Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 4-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (15-3, 0.40 g, 1.22 mmol) in THF (6.1 mL) was added triethylamine (0.370 g, 3.65 mmol) followed by isonicotinoyl chloride hydrochloride (0.430 g, 2.42 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was purified by column chromatography on silica gel (EtOAc:hexanes=5:1 as eluant) to give N-(4-(4-(5-methoxypyrazin-2-yloxy)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (15, 0.12 g) as yellow solids in 23% yield: 1H NMR (500 MHz, CDCl3) δ 8.87 (d, J=5.0 Hz, 2 H), 8.03 (d, J=6.5 Hz, 2 H), 7.96 (s, 1 H), 7.91 (s, 1 H), 6.81 (s, 3 H), 3.97 (s, 3 H), 2.08 (s, 6 H). ESI-MS: m/z 433.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[S:21][CH3:22].I([O-])(=O)(=O)=[O:24].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:22][S:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=1)=[O:24]
Reactant: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccncc2S(C)=O)nc2cc(C(F)(F)F)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a mixture of 0.49 g of 1-methyl-2-(3-methylthiopyridine-4-yl)-5-trifluoromethyl-1H-benzimidazole, 5 ml of methanol and 10 ml of water was added 0.65 g of sodium periodate under ice cool, then, the mixture was stirred for 1 hour at 40° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium thiosulfate aqueous solution were poured, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 2-(3-methanesulfinylpyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 18).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:35]=2[CH3:36])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][C:35]=4[CH3:36])[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1cccc(C2=Nc3cc(C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M213) (291 mg, 0.552 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (182 mg, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([C:39]([F:42])([F:41])[F:40])[CH2:36][C@H:35]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([C:39]([F:41])([F:40])[F:42])[CH2:36][C@H:35]([NH:43][C:44]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:50])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.45 g, 1.2 mmol) and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL), DIPEA (0.65 mL, 3.7 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.492 g, 53%). LCMS calc. for C34H35BrF3N6O5 [M+H]+: m/z=743.2. found: 743.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])(C)(C)C.C(C1C=CC(S([N:41]=[N+:42]=[N-:43])(=O)=O)=CC=1)CCCCCCCCCCC.[NH4+].[Cl-]>O1CCCC1>[N:41]([C:4]1[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[N+:42]=[N-:43]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a −78° C. solution of N-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) in tetrahydrofuran (25 mL) was added tert-butyllithium (1.31 mL of a 1.7 M solution, 20.5 mmol) drop wise. After 3 h at −78° C., 4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at the reaction was allowed to warm to room temperature. After 1 h, saturated aqueous NH4Cl was added, and the tetrahydrofuran was removed via rotary evaporator. Dichloromethane was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by two successive silica gel chromatographies (10%→80% EtOAc/hexanes, then 5%→42% EtOAc/hexanes) to give the title compound (0.275 g). MS 234.0 (M+1).
Reaction SMILES: C([NH:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1)C1C=CC=CC=1.Cl>C(O)C.CO.[Pd]>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1
Reactant: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 81 %

Procedure:
A solution of 750 mg (1.28 mmol) N-(6-benzylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (Example 73, step d) in 25 ml of a 5 N solution of hydrochloric acid in ethanol was evaporated to dryness and the residue was dissolved in 30 ml methanol and hydrogenated in the presence of 60 mg 10% palladium on activated charcoal (room temperature, 10 bar) for 20 h. After filtration of the catalyst and evaporation of the solvent the residue was dissolved in 30 ml ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Evaporation of the solution afforded 514 mg (81%) of the title compound as light brown crystals.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C:13](=O)[C:12]=2[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].[ClH:30].Cl.O>C(O)C>[ClH:30].[C:1]([N:9]1[C:17]2[CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C:13](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[C:12]=2[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Cc2c1ccn2C(=O)c1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2c1ccn2C(=O)c1ccccc1
Yield: 94.4 %

Procedure:
A mixture of 1-benzoyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.68 g), aminoguanidine hydrochloride (0.26 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water to give crystals, which were recrystallized from ethanol to give 1-benzoyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 11) (0.83 g) as colorless crystals.
Reaction SMILES: [C:1](OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:18])[CH3:17]>C1(C)C=CC=CC=1>[C:1]([O:18][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CCCCN
Reactant: COC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(CCCCN)OC(=O)c1ccccc1
Yield: 66 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (1.0 mmol), 6-aminohexan-2-ol (1.2 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and toluene (1.7 ml) was heated to reflux for 46 hours, and as a result, 6-amino-2-hexyl benzoate was obtained at a yield of 66%. The yield of 6-benzoylamino-2-hexyl benzoate was 21%.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12]([O:14][C:15](=[O:16])[C:5]3=[CH:4][CH:3]=1)=O)[CH:8]=[CH:9][CH:10]=2.[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:21]=1[NH2:22])([CH3:19])[CH3:18]>CN1CCCC1=O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Br:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:14])[N:22]([C:21]4[C:23]([CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=[CH:26][C:20]=4[CH:17]([CH3:19])[CH3:18])[C:15](=[O:16])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Yield: 60.1 %

Procedure:
27.7 g of 4-bromonaphthalene-1,8-dicarboxylic anhydride, 19.0 g of 2,6-diisopropylaniline and 9.2 g of anhydrous zinc acetate in 65 ml of N-methylpyrrolidone were heated at 200° C. for 3 hours. After cooling, the precipitate formed was filtered off, washed and dried to give 26.2 g of 4-bromo-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide having a melting point of 277° C.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26](=[O:28])[NH:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with triphosgene, NEt3 in THF at room temperature. A white solid was isolated, mp. 184–186° C. Anal. For C21H27N3O2 calc. C, 71.36; H, 7.70; N, 11.89; found: C, 71.09; H, 7.75; N, 11.63.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(=O)(O)[O-:22].[Na+].C(OO)(C)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][C:17](=[O:22])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Reactant: O=C([O-])O
Agent: CC(C)(C)OO
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.4 %

Procedure:
To a solution of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindine (76.0 mg, 0.27 mmol) and dirhodium(II, III) tetrakis caprolactamate (1.8 mg, 0.0027 mmol; synthesis described in M. P. Doyle et al., J. Am. Chem. Soc. 1993, 115, 958-964) in dichloromethane (0.5 mL) was added sodium bicarbonate (22.7 mg, 0.27 mmol) and tert-butyl hydroperoxide (0.25 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 48 h. During this time period additional equivalents of tert-butyl hydroperoxide (1.25 mL, 6.75 mmol) were added in small portions. The solvent was removed under reduced pressure and the crude reaction mixture purified by flash chromatography (20 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc-heptane gradient to provide 15.5 mg (19%) of 4-(3-fluoro-4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one (intermediate A-14 [C1]) as slightly yellow solid; MS: 296.1 (M+H)+; and 17.4 mg (22%) of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-14 [C2]) as slightly yellow solid. MS: 296.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(Cl)(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
[7-(Methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (2.31 g, 10.65 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.15 g, 15.98 mmol) were stirred in a 1:1 mixture of chloroform and methanol (140 ml) for 1 h at rt under argon. This mixture was then treated with NaBH(OAc)3 (10.16 g, 47.93 mmol) and stirred for a further 45 mins. The solvents were then removed from the reaction and crude residues purified by column chromatography on silica gel using a 0-35% MeOH/DCM gradient, to give the desired product (2.0 g; 47%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10]2)[C:5]([Cl:20])=[CH:4][N:3]=1.CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]#[N:34]>>[C:33]([CH2:32][N:15]([C@@H:11]1[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)[S:16]([CH3:19])(=[O:18])=[O:17])#[N:34]
Reactant: N#CCBr
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(CC#N)[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
rel-N-[(1R,3R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (400 mg, 1.18 mmol) was dissolved in acetone (15.0 mL, 204 mmol) and cesium carbonate (576 mg, 1.77 mmol) was added. After 15 min, bromoacetonitrile (130 uL, 1.86 mmol) was added and the mixture stirred at room temperature for 4 days. LCMS analysis showed that the reaction had only gone to 50% completion. A second aliquot of bromoacetonitrile (90.4 uL, 1.30 mmol) was added and the reaction was heated at 45° C. overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in DCM (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide as a white foam (261 mg, 58%). LCMS (m/e) 378 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 5.32 (d, 1H, J=7.3 Hz), 4.34-4.07 (m, 3H), 3.97-3.85 (m, 1H), 3.08 (s, 1H), 2.49-2.39 (m, 1H), 2.17-2.08 (m, 1H), 2.03-1.94 (m, 2H), 1.62-1.45 (m, 3H), 1.30-1.15 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O.C1(C)C=CC=CC=1.[OH-].[Na+]>CN(C)C=O>[Cl:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCl)cn1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of (6-methoxypyridin-3-yl)methanol (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23° C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>O1CCOCC1>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:11]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-n2cc(C#N)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)c1ccc(-n2cc(C#N)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
1-(4-acetylphenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (30 mg, 0.079 mmol) and sodium borohydride (5.97 mg, 0.158 mmol) were stirred in dioxane (1 mL) at 60° C. overnight. Additional sodium borohydride (5.97 mg, 0.158 mmol) was added and stirring at 60° C. continued for 24 hours. Room temperature was attained, water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in DCM to give 1-[4-(1-hydroxyethyl)phenyl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][CH:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:19]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)[CH3:18])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To a stirred mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (4.99 mmol, 1.170 g), tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (4.99 mmol, 1 g) and triethylamine (11.98 mmol, 1.670 mL, 1.213 g) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.99 mmol, 1.149 g). The reaction was stirred for 20 hours. Chromatography on silica (eluting with a gradient of dichloromethane to ethyl acetate) gave the intermediate tert-butyl 3-(4-(3-(cyclopropylmethyl)ureido)-N-methylbenzamido)-pyrrolidine-1-carboxylate (2 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].CI>CS(C)=O>[Cl:7][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: O=C(O)c1ccncc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
Potassium carbonate (36.3 g, 263 mmol) was added to 3-chloroisonicotinic acid (10.35 g, 65.7 mmol) in DMSO (50 mL). After 30 min, MeI (8.22 mL, 131 mmol) was added. The mixture was stirred at room temperature for 2 h, quenched with saturated NH4Cl (300 mL) and water (200 mL), and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine (2×50 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes, gave methyl 3-chloroisonicotinate as a colorless liquid (6.275 g, 56% yield). MS (ES+) m/z: 172 (M+H); LC retention time: 2.45 min (analytical HPLC Method A).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1cccnc1
Reactant: CCCCC#CCCCCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1cccc(C)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 3-picoline (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 3-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (82%). 1HNMR (300 MHz, CDCl3, ppm) 9.36 (s, 1H), 9.18 (d, 1H), 8.24 (d, 1H), 8.00 (dd, 1H), 4.92 (t, 2H), 2.62 (s, 3H), 1.95-2.18 (m, 6H), 1.15-1.25 (br, 10H), 0.90 (t, 3H); 13CNMR, 145.51, 144.12, 144.78, 139.46, 127.56, 80.44, 79.42, 61.75, 31.72, 31.16, 28.65, 28.04, 25.52, 21.92, 18.75, 18.55, 18.40, 13.63.