Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].O[Li].O>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:9]=2)=[O:15])[CH:17]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a stirred solution of the product of Example 300 (140 mg, 0.29 mmol) in THF (6 mL) was added a solution of LiOH.H2O (37 mg, 88 mmol) in H2O (1 mL) and the resulting solution stirred for 2 hours at ambient temperature. The reaction was concentrated in vacuo and 1 N HCl was added to the residue. The resulting precipitate was filtered and washed with H2O. Lyopholization gave the title compound (87 mg, 59%) as a white powder. 1H NMR (300 MHz, DMSO-d6, 90° C.) δ 9.12 (d, 1H, J=2.4 Hz), 8.74 (dd, 1H, J=4.9, 1.9 Hz), 8.31 (dt, 1H, J=7.9, 1.8 Hz), 7.84 (dd, 1H, J=7.9, 1.8 Hz), 7.63 (s, 1H), 7.61 (d, 1H, J=2.4 Hz), 7.54 (dd, 1H, J=7.9, 4.9 Hz), 7.45 (d, 1H, J=7.9 Hz), 7.23-7.21 (m, 2H), 7.19-7.15 (m, 2H), 4.30-4.26 (m, 1H), 2.28-2.22 (m, 1H), 2.20-2.14 (m, 1H), 2.11 (s, 3H), 1.98 (s, 3H), 1.88-1.81 (m, 1H), 1.75-1.68 (m, 1H), MS m/z 464 (M+1)+, 446. Anal calcd for C25H25N3O4S.HCl.0.5 H2O (509.01): C, 58.99; H, 5.35; N, 8.26. Found: C, 59.38; H, 5.49; N, 7.89.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:18])[CH3:17]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-hydroxybenzophenone and acetyl chloride in pyridine and recrystallized from ethanol (M.P.~82°-83.5° C.). See J. Chem. Soc., 2867 (1927).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.[In].[C:28](O)(=O)[CH3:29].C(OC)(OC)(OC)C>C1C=CC=CC=1.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]3[N:24]=[C:28]([CH3:29])[O:23][C:16]=3[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Agent: COC(C)(OC)OC
Agent: [In]
Solvent: CO
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C)oc12
Yield: 51.8 %

Procedure:
To a solution of methyl 2-[(2,6-dichlorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (0.150 g, 0.370 mmol) in benzene (5 mL), indium (0.172 g, 1.51 mmol), acetic acid (0.468 g, 7.54 mmol) and trimethyl orthoacetate (0.480 g, 2.96 mmol) were added under N2 atmosphere. The reaction mass was refluxed for 3-4 h. A mixture of MeOH:DCM (15%) was added to the reaction mixture. The reaction mass was filtered. The organic layer was concentrated. The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH: DCM to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 2.63 (s, 3H), 3.88 (s, 3H), 7.40 (m, 1H), 7.61-7.69 (m, 3H), 9.56 (s, 1H), 11.56 (s, 1H); MS [M+H]+: 391.33.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NC(C)(C)C[C:22]1[CH:34]=[CH:33][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=1>>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:33][CH:34]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(C)(N)Cc1ccc(Oc2ccccn2)cc1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccccn2)cc1

Procedure:
Titled compound was prepared substantially in accordance with Example 118 from (S)-4-(oxiranylmethoxy)-9H-carbazole (0.375 g) and 2-(4-(2-amino-2-methylpropyl)phenoxy)pyridine (0.496 g) to yield product (0.26 g) after purification. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12]O)[C:6]=2[CH:14]=1.S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][Cl:17])[C:6]=2[CH:14]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCl
Reaction time: 7 h
Yield: 35.5 %

Procedure:
To a stirred mixture of 13 parts of 6-chloro-1,3-dihydro-1-(2-hydroxyethyl)-2H-benzimidazol-2-one in 225 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, stirring is continued for 7 hours at reflux temperature. The reaction mixture is evaporated and the residue is triturated in water. The solid product is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. It is filtered off again and dried, yielding 5 parts (35.5%) of 6-chloro-1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[N:12]1([C:18]([S:20][CH3:21])=[S:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:15]1[CH2:16][CH2:17][N:12]([C:18]([S:20][CH3:21])=[S:19])[CH2:13][CH2:14]1)([O-:3])=[O:2]
Reactant: CSC(=S)N1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To 30 ml of ethanol were added 3.43 g (20 mmol.) of 2-nitrobenzyl chloride,3.52 g (20 mmol.) of methyl 1-piperazinecarbodithioate, and 2.12 g (20 mmol.) of sodium carbonate. The mixture was then stirred for 4 hours at room temperature and futher stirred overnight at 50°-60 ° C.Ethanol was distilled off under reduced pressure, and the residue was extracted using water and chloroform. The organic solvent portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was crystallized from 40 ml of ether,collected by filtration and washed with ether, to give 4.3 g of the desiredcompound, as a yellow crystalline product, yield 69.1%.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C>O>[CH:10]1([N:16]2[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]2[CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1occc(=O)c1O
Reactant: NC1CCCCC1
Solvent: O
Product: Cc1c(O)c(=O)ccn1C1CCCCC1
Reaction time: 0.5 h

Procedure:
1-Cyclohexyl-3-hydroxy-2-methylpyrid-4-one was prepared by dissolving 10.0 g of 3-hydroxy-2-methylpyr-4-one (Maltol) and 3 equivalents (~27 ml) of cyclohexylamine (99+ %) in 200 ml of water. Decolorizing charcoal was added and the mixture was stirred for 0.5 hours. The aqueous mixture was filtered through a course frit then concentrated in vacuo, leaving an oily residue. Crystallization from hot water yielded crystals of the desired product. m.p. 199° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]#[N:26])[C:9]=1[S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28].[CH3:34][NH:35][CH2:36][CH2:37][OH:38].[Cl-].[NH4+]>CN(C)C=O>[Cl:24][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:8]([N:35]([CH2:36][CH2:37][OH:38])[CH3:34])=[C:9]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[C:10]([C:25]#[N:26])=[N:11]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
Finely powdered potassium carbonate (7.29 g, 52.2 mmol) was added to a solution of 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphonylpyrazole (10.00 g, 19.3 mmol) in dry N,N-dimethylformamide (85 ml) and stirred for 1 hour at 20° C. 2-(Methylamino)ethanol (3.11 ml, 38.7 mmol) was then added and stirring continued for 2 hours at 20° C. The resulting mixture was poured into saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer washed with water and brine, dried (sodium sulfate), evaporated and purified by column chromatography eluting with hexane and ethyl acetate (2:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(2-hydroxyethyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole as a fine white powder (5.65 g, yield 57%), 19F-NMR: −63.7, −78.4.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19]([CH2:21][CH2:22][CH2:23][OH:24])=[O:20])=[C:17]2[C:12]([N:13]([CH:28]([CH3:30])[CH3:29])[C:14](=[O:27])[N:15]([CH3:26])[C:16]2=[O:25])=[CH:11]1.ClC1C=C(C=CC=1)C(OO)=[O:36].O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19]([CH2:21][CH2:22][CH2:23][OH:24])(=[O:36])=[O:20])=[C:17]2[C:12]([N:13]([CH:28]([CH3:30])[CH3:29])[C:14](=[O:27])[N:15]([CH3:26])[C:16]2=[O:25])=[CH:11]1
Reactant: CC(C)n1c(=O)n(C)c(=O)c2c(S(=O)CCCO)n(C3Cc4ccccc4C3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)n1c(=O)n(C)c(=O)c2c(S(=O)(=O)CCCO)n(C3Cc4ccccc4C3)cc21
Reaction time: 1.25 h

Procedure:
The compound of Example 8, 6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (80 mg), was dissolved in dichloromethane (5 ml) and 3-chloroperoxybenzoic acid (57-85%) (50 mg) was added. The reaction mixture was stirred for 75 minutes then water and sodium metabisulphite (45 mg) were added and the mixture was stirred for 5 minutes. The phases were separated and the organic phase was washed with sodium bicarbonate (aqueous), then dried, filtered and evaporated. The resultant foam was recrystallised from isohexane-ethyl acetate-ether to give the title compound (15 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([NH:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:18])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1COc2ccc(C(=O)c3ccccc3C(=O)NCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 211.7 %

Procedure:
To a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)carbonylbenzoic acid (100 mg, 033 mmol) in N,N-dimethylformamide (2.00 mL) was added N-methylmorpholine (0.14 mL 1.32 mmol) followed by addition of HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.33 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of benzylamine (36 uL, 0.33 mmol). The reaction mixture was then heated to 60° C. for 18 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate the organic layer was washed with brine, 1.0 M aq. hydrochloric acid, brine, saturated aq. sodium-hydrogencarbonate and brine. The organic layer was separated dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford the title compound (0.27 g, 80%). MS (EI) for C23H18N2O4: 387 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]1=2)[CH3:2].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[CH2:14]([C:3]1([CH2:1][CH3:2])[C:4]2[CH:13]=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=[CH:10][C:5]=2[NH:6][C:7](=[O:9])[O:8]1)[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CCC1(CC)OC(=O)Nc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCC1(CC)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (6.00 g, 29.20 mmol) in a mixture of glacial acetic acid (25 mL) and concentrated sulfuric acid (25 mL) was slowly added concentrated nitric acid (5 mL). After stirring 10 minutes, the reaction mixture was quenched with a chilled brine solution (100 mL) and ice. A solid precipitated, which was collected on a filter and washed with water. After drying in vacuo, 4,4-diethyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one was obtained as a white solid (5.02 g, 69%). 1H NMR (DMSO-d6): δ 10.85 (s, 1H), 8.20 (dd, J=8.8, 2.5 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 2.14 (m, 4H), 0.79 (t, J=7.3 Hz, 6H); MS (ESI) m/z 251 ([M+H]+); MS (ESI) m/z 249 ([M−H]−); Anal. calcd for C12H14N2O4: C, 57.59; H, 5.64; N, 11.19. Found: C, 57.44; H, 5.57; N, 11.16.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[F:23])[C:11](=[O:24])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[F:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:24])[C:19]#[N:20]
Reactant: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(-n2ccc(O)cc2=O)c(F)c1
Reaction time: 6 h

Procedure:
To 4-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3-fluorobenzonitrile (250 mg, 0.780 mmol) and 10% palladium on carbon (50 mg, 0.470 mmol) was applied vacuum then placed under an atmosphere of nitrogen. Methanol (5 mL)was added and vacuum applied briefly. The reaction was placed under an atmosphere of hydrogen for 6 hours. The reaction mixture was passed through a 10×10 mm CELITE® 545 filter aid plug eluting with an additional 10 mL each of MeOH and CH2Cl2. The filtrate was concentrated to 170 mg of a pale tan foam. Added 5 mL MeOH and heated to reflux, filtered hot and rinsed with 3×2 mL warm MeOH. The filtrate was concentrated to crude product (166 mg, 0.577 mmol, 74%) as a pale yellow solid which was used as obtained in the subsequent step. MS (ESI) 231.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[C@H:22]([OH:23])[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC[C@@H]([C@@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (71 mg, 0.154 mmol)(Example 210, StepA) in THF (2 mL) was sparged with argon for 5 minutes. The mixture was cooled to 0° C. and methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (0.113 ml, 0.339 mmol) was added at such a rate that the internal temperature did not get above 4° C. The mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (2×4 g stacked columns, eluent: 5 to 15% isopropanol/hexanes) to give the title compound as the more polar diastereomer.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]1[C:8]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])=[N:9][CH:10]=[CH:11][CH:12]=1.C(O)C(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1>C(N(CC)CC)C>[Cl:25][C:26]1[N:27]=[C:28]([NH:5][CH2:6][C:7]2[C:8]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][N:31]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: OCC(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of B5 and trifluoroethanol (120 mL) was treated with triethylamine (TEA) (16.6 mL) and stirred at 25° C. for 1 hour. In a separate reaction flask, a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (13.2 g, 60.8 mmol) and trifluoroethanol (120 mL) was cooled to −45° C. The cold 2,4-dichloro-5-trifluoromethylpyrimidine solution was then treated drop-wise with the solution containing B5 and stirred at −45° C. for 2 hours. The mixture was allowed to warm to 25° C., and it was stirred at 25° C. for about 20 hours. The reaction mixture was then concentrated and cooled to 0° C. The resultant white mixture was diluted with EtOAc (15 ml), and the solids collected by filtration. The white solids were then washed with water and EtOAc to provide C9. Yield: 0.7 g, 45%. 1H NMR (400 MHz, d6-DMSO) δ: 3.07 (s, 3H), 3.29(s, 3H), 4.68 (d, 2H), 7.39 (m, 1H), 7.72 (d, 1H), 8.40 (s, 1H), 8.50 (t, 1H); ESI-MS: 396.0 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O[Li].O>C1COCC1.CO.O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 18-3 (3.4 g, 15.1 mmole), and LiOH·H2O (3.1 g, 75.5 mmol) were dissolved in THF/MeOH/H2O (30 mL/30 mL/30 mL) and stirred at room temperature overnight. The solution was diluted with EtOAc and washed with 10% KHSO4. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield 18-4 as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=3)=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[CH:23](O)=O>>[C:20]([C:16]1[CH:15]=[C:14]([N:13]2[C:9]3[CH:8]=[CH:7][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[CH:12][C:10]=3[N:11]=[CH:23]2)[CH:19]=[CH:18][CH:17]=1)([OH:22])=[O:21]
Reactant: O=CO
Reactant: Nc1cc(-c2ccoc2)ccc1Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(-n2cnc3cc(-c4ccoc4)ccc32)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
To 13r from Example 4 (2.4 g, 8.16 mmol) is added formic acid (25 ml) and the mixture is stirred at 80° C. for 1.5 hours. After cooling the mixture is poured into ice-water. The precipitate is filtered off, washed with methanol and dried to yield 14r (0.89 g, 40%). Mp 272-274° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>C(#N)C>[C:19]([S:21][C@H:11]1[CH2:12][CH2:13][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:10]1)(=[O:22])[CH3:20]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1CCN(c2nc(C(N)=O)cs2)C1
Yield: 76.3 %

Procedure:
To a solution of (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (190 mg, 0.652 mmol) (obtained as described in Reference Example 18(7)) in acetonitrile (6 ml) was added potassium thioacetate (223 mg, 1.96 mmol) at room temperature. The mixture was heated under reflux for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate→2% methanol in ethyl acetate as the eluant to afford (3S)-3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (135 mg, yield 77%) as a pale brown solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:32][CH2:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)[N:17]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Reactant: NCc1cccc(F)c1
Solvent: CS(C)=O
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 105 °C
Reaction time: 40 h

Procedure:
A mixture of N-(trans-4-(aminomethyl)cyclohexyl)-5′-chloro-6-fluoro-2,4′-bipyridin-2′-amine (15 mg, 0.045 mmol), DMSO (0.35 ml), TEA (0.012 ml, 0.090 mmol) and (3-fluorophenyl)methanamine (50.5 mg, 0.403 mmol) reaction mixture was flushed with argon and then stirred at about 105° C. for about 40 hours. The excess (3-fluorophenyl)methanamine was removed under reduced pressure to yield a crude material, which was mixed with 0.5 ml DMSO, filtered, purified by prep LC, and then lyophilized to yield 11.2 mg of the title compound, as a TFA salt. LCMS (m/z): 440.2(MH+), retention time=0.62 min. 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.11-1.28 (m, 2 H) 1.28-1.47 (m, 2 H) 1.67 (ddd, J=10.92, 7.40, 3.66 Hz, 1 H) 1.92 (d, J=11.72 Hz, 2 H) 2.14 (d, J=10.55 Hz, 2 H) 2.83 (d, J=6.74 Hz, 2 H) 3.57-3.69 (m, 1 H) 4.63 (s, 2 H) 6.84 (d, J=8.79 Hz, 1 H) 6.90 (s, 1 H) 6.94 (d, J=7.03 Hz, 1 H) 6.96-7.03 (m, 1 H) 7.10 (d, J=9.96 Hz, 1 H) 7.18 (d, J=7.62 Hz, 1 H) 7.29-7.39 (m, 1 H) 7.69-7.77 (m, 1 H) 8.01 (s, 1 H)