Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]1([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([N:32]1[CH2:31][CH:30]2[CH:34]([C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28][C:29]2=[O:35])[CH2:33]1)=[O:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.75 h
Yield: 28.7 %

Procedure:
N,N'-Carbonyldiimidazole (1.62 g) is added to a solution of (2-tert-butoxycarbonylaminophenyl)acetic acid (2.51 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 125 cc fractions. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-[(2-tert-butoxycarbonylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.5 g) in the form of a yellow meringue.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][C:10]=1[N+]([O-])=O.P(Cl)(Cl)[Cl:20]>C(Cl)(Cl)Cl>[Cl:20][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: ClP(Cl)Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccccc1Oc1cnccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4.9 g of 3-(o-chlorophenoxy)-4-nitropyridine N-oxide in 200 ml of chloroform is cooled to -5° C. and a large excess of phosphorous trichloride is added. The mixture is stirred 1 hour at 0° C. and slowly warmed to 25° C. The solution is refluxed 1 hour, cooled, concentrated at reduced pressure and dissolved in 100 ml of dichloromethane. The solution is washed with 50 ml of ice-cold concentrated ammonium hydroxide. The solution is dried over anhydrous MgSO4, filtered, concentrated at reduced pressure and distilled to yield 4-chloro-3-(o-chlorophenoxy)pyridine; bp 103°-105° C. at 0.1 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:23]([C:22]4[CH:26]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:15]3)[CH2:10]2)[N:5]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC[C@H]3CN(c4nc(C)cc(C)n4)[C@H]3C2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 20.7 %

Procedure:
A mixture of (1R,6S)-8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (60 mg, 0.28 mmol), 5-methyl-2-pyrimidin-2-yl-benzoic acid (61.82 mg, 0.29 mmol), HOAT (56.12 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (79.1 mg, 0.41 mmol), TEA (83.5 mg, 0.83 mmol) was taken into DMF (5 mL) and stirred at 50° C. for 4 h. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). It was washed with sat. aqueous NaHCO3 solution (2×25 mL) and with water (2×60 mL). The ethyl acetate layer was dried over Na2SO4, filtered and concentrated. The crude product was purified three times on Agilent Basic HPLC system to yield the title compound (24 mg, 21%). MS (ESI) mass calcd. for C24H26N6O, 414.51; m/z found 415.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.17-5.47 (m, 7H), 4.89-1.08 (m, 19H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:20]([C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: COC(=O)c1ccccc1S
Reactant: CCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 22.4 %

Procedure:
A mixture of methyl thiosalicylate (1.3 g, 7.5 mmol), 2-cyano-6-ethylpyridine (0.99 g, 7.5 mmol), triethylamine (1.60 ml, 11.5 mmol) and toluene (6.0 ml) was refluxed for 16 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.45 g, 22%).
Reaction SMILES: CS([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=O)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][CH2:24][CH2:25][O:26][C:5]2[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]3[N:6]=2)=[CH:21][CH:22]=1
Reactant: OCCSc1ccc(Cl)cc1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Product: Cc1cc(C)n2nc(OCCSc3ccc(Cl)cc3)nc2n1
Yield: 38 %

Procedure:
The title compound was prepared according to the experimentals described for Example 11 above from 2-methanesulfonyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 2-[(4-chlorophenyl)sulfanyl]ethan-1-ol in 38% yield. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.47 (dd, 1H), 7.45 (dd, 1H), 7.39 (dd, 1H), 7.37 (dd, 1H), 7.08 (s, 1H), 4.51 (t, 2H), 3.45 (t, 2H), 2.62 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][C:66]([N:68]([CH3:70])[CH3:69])=[O:67])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:60][CH2:61][N:62]([CH2:65][C:66]([N:68]([CH3:70])[CH3:69])=[O:67])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(=O)CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CC(=O)N(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for the synthesis of the compound 16 using HATU except that 2-(4-aminopiperidin-1-yl)-N,N-dimethylacetamide was used. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-2.17 (m, 14H) 2.94 (d, J=10.61 Hz, 6H) 3.01-3.20 (m, 2H) 3.33 (s, 3H) 4.06 (t, J=13.89 Hz, 5H) 4.24 (d, J=4.55 Hz, 2H) 4.78 (t, J=7.45 Hz, 1H) 7.43-7.62 (m, 2H) 8.06 (br. s., 1H) 8.27 (s, 2H) 8.36 (d, J=7.07 Hz, 1H) 9.52 (br. s., 1H) [M+H] calc'd for C30H40F2N8O4, 614. found 614.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42].[C:43]([NH:50][CH2:51][C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:28]([CH2:31][C@H:32]([O:34][C:52](=[O:53])[CH2:51][NH:50][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of (R)—N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.5 mmol), N-Boc-glycine (1.23 g, 7.0 mmol) and DMAP (0.86 g, 7.0 mmol) in CH2Cl2 (45 mL) at 0° C. was added EDC solid (2.02 g, 10.5 mmol) in portions. The reaction mixture was stirred at 0° C. for 2 h, then warmed up to rt and continued to stir overnight. The reaction mixture was diluted with CH2Cl2 (50 mL), and washed with 0.5 N HCl aqueous (20 mL), saturated NaHCO3 (20 mL), and followed by brine (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (n-hexane/ethyl acetate at the ratio of 1:1 to 1:8) to give the title compound as a white powder (2.43 g, 95.2%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[O:23][CH:24]=1>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1/[CH:26]=[CH:25]/[C:22]1[O:23][CH:24]=[C:20]([CH2:19][O:15][C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)[CH:14]=[CH:13][CH:12]=2)[N:21]=1
Reactant: Oc1cccc(CCCn2ccnn2)c1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(/C=C/c2nc(COc3cccc(CCCn4ccnn4)c3)co2)c(F)c1
Yield: 86.5 %

Procedure:
Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (143 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188 mg), the same reaction as Example 2 was carried out to yield the titled compound (257 mg).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=1)[CH3:7].N1C(C)=CC=CC=1C.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=1[NH2:40]>CC(N(C)C)=O>[CH2:6]([NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:15]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=2[C:37]([F:36])([F:45])[F:46])=[O:17])=[CH:13][N:12]=1)[CH3:7]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: Nc1ccccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccccc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
An ice-cold solution of methane sulfonyl chloride (18 μL, 0.23 mmol) in DMA (2.0 mL) was stirred for 10 min followed by sequential drop wise addition of a solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol) in DMA (5.0 mL) and 2,6-lutidine (55 μL, 0.46 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min followed by addition of a solution of 2-trifluoromethyl aniline (31 μL, 0.25 mmol) in DMA (1.0 mL). The reaction mass was further stirred at RT ° C. for 10 min and then heated at 50° C. for 4 h. The reaction mass was then cooled to 0-5° C. and quenched with H2O (5.0 mL), followed by addition of conc. HCl (0.50 mL). The resulting solution was stirred for 5 min followed by extraction with EtOAc (3×50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via preparative TLC to obtain Compound 11 (5.0 mg, 8%). 1H NMR (300 MHz, DMSO-d6): δ 10.23 (br s, 1H), 10.07 (br s, 1H), 9.12 (br s, 1H), 8.61 (s, 1H), 7.89 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74 (m, 1H), 7.57 (m, 2H), 7.38-7.43 (m, 2H), 7.31 (s, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 3.14 (m, 2H) and 1.06 (t, J=7.20 Hz, 3H). [M+H]+ m/z=444.17.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C(Cl)=O.ClCCl.[Br:22][C:23]1[C:27]2[CH:28]=[N:29][C:30]([NH2:32])=[CH:31][C:26]=2[N:25]([CH3:33])[CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[C:27]2[CH:28]=[N:29][C:30]([NH:32][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([C:2]([CH3:3])=[CH2:1])=[CH:12][CH:11]=3)=[CH:31][C:26]=2[N:25]([CH3:33])[CH:24]=1
Reactant: Cn1cc(Br)c2cnc(N)cc21
Reactant: C=C(C)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
In a 50 ml round bottom flask, 4-(prop-1-en-2-yl)benzoic acid (580 mg, 3.6 mmol) was dissolved in 15 ml toluene, and 2.0 M oxalyl chloride in dichloromethane (3.6 ml, 7.2 mmol) was added slowly. Stirring continued for 3 hours, and then volatiles were evaporated from the reaction mixture. To the residue was added 5 ml toluene and the mixture was concentrated in vacuo to azeotropically remove residual water. The residue was then dissolved in DMA (12 ml) and 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-amine (400 mg, 1.8 mmol) was added. Stirring continued at 50° C. for another 3 hours. The mixture was then poured into ice water. The precipitate was collected and dried to obtain the product N-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (6A, 440 mg, 67%). This was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]([N:22]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]2)=[O:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]1COCC1.C[Mg]Br.O.O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]([N:22]2[CH2:28][CH2:27][CH2:26][C:25]([OH:29])([CH3:30])[CH2:24][CH2:23]2)=[O:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCCN(C(=O)C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(O)CCCN(C(=O)C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydropyrazin-2-yl)acetyl)azepan-4-one (4) (0.0250 g, 0.054 mmol) in THF (8.00 ml, 0.054 mmol) under N2 was added methylmagnesium bromide (1.4M solution in THF/Toluene (75:25), 2.70 ml, 3.78 mmol) in thee times, and stirred overnight. The reaction mixture was cooled in ice-water bath and sodium sulfate dodecahydrate (10.0 g) was added slowly followed by AcOEt (20 ml). After stirring at r.t. for 1 h, the mixture was filtered and the solid was washed with AcOEt. The filtrate was concentrated under reduced pressure and the crude product was chomatographed on silica (CH2Cl2→CH2Cl2/MeOH=20/1) to yield the product. MS 476 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][S:7][CH:6]=1)=[O:4].C1C(=O)N([Br:29])C(=O)C1>CCOCC>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:29])[S:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cscc1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of the product of Example 2 in 5.0 mL of AcOH--CHCl3 (1:1) at room temperature was added 0.299 g (1.682 mmol) of N-bromosuccimide. The reaction was stirred for 18 h and then diluted with ether, washed with water and saturated sodium bicarbonate solution, dried over MgSO4, filtered and concentrated in vacuo. The tan solid residue was washed with ether-hexanes (1:1) to provide 0.504 g (81%) of the desired product as a tan solid. Electrospray Mass Spec: 406.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.Cl.[OH-:21].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:10])=[O:21])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: COc1cc(C#N)ccc1-c1nc2ncncc2[nH]1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
One gram of 8-(2'-methoxy-4'-cyano-phenyl)-purine was dissolved in 75 ml of 2N sodium hydroxide solution and refluxed for 15 minutes. Then, the mixture was acidified with hydrochloric acid, and the mixture precipitated was separated into its components by use of silica gel [eluant:methylene chloride/ethanol (7:3 to 1:1)].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([NH:18][C:19](=[O:22])[O:20][CH3:21])(=[O:17])[CH:13]=[CH:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]([CH2:15][CH3:16])[CH2:13][C:12]([NH:18][C:19](=[O:22])[O:20][CH3:21])=[O:17])=[CH:5][CH:4]=1
Reactant: CCC=CC(=O)NC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CCC(CC(=O)NC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 4-trifluoromethylaniline (121 mg, 0.75 mmol) and methyl 2-pentenoylcarbamate (79 mg, 0.5 mmol) in toluene (2 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (13.3 mg, 0.0125 mmol) and the resulting mixture was stirred at 50° C. for 5 hours. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give the objective compound methyl 3-(4-trifluoromethylanilino)pentanoylcarbamate (143 mg, 45% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: OJ-R) to be 59% e.e. (S form).
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7]>CCOCC>[Cl:1][Ge:2]([Cl:4])([Cl:3])[CH2:7][CH2:6][C:5]([OH:9])=[O:8]
Reactant: Cl[GeH](Cl)Cl
Reactant: C=CC(=O)O
Solvent: CCOCC
Product: O=C(O)CC[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a magnetically stirred solution of 18 g (0.1 mole) of trichlorogermane in 30 ml of anhydrous ether was added dropwise with a solution of 7.2g (0.1 mole) of acrylic acid in 20 ml of ether at -30°. Then, the mixture was allowed to stand at room temperature for 2 hrs. Evaporation of the solvent left a solid, which was recrystallized from n-hexane to give 22.5 g (89.3% yield) of white needles, mp 84°~85°. Lit. (V. F. Mironov, E. M. Berliner, and T. K. Gar, Zh. Obshch, Khim., 37, 962 (1967) reports mp 83°~85° for this compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>O>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cnc(Br)s1
Solvent: O
Product: Brc1cnc(N2CCOCC2)s1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2,5-Dibromo-1,3-thiazole (500 mg) was mixed with morpholine (2 ml), followed by stirring at 60° C. for 5 hours. Water was added to the reaction mixture, followed by stirring for 1 hour, and the resulting insoluble matter was collected by filtration, followed by washing with water, to obtain 4-(5-bromo-1,3-thiazol-2-yl)morpholine (475 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]I>CN(C=O)C>[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:24]=[CH:25][N:26]([CH3:28])[N:27]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C)n4)n3Cc3ccccc3)n12
Reaction time: 0.17 h

Procedure:
Sodium hydride (4.0 mg, 0.099 mmol, 60% in mineral oil) was added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.5 mg, 0.020 mmol, from Example 62) in DMF (0.20 mL). After 10 minutes, methyl iodide (3.7 μL, 0.059 mmol, Aldrich) was added. After 15 minutes reaction time, the reaction was quenched with water. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the major isomer was isolated. Yield: (2.7 mg, 40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:34]1[C:43]2[C:38](=[CH:39][C:40]([NH2:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:40]4[CH:39]=[C:38]5[C:43](=[CH:42][CH:41]=4)[CH:34]=[N:35][CH:36]=[CH:37]5)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc2cnccc2c1
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4cnccc4c3)n2)c1)c1c(F)cccc1F

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 6-isoquinolinamine and 6-isoquinolinamine in i-PrOH was heated in a microwave in a procedure analogous to that described in Example 64 to give, after purification, the title compound. LC MS (ES)+ 570.25. 1H NMR (400 MHz, DMSO-d6) δ 6.95 (s, 1H), 7.17-7.30 (m, 4H), 7.41 (d, 1H, J=7.5), 7.51-7.56 (m, 3H), 7.64 7.68 (m, 1H), 7.78-7.81 (m, 2H), 8.05 (s, 1H), 8.09 (bs, 2H), 8.19 (d, 1H, J=9.1), 8.41 (d, 1H, J=9.0), 8.85-8.89 (m, 2H), 8.96 (d, 1H, J=6.8), 9.8 (s, 1H), 10.94 (s, 1H).