Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[OH:23][C:24]1[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH2:29]1)=[O:27]>>[CH3:45][O:44][C:42]([C:39]1[CH:40]=[CH:41][C:24]([O:23][CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)=[C:25]([CH:38]=1)[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:33]1)=[O:27])=[O:43]
Reactant: BrCCCc1ccc(OCCCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-(5-(methoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}-benzoyl)-4-piperidinecarboxylate is prepared in analogy to the process described in Example 2 from 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene and methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-hydroxy-phenyl)-nicotinonitrile (Preparation 18) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (112 mg, 64.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[NH:8][C:7]2=O.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:8]=1
Reactant: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Cl)cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Cl)c3n2)nc1
Temperature: 115 °C
Yield: 111 %

Procedure:
To 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4(3H)-one (250 mg, 0.77 mmol) were added DIEA (0.28 mL, 1.53 mmol) and phosphorous oxychloride (5.3 mL, 57 mmol), and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. Toluene was added and evaporated twice, and the residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL). The separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (2×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline as a brown viscous oil (294 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[CH:17]([CH:20]1[O:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][O:21]1)([CH3:19])[CH3:18]>CC(N(C)C)=O>[CH:17]([CH:20]1[O:25][CH2:24][CH:23]([C:26]([NH:1][C:2]2[C:10]([I:11])=[C:6]([C:7]([Cl:9])=[O:8])[C:5]([I:12])=[C:4]([C:3]=2[I:16])[C:13]([Cl:15])=[O:14])=[O:27])[CH2:22][O:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)C1OCC(C(=O)Cl)CO1
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CC(C)C1OCC(C(=O)Nc2c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c2I)CO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
137 g of 5-amino-2,4,6-triiodoisophthaloyl chloride (0.23 mole) are dissolved in 460 ml of DMAC to which are added 110 g (0.57 mole) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride. The reaction mixture is stirred under argon at ambient temperature for 4 days. The DMAC is removed in a vacuum. The oil obtained is extracted with 3 l of ethyl acetate and washed twice with 1 l of ice-cold water. The organic phase is dried and concentrated to dryness. The product is crystallized from 200 ml of CH2Cl2. After filtration, 110 g of solid are obtained:
Reaction SMILES: [CH3:1][C:2]1O[C:6]([CH2:8][OH:9])=[CH:5][C:4](=[O:10])[C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH3:1][C:2]1[N:22]([OH:23])[C:6]([CH2:8][OH:9])=[CH:5][C:4](=[O:10])[C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(COc2c(C)oc(CO)cc2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2c(C)n(O)c(CO)cc2=O)cc1
Reaction time: 7 h
Yield: 30.8 %

Procedure:
To a solution of 4 g of 6-methyl-5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone in 50 ml of pyridine was added 5 g of hydroxylamine hydrochloride at room temperature. The mixture was stirred at 70° to 75° C. for 7 hours. After the reaction liquid was concentrated under reduced pressure, the residue was dissolved in 600 ml of chloroform and washed in succession with water and saturated aqueous sodium hydrogencarbonate solution. After drying the chloroform layer over anhydrous magnesium sulfate, the organic phase was dried and concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (manufactured by Wako Pure Chemical Industry Co., Ltd.) (100 g) to give 1.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37].[C:40](N1C=CN=C1)(N1C=CN=C1)=[O:41].C(N(CC)CC)C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[O:25][C:40](=[O:41])[NH:27][N:26]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(=O)NN)C1c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2n[nH]c(=O)o2)C1c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 343 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 6.9 ml of THF was cooled to 0° C., and 116 mg of 1,1′-carbonyldiimidazole and 0.12 ml of triethylamine were added thereto, followed by stirring at 0° C. for 2 hours, and then stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 221 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[O:18][CH3:19])#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:5][C:4]=1[O:18][CH3:19])#[N:2]
Reactant: COc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)OC(C)(C)C)ccc1C#N
Yield: 99.2 %

Procedure:
To a solution of tert-butyl 3-(4-cyano-3-methoxyphenyl)acrylate obtained in step 1 (3.5 g) in ethyl acetate (150 mL) was added palladium on carbon (500 mg) and the mixture was put under a pressure of 4 kg of hydrogen for 12 h at RT. The catalyst was removed by filtration and the solvents were removed under vacuum to afford the title compound as white solid (3.5 g, 97%). 1H-NMR (CDCl3, 400 MHz) δ 7.41-7.43 (1H, s), 6.80-6.83 (2H, m), 3.88 (3H, s), 2.89-2.93 (2H, t), 2.51-2.55 (2H, t), 1.34 (9H, s). LC/MS: 279.1 (M+H)+. HPLC (Method C) Rt 2.40 min (Purity: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:32])[N:13]2[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].[CH3:33][C:34]([CH3:36])=O.C([BH3-])#N.[Na+]>CO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:19][CH2:20][N:21]([CH:34]([CH3:36])[CH3:33])[CH2:22][CH2:23]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:32])[N:13]2[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(C)=O
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(C3CCNCC3)cc2n1-c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 14 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-piperidin-4-yl-1,6-naphthyridin-2(1H)-one in 1 mL of MeOH was added 0.1 mL of acetone, then 9 mg of sodium cyanoborohydride. The mixture was stirred 5 h at rt, then diluted with 1 mL of EtOAc and 10 mL NaHCO3. The phases were separated and the aqueous phase was extracted with 2×10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH to yield the title compound. Mass spectrum (ESI) 528 (M+1). 1H NMR (500 MHz, CDCl3): selected peaks δ 1.07 (d, J=6.5 Hz, 6H), 1.71 (br s, 2H); 1.99 (br s, 2H); 2.26 (br s, 2H); 2.80 (br s, 2H); 3.02 (br s, 2H).
Reaction SMILES: [C:1]([NH2:5])(=[S:4])[CH2:2][CH3:3].Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[CH2:2]([C:1]1[S:4][C:7]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:5]=1)[CH3:3]
Reactant: CCC(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Yield: 84.2 %

Procedure:
In 40 ml of acetonitrile was dissolved 493 mg of thiopropionic acid amide. In the solution was suspended 2.15 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone. To the suspension was added dropwise slowly 0.78 ml of triethylamine while stirring. The mixture was stirred for 3 hours at a refluxing temperature, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried, then the solvent was evaporated off. The residue was recrystallised from ethyl acetate-isopropyl ether to yield 1.38 g (91%) of 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 59°-60° C.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[CH2:15]([O:22][C:23]([NH:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][C@@H:31]([C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])[NH2:32])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]([NH:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][C@@H:31]([C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])[NH:32][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@@H](CCSCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccc(Cl)cc1
Product: O=C(NCCSCC[C@H](NC(CCc1ccc(Cl)cc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1

Procedure:
In the manner described in Examples 3, 5 and 6, 2-oxo-4-(4-chlorophenyl)butyric acid and N-[S-(2-benzyloxycarbonylaminoethyl)-L-homocysteinyl]-L-proline were condensed to afford N-[S-(2-benzyloxycarbonylaminoethyl)-N-{1-carboxy-3-(4-chlorophenyl)propyl}-L-homocysteinyl]-L-proline. This reaction was followed by the removal of the carbobenzoxy group with 30-32% HBr in glacial acetic acid to give N-[S-(2-aminoethyl)-N-{1-carboxy-3-(4-chlorophenyl)propyl}-L-homocysteinyl]-L-proline in 67% yield; a white solid on freeze drying; ms (trimethylsilyl): 672 (M+3TMS-15), 600 (M+2TMS-15), 570 (M+2TMS-CO2H), 498 (M+1TMS-CO2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:19](=[O:21])[CH3:20])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Sc2cccc(N)c2)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared using 3-(4-Methyl-2-nitro-phenylsulfanyl)-phenylamine (8.20 g, 31.50 mmol) and acetyl chloride (2.72 g, 34.65 mmol) dissolved in CH2Cl2. This was stirred at room temperature for 2 hrs at which time the title compound was collected by filtration (8.78 g, 92
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][N:44]1[C:52]2[CH:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][NH:62][CH2:63][CH3:64])=[C:55]([C:65]([F:68])([F:67])[F:66])[CH:54]=3)[N:49]=[C:48]([C:69]#[N:70])[C:47]=2[N:46]=[CH:45]1>ClCCl>[C:69]([C:48]1[C:47]2[N:46]=[CH:45][N:44]([CH3:43])[C:52]=2[CH:51]=[C:50]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][N:62]([CH2:63][CH3:64])[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[O:9])=[C:55]([C:65]([F:68])([F:66])[F:67])[CH:54]=2)[N:49]=1)#[N:70]
Reactant: CCNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.5 %

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(ethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (55 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (40 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]([CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH3:32])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCCOC
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3OC)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.04 (m, 2H) 3.09 (d, J=7.3 Hz, 3H) 3.21 (s, 2H) 3.36 (s, 2H) 3.43-3.56 (m, 2H) 3.65 (t, J=6.9 Hz, 1H) 3.98 (s, 3H) 7.31-7.36 (m, 2H) 8.05 (br. s., 1H) 8.28-8.64 (m, 3H). MS m/z [M+H]+ 422.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[C:23]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:22][C:21](F)=[CH:20][N:19]=1)=[O:17].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCOC(C)=O>[F:35][C:33]1[CH:32]=[C:4]([CH:3]=[C:2]([F:1])[CH:34]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[C:23]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:22][C:21]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[CH:20][N:19]=1)=[O:17]
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ncc(F)cc1NC1CCOCC1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cnc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1

Procedure:
A solution of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-fluoro-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide (925 mg, 1.92 mmol) and N-methylpiperazine (20 mL) was stirred at 60° C. for 48 hours. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 sat. sol. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography on silica gel using DCM/EtOH/NH3 5N in MeOH 100:5:0.5 as the eluant, affording 600 mg of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:20])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: c1cc(C2CO2)ccn1
Reactant: C=CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-allyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (1000 mg, 4.42 mmol) in DMF (10 mL) was portionwise added sodium hydride (526 mg, 13.26 mmol). After stirring at RT for 5 min., 4-(oxiran-2-yl)pyridine (669 mg, 5.31 mmol) was added dropwise into the reaction mixture, which was stirred at RT for 16 h. Ice water was added into the reaction mixture and the solid mass obtained was filtered, washed with water (2×10 mL), hexane (2×50 mL) and ether to yield 2-(2-allyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.6 (d, 2H), 7.24 (s, 1H), 7.2 (d, 2H), 7.0 (d, 2H), 5.98 (m, 1H), 5.2 (dd, 2H), 5.0 (m, 1H), 4.1 (m, 2H), 3.6 (dd, 2H), 3.22 (d, 2H), 2.7-2.9 (m, 3H), 2.6 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers II-63a-b.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([S:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Sc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Sc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenylsulfanyl-pyridine.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].O.[Br:11][CH:12]([CH3:16])[C:13](Br)=[O:14]>C(Cl)(Cl)Cl>[Br:11][CH:12]([CH3:16])[C:13]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)NC(C)(C)C(=O)O
Temperature: -12 °C
Reaction time: 17 h
Yield: 70.4 %

Procedure:
To a stirring mixture of 2-aminoisobutyric acid (52.08 g; 0.51 mol), sodium hydroxide (20.20 g; 0.51 mol), 200 mL water and 50 mL chloroform cooled to −12° C., was added a solution of 2-bromopropionyl bromide (100 g; 0.463 mol) in 150 mL chloroform. The temperature was maintained between −15 to −12° C. during the addition. The reaction mixture was then allowed to warm to room temperature and stirred for 17 hours. The precipitated solid was filtered, mixed with 700 mL hot toluene, then cooled to room temperature. The solid was filtered and dried under vacuum to afford 77.6 g (70%) of product.
Reaction SMILES: CO[N:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[NH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1
Reactant: CON=C(Cc1ccc(Br)cc1)c1ccccc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: NC(Cc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the mixture of oxime isomers 8 (4.92 g, 16.2 mmol) in 75 ml THF (freshly distilled from sodium benzophenone ketyl) under nitrogen was added borane-tetrahydrofuran complex (1.0M in THF, 55.0 ml, 55.0 mmol) by syringe at room temperature. The resulting pale orange solution was brought to reflux and held there for 16 hours. With cooling by an ice bath, water (125 ml) was carefully added to quench, followed by 20% NaOH (125 ml).The resulting biphasic solution was refluxed with vigorous magnetic stirring overnight. After cooling to room temperature, hexanes (60 ml) were added and the layers were separated. The aqueous portion was extracted with hexanes (2×50 ml). The combined organic portions were dried over potassium carbonate and concentrated in vacuo to a cloudy, colorless syrup. This syrup was purified by column chromatography on 20 g neutral alumina (activity I) using a 20% ethyl acetate-hexanes to 4% diethylamine-chloroform elution gradient. The amine 13 was isolated as 3.985 g of a clear, colorless syrup (89% yield): Rf 0.18 (2% diethylamine in CHCl3); 1H NMR (CDCl3) δ7.41 (d, J=8.2 Hz, 2H), 7.35-7.28 (m, 5H), 7.03 (d, J=8.2 Hz, 2H), 4.18 (dd, J=8.2, 5.3 Hz, 1H), 2.97 (dd, J=13.3, 53 Hz, 1H), 2.83 (dd, J=13.3, 8.3 Hz, 1H), 1.45 br s, 2H); low resolution mass Spec. 277 (M+, 1.5), 275 (M+, 1.5), 261 (2.2), 259 (2.2), 171, (4.5), 169 (4.5), 106 (100), 79 (45).