(C)=O.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:9][CH:10]([CH2:11][CH2:12]2)[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Clc1ccc(-c2ccco2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1=C(C(=O)OC)C2(c3ccc(Cl)cc3)CCC1O2

Procedure:
2-(4-Chlorophenylfuran (2.3 g) and dimethyl acetylenedicarboxylate (1.54 ml) were subjected to Diels-Alder reaction in water (5.48 ml) as described in Example 53. The resulting adduct was dissolved in EtOAc (140 ml) and hydrogenated over Adam's platinum catalyst (100 mg) at room temperature and atmospheric pressure. The uptake of one equivalent of H2 required about 3 hours. The catalyst was removed by filtration and the solvent removed in-vacuo to provide a gummy product which was chromatographed over silica gel column. Elution of column with 10% acetone in n-hexane gave fractions containing the pure title compound (3.25 g) as colorless crystals:m.p. 90°-91° C.; PMR δH (CDCl3): 1.55-1.7 (n,1H), 2-2.3 (m,3H), 3.62 (s,3H), 3.79(s,3H), 5.37 (d, 1H, J=4.2 Hz), 7.3-7.44 (m,4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH2:22])(=[O:21])=[O:20]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([NH2:22])(=[O:20])=[O:21])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Reaction time: 4 h
Yield: 47.6 %

Procedure:
3-Bromo-benzenesulfonyl chloride (8.34 mL, 57.9 mmol) was added to a solution of 2-amino-benzenesulfonamide (9.965 g, 57.9 mmol) dissolved in pyridine (90 mL). The reaction was stirred for 4 h followed by solvent removal under vacuo. The reaction mixture was added to water and the product was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to furnish a dark yellow oil. The oil was dissolved in EtOAc and precipitated by addition of heptane. The solid was finally recrystallized from EtOH to give the title compound (10.784 g, 48%) as a white solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[SH:10].[H-].[Na+].CN(C)C=O.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1>O>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:32]2[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=[C:28]2[NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][S:10][C:2]3[S:3][C:4]4[C:9]([N:1]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:26][CH2:25]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: Sc1nc2cccnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4nc5cccnc5s4)CC3)nc3ccccc32)cc1
Reaction time: 1 h
Yield: 6.4 %

Procedure:
A mixture of 2.5 parts of thiazolo[5,4-b]pyridine-2-thiol, 1 part of a sodium hydride dispersion 50% and 45 parts of N,N-dimethylformamide was stirred for 1 hour. Then there was added a solution of 6.9 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in 45 parts of N,N-dimethylformamide. The whole was stirred overnight. Water was added dropwise. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.5 parts (6.4%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(thiazolo[5,4-b]pyridin-2-ylthio)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 159.9° C. (compound 105).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:5][C:4]=1[NH:24][CH3:25])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][NH:24][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CNc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(CCN2CCNCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-{2-[4-cyano-3-(methylamino)phenyl]ethyl}piperazine-1-carboxylate (18 mg, 0.05 mmol) in 5 mL of DCM was added TFA (3 mL), and then stirred at room temperature for 2 hours. The solvents were removed off under vacuum to afford crude 2-(methylamino)-4-(2-piperazin-1-ylethyl)benzonitrile.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[CH3:20]I>CN(C=O)C>[CH3:20][N:3]1[CH:4]=[CH:5][S:1]/[C:2]/1=[N:6]\[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1ccs/c1=N\C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 21 %

Procedure:
To a solution of tert-butyl 4-(1,3-thiazol-2-yl)amino-1-piperidinecarboxylate (2.5 g) obtained in Example 135b) in DMF (50 ml) was added methyl iodide (1.1 ml), and mixed at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform and an aqueous potassium carbonate solution. The organic layer was collected by separation, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a pale yellow solid (0.54 g, 21%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21](I)=[CH:20][C:19]=1[CH3:26]>>[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[CH:20][C:19]=1[CH3:26]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cc(-c2cc(C)c(Br)c(C)c2)ccn1

Procedure:
The title compound is prepared from 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.87 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:10][N:11]=[C:12]([CH2:14][O:15][CH3:16])[N:13]=2)[CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].O>C(O)(=O)C>[Cl:17][CH2:18][C:19]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[NH:10][N:11]=[C:12]([CH2:14][O:15][CH3:16])[N:13]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: COCc1n[nH]c(-c2cc(Cl)ccc2N)n1
Solvent: CC(=O)O
Solvent: O
Product: COCc1n[nH]c(-c2cc(Cl)ccc2NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.9 %

Procedure:
4-Chloro-2-(5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-phenylamine (60.6 g, 239 mmol) was dissolved in acetic acid (1.2 L) and chloroacetic chloride (40.4 mL, 508 mmol) was added dropwise at 14-16° C. over a period of 30 min. The resulting reaction mixture was stirred for 22 h at ambient temperature. After addition of water (600 mL) and stirring for another 90 min, the solid was filtered off and washed with water (600 mL). Drying in vacuo afforded the title compound (66.2 g, 83%) which was obtained as a yellow solid. MS: m/e=314.9 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.Cl.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:27]1([NH:33][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]nicotinic acid (200 mg, 0.77 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (427 ul, 3.07 mmol) was added followed by cyclohexylamine hydrochloride (88 ug, 0.77 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml). The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 35:65) as eluant to give a white solid which was recrystallised from diethyl diethyl ether/pentane to give N-cyclohexyl-2-[3-(methylsulfanyl)phenoxy]nicotinamide (134 mg) as a white solid.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C@@H:23]([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:35]2([CH3:41])[C@H:16]([C@H:15]3[C@H:38]([CH2:37][CH2:36]2)[C@:39]2([CH3:40])[C:12]([CH2:11][C@@H:10]([OH:42])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:34])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@H](CC[C@H](F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A mixture of 0.356 g. (0.00053 mole) of [1α,3β,24S]-1,3-bis-[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, 15 ml. of methanol and 0.05 g. of p-toluenesulfonic acid monohydrate was stirred at 25° for 3 hr. The mixture was quenched with 0.25 g. of sodium bicarbonate and stirring for 0.5 hr. The mixture was evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness to yield [1α,3β,24S]-24-fluorocholest-5-en-1,3,25-triol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:19](=O)[CH3:20])=[CH:10][C:11]([CH3:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH:19]([NH2:28])[CH3:20])=[CH:10][C:11]([CH3:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(C)c2cccnc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanone (50 mg, 0.2 mmol) and ammonium acetate (138 mg, 1.79 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (22.5 mg, 0.358 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C18H18FN2 (M+H)+: m/z=281.1; Found: 281.1.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([CH3:13])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.C(O)C.[Cl:18][C:19]1[C:20]([NH:26][NH2:27])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[N:27][N:26]([C:20]2[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=2)[C:11]=1[CH3:13])=[O:7])[CH3:10]
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(Cl)cc2Cl)c1C

Procedure:
To ethyl 2-(ethoxymethylene)acetoacetate (25.1 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added 1N hydrochloric acid aqueous solution (135 ml) and an ethanol solution (135 ml) of 3,5-dichloropyridin-2-ylhydrazine (24.02 g) described above, stirred at reflux temperature for three hours and left to stand at room temperature. Water was added to the reaction solution, the precipitated solid was collected by filtration and purified with a mixed solvent of ethyl acetate and n-hexane to give 1-(3,5-dichloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH:26]=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][NH2:40].C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH2:39][NH:40][CH2:26][CH2:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]2[CH:28]=[CH:29][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:31]([CH3:32])[CH3:33])=[CH:4][C:3]([C:1]#[N:2])=[CH:30][C:7]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCNCc5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-oxoethyl)cyclohexyl]methyl}benzamide (25 mg, 0.056 mmol) in methanol (2 ml) were added 3,5-bis(trifluoromethyl)benzylamine (20 mg, 0.082 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol). The mixture was stirred overnight at room temperature, at which point LC/MS analysis showed a new peak at the desired molecular weight. The reaction mixture was then diluted with 10 ml of saturated sodium bicarbonate solution and 10 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with 2×10 ml of ethyl acetate. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (11.9 mg, 0.018 mmol, 31.5% yield). Mass spectrum (ESI) 671.5 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.96 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.83 (s, 2H), 7.75 (s, 1H), 7.51 (s, 1H), 6.35 (br t, J=5.5 Hz, 1H), 5.30 (s, 2H), 3.85 (s, 2H), 3.48 (septet, J=6.5 Hz, 1H), 3.35 (t, J=6.5 Hz, 2H), 2.65 (t, J=6.5 Hz, 2H), 1.80 (m, 4H), 1.60 (m, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.52 (m, 1H), 0.90-1.15 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:19][O:20][C:21](=[O:26])[C:22]([NH2:25])([CH3:24])[CH3:23]>>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([NH:25][C:22]([CH3:24])([C:21]([O:20][CH3:19])=[O:26])[CH3:23])=[O:18])=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3[nH]c2c1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(=O)c3ccccc3[nH]c2c1

Procedure:
Example 128 was prepared from compound 1C by a route analogous to that used for the preparation of Example 1, replacing the amine in Step E with 2-Amino-2-methyl-propionic acid methyl ester. HPLC retention time=2.453 min./condition A.