Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([C:7]([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27].O>CN(C=O)C>[CH3:24][N:25]([CH3:30])[S:26]([N:11]1[CH:12]=[N:13][C:9]([C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)=[N:10]1)(=[O:28])=[O:27]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cnc(C(=O)c2ccc(C(F)(F)F)cc2)n1
Yield: 69.2 %

Procedure:
0.31 g of 3- (4-trifluoromethylbenzoyl)-1,2,4-triazole was dissolved in 3 ml of DMF, 0.21 g of potassium carbonate was added thereto, and then 0.22 g of dimethylsulfamoyl chloride was added at room temperature with stirring. After stirring the reaction mixture for 1.5 hours at room temperature, water was added to precipitate crystals, and the crystals were collected by filtration and washed with diethyl ether. Drying of the mixture under reducing pressure afforded 0.31 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCCl.C(Cl)(Cl)Cl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:3]=[C:4]([C:10]2[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[N:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1N
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1N(S(C)(=O)=O)S(C)(=O)=O

Procedure:
To a solution of 3,4-dihydro-6-(3-amino-4-methoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.39 g) in 1,2-dichloroethane (5 ml) were added methanesulfonyl chloride (0.40 ml) and triethylamine (0.52 ml) successively, and the mixture was refluxed for 2.5 hours. After cooling, the reaction mixture was dissolved in chloroform, and washed with water. The organic layer was dried over magnesium sulfate, evaporated, and crystallized from ethanol to give 3,4-dihydro-6-[3-(dimethanesulfonylamino)-4methoxyphenyl]-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2-(1H)-pyrimidinone (0.33 g).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][N:36]([C:9]([C:8]1[CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([O:15][CH3:16])=[CH:6][C:7]=1[O:13][CH3:14])=[O:11])[CH2:35]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3-dihydro-1H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (×2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)methanone as a beige solid (3 g). 1H NMR (Me-d3-OD) 7.60-7.13 (3H, m), 7.14 (1H, s), 6.71 (1H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:15]1[CH2:16][C:17]([C:27](=[O:28])[N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:8]3[CH:9]=[CH:10][C:5]([CH2:3][C:36]([O:37][CH2:3][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:39])=[CH:6][CH:7]=3)=[CH:22][C:20]=2[N:21]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCc4ccccc4)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 33 %

Procedure:
Benzyl 2-(4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate (33%) was prepared as follows, substituting benzyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. m/z (APCI-pos) M+1=510.3.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].I[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1>>[NH2:1][C:2]1[C:3]([C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: COc1cccc(I)c1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Product: COc1cccc(C(=O)c2ccc(Cl)nc2N)c1

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 3-iodoanisole (Aldrich) using the procedure described in Example 7. HRMS, observed: 262.0514, Calcd for M+: 262.0509.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.6 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.0 g, 3.7 mmol) and benzaldehyde (0.4 ml, 3.9 mmol) in acetic acid (20 ml) was stirred at room temperature for 17 h, then was heated to reflux for 3 h. The mixture was cooled to room temperature. To the stirred mixture was added sodium borohydride (140 mg, 3.7 mmol) and kept at room temperature for 18 h. The mixture was then heated to reflux for 2 h. To the mixture was added additional benzaldehyde (0.4 ml, 3.9 mmol) during reflux. After 30 min of reflux the reaction was allowed to cool to room temperature. To the mixture was added sodium borohydride (180 mg, 4.8 mmol) and the mixture stirred at room temperature for 3 days. The solvent was removed in vacuo to yield an oil. The oil was diluted with ethyl acetate (90 ml) and aqueous sodium hydrogen carbonate (sat, 100 ml). The organic layer was separated and was washed with aqueous sodium hydrogen carbonate (sat, 2×100 ml), brine (100 ml) and dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2) to give a yellow solid. The solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water) to give 2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione as a yellow solid (210 mg, 16% yield): mp, 209-211° C.; 1H NMR (DMSO-d6) δ 2.02-2.08 (m, 1H, CHH), 2.46-2.63 (m, 2H, CH2), 2.82-2.97 (m, 1H, CHH), 4.56 (d, J=6.2 Hz, 2H, CH2), 5.07 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.96 (d, J=8.6 Hz, 1H, Ar), 7.02 (d, J=7.0 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar, NH), 7.51 (dd, J =7.5, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.15, 30.99, 45.44, 48.59, 109.58, 110.74, 117.63, 126.95, 126.99, 128.53, 132.21, 136.09, 138.95, 146.09, 167.27, 168.78, 170.07, 172.79; Anal Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C, 65.96; H, 4.60; N, 11.49.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(Cl)=[O:11].[Cl-].[O:15]=[C:16]1[NH:20][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][N:17]1[CH:27]1[CH2:32][CH2:31][NH2+:30][CH2:29][CH2:28]1.[NH2:33][C@@H:34]1[CH2:40][CH2:39][CH2:38][C@H:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:36]([CH2:47][CH:48]2[CH2:50][CH2:49]2)[C:35]1=[O:51]>ClCCl>[CH:48]1([CH2:47][N:36]2[C@@H:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:38][CH2:39][CH2:40][C@@H:34]([NH:33][C:10]([N:30]3[CH2:31][CH2:32][CH:27]([N:17]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:20][C:16]4=[O:15])[CH2:28][CH2:29]3)=[O:11])[C:35]2=[O:51])[CH2:49][CH2:50]1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CC[NH2+]CC1
Reactant: N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
Diisopropylethylamine (0.020 mL, 0.11 mmol) and phosgene (0.06 mL, 0.56 mmol) were added to a solution of 4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidinium chloride (27 mg, 0.111 mmol) in dichloromethane (1 mL) at 0° C. After 30 min, the mixture was concentrated in vacuo and azeotroped with dichloromethane (2×) to give the crude amine. Diisopropylethylamine (0.04 ml, 0.22 mmol) was added to a solution of the crude amine and (3R,7R)-3-amino-1-(cyclopropylmethyl)-7-phenylazepan-2-one (28.7 mg, 0.11 mmol) in dichloromethane (1 mL) and the mixture heated to reflux. After 15 min, the mixture was concentrated and purified by silica gel chromatography (1% methanol/dichloromethane—5% methanol/dichloromethane) gave the title compound (38 mg). MS 528.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.Cl.[NH2:12][OH:13]>C(O)C>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[N:12][OH:13])[CH2:6]2
Reactant: NO
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Product: CN1C2CCC1CC(=NO)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
A 500-mL one-neck round-bottomed flask equipped with a magnetic stirrer was charged with 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (5.00 g, 35.9 mmol), hydroxylamine hydrochloride (7.08 g, 102 mmol) sodium acetate (39.0 g, 476 mmol) and ethanol (45 mL). After stirring at ambient temperature for 4 h, the reaction mixture was evaporated to a solid residue. This residue was triturated with ethyl acetate (200 mL) and filtered. Evaporation of the filtrate to dryness gave 5.08 g (93% yield) of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one oxime as a white solid: mp 140-142° C.; 1H NMR (300 MHz, CD3OD) δ 3.76 (m, 2H), 3.33-3.23 (m, 2H), 2.75 (m, 1H), 2.69 (s, 3H), 2.46-2.14 (m, 4H), 1.88-1.66 (m, 2H); MS (APCI) m/z 155 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(C=O)cc1
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(C)cc1

Procedure:
Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119°C (ethyl acetate/petroleum ether) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](O)=[O:27])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:25])([CH3:24])[C:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:27])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCOCC3)c1)N2
Yield: 90.7 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), morpholine (0.53 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 36 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.87 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C28H37N3O4 (M+H)+: 480.62, observed: 480.1.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7].N1C=CC=CC=1.C(OCC)C>C1C=CC=CC=1>[C:6](=[O:7])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:4][CH2:3][CH2:2][I:1]
Reactant: OCCI
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCOC(=O)OCCI
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a well-stirred solution consisting of 17.89 g. (0.104 mole) of 2-iodoethanol dissolved in 25 ml. of benzene precooled to 0° C. with the aid of an ice/water bath, there is added in a dropwise manner a solution consisting of 20 g. (0.104 mole) n-octyl chloroformate dissolved in 25 ml of benzene. Upon completion of this step, the reaction mixture is treated with 8.3 ml (0.104 ml.) of pyridine which is also added in a dropwise manner. The resulting suspension is then stirred for 30 minutes at 0° C. and thereafter for a period of five hours at room temperature while under a nitrogen atmosphere. At the end of this time, 100 ml. of diethyl ether is added to the mixture and the precipitated pyridine hydriodide is then removed by filtration. The organic filtrate is thereafter washed twice with 3N hydrochloric acid and once with brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there is obtained 2-iodoethyl n-octyl carbonate as the residual material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][OH:18])=[C:10]([C:13]([F:16])([F:15])[F:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:12][S:11][C:10]=1[C:13]([F:14])([F:15])[F:16])(=[O:29])=[O:28]
Reactant: OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methanol (500 mg, 1.71 mmol, 1.00 equiv), triethylamine (521 mg, 5.15 mmol, 3.01 equiv), dichloromethane (10.0 mL). This was followed by the addition of MsCl (390 mg, 3.42 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 0.5 h at 25° C. The reaction progress was monitored by TLC(ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 675 mg of [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate as a light yellow solid. The crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C13H10C1F3O3S2, 371.0 (M+H). found 371.0.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN[C@@H]3CCN(Cc4ccccc4)C3)cc2)nc1
Yield: 30.9 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), (3R)-1-benzylpyrrolidin-3-yl amine (0.22 mL, 1.27 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.154 g (31%) of the title compound as a white foam (chromatography solvent: ethyl acetate→4:1 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C24H27N4O, 403.2134, found 403.2131; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H), 7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J−12.7 Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t, 2H, J=6.8 Hz), 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CC1(C)O[C:31](=[O:33])[C:30](=[CH:34][NH:35][C:36]2[C:40]([CH3:41])=[CH:39][S:38][CH:37]=2)C(=O)O1>>[CH3:41][C:40]1[C:36]2=[N:35][CH:34]=[CH:30][C:31]([OH:33])=[C:37]2[S:38][CH:39]=1
Reactant: Cc1cscc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1csc2c(O)ccnc12
Temperature: 235 °C
Reaction time: 0.08 h
Yield: 101.9 %

Procedure:
A solution of Dowtherm A (7 mL) was heated in oil bath at 235° C. under nitrogen. 2,2-Dimethyl-5-((4-methylthiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (5.0 g, 19 mmol) was added in portions over a 20 minutes period. After the last portion was added, the solution stirred at 235° C. for another 5 minutes. The solution was removed from the oil bath and allowed to cool to ambient temperature. Upon cooling, the product precipitated out of solution. Diethyl ether was added and the solid was filtered and dried to give the title compound (3.2 g) with residual amounts of Dowtherm A remaining.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CC[N:37](C(C)C)C(C)C.N>C(#N)C>[C:8]([C:7]1[N:6]=[N:5][C:4]([S:13][CH3:14])=[N:3][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)(=[O:10])[NH2:37]
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: N
Solvent: CC#N
Product: CSc1nnc(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (1.20 g, 5.15 mmol) in acetonitrile (40 mL) was added tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.14 g, 7.73 mmol) and then DIEA (1350 μL, 7.73 mmol). The mixture was stirred at RT for 1 hour. To the mixture was then added ammonia (7.0 N solution in methanol, 30 mL). The mixture turned cloudy in 10 min and then into a suspension. The mixture was stirred for 8 hours, and the solid was isolated by filtration. It was washed with cold acetonitrile (10 mL×2) and then washed with hexane (10 mL×3). The solid was dried in a vacuum oven to afford tert-butyl 4-(4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (490) (1.82 g, 79% yield) in high purity. Compound 490 (600 mg, 1.35 mmol) was dissolved in 20 mL NMP. To it were added dry mCPBA (77% strength, 840 mg, 3.38 mmol). The mixture was stirred at RT for 1 hour. To the mixture was added DIEA (2.10 mL, 12.1 mmol) and (R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) (550 mg, 2.03 mmol). The mixture was stirred at 70° C. for 30 min. The mixture was cooled to RT, diluted with 200 mL chloroform, washed with 1N NaOH (aq) ×2 and water, dried, concentrated in vacuo to dryness for crude (R)-tert-butyl 4-(4-(6-carbamoyl-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (491) (740 mg, 87%). It was treated with 35 mL commercial 4N HCl in dioxane at RT for 45 min. The mixture was concentrated in vacuo to dryness to afford crude (R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(piperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (492). A small amount of crude 492 was purified using reverse phase prep HPLC to isolate as HCl salt. LC-MS (ESI): m/z (M+1) 531.1. UV: λ=255 nm.