Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][C:10](=[O:34])[N:11]2[C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:30])[C:17]([O:31][CH3:32])=[CH:16][C:15]=2[Cl:33])=[C:7]([O:35][CH3:36])[N:6]=1)(O)=[O:2].B.O1CCCC1.Cl>O1CCCC1>[Cl:33][C:15]1[CH:16]=[C:17]([O:31][CH3:32])[C:18]([O:20][CH2:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:30])=[CH:19][C:14]=1[N:11]1[C:10](=[O:34])[NH:9][C:8]2[C:12]1=[N:13][C:5]([CH2:4][CH2:1][OH:2])=[N:6][C:7]=2[O:35][CH3:36]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CC(=O)O)nc32)cc1OCc1c(F)cccc1OC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CCO)nc32)cc1OCc1c(F)cccc1OC
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of 2-carboxymethyl-9-[2-chloro-5-(2-fluoro-6-methoxy-benzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (20 mg) in tetrahydrofuran (2 mL) was added borane-tetrahydrofuran complex (1.03 mol/L tetrahydrofuran solution, 0.08 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 4 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (11 mg).
Reaction SMILES: [C:1]([CH:6]([OH:24])[C:7]([CH2:22][OH:23])([CH2:20][OH:21])[C:8]([C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])([C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([O-:34])=[O:33])=[CH:30][CH:29]=1)([O-])=O.O1CCCC1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([CH:6]([OH:24])[C:7]([CH2:22][OH:23])([CH2:20][OH:21])[C:8]([C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])([C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:25][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O-:34])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1
Agent: C=C(C)C(=O)C(O)C(CO)(CO)C(O)(C(=O)C(=C)C)C(=O)C(=C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A reactor was charged with 15.1 g of tris-(methacryloyl)pentaerythritol p-nitrobenzoate, 35.1 g of stannous chloride and 150 ml of tetrahydrofuran. While stirring the contents and chilling with ice water, hydrogen chloride gas was introduced therein. After a reaction was conducted for 1 hour while chilling ice water and subsequently for 1 hour at room temperature, water and sodium carbonate were added to the liquid reaction mixture to weakly alkalify it. The liquid reaction mixture was subjected to extraction with chloroform. Chloroform was distilled out of the chloroform layer under reduced pressure, and the residue was then purified by column chromatography, thereby obtaining 13.8 g (yield: 92.3%) of tris(methacryloyl)pentaerythritol p-aminobenzoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15]N1C(=O)CCC1=O>CO>[Cl:15][C:5]1[C:4]([OH:8])=[C:3]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1c(O)cccc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: COC(=O)CCc1c(O)ccc(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 30 (5.0 g, 25.5 mmol) in 50 ml of methanol was added 3.4 g (25.5 mmol) of N-chlorosuccinimide. The reaction was stirred overnight at room temperature and concentrated. The residue was suspended in a mixture of hexane and ethyl acetate and the precipitated succinimide was removed by filtration. Crude product obtained after evaporation of the solvent was chromatographed on silica eluting with 4:1 hexane-ethyl acetate. Concentration of the pure product fractions afforded 4.4 g of the title compound as colorless oil that slowly crystallized during prolonged drying under vacuum. 1H NMR (d6-DMSO) δ: 9.52 (s, 1H), 8.95 (s, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.35 (d, J=8.5 Hz, 1H), 3.59 (s, 3H), 2.81 (t, J=7.5 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.O1CCCC1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH2:30][C:31]#[CH:32])=[CH:24][CH:23]=1>O.CN(C)C=O>[CH2:30]([O:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:27][CH:26]=1)[C:31]#[CH:32]
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: C#CCOCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCOCc1ccc(Cn2cc(-c3cccnc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (30 mg, 0.19 mmol) described in Manufacturing Example 32-1-4 and tetrahydrofuran (1 mL) was added sodium hydride (12 mg, 0.24 mmol, 50% in oil) at 0° C., and then N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 10 minutes at room temperature, after which 1-chloromethyl-4-prop-2-ynyloxymethyl-benzene (47 mg, 0.24 mmol) described in Manufacturing Example 194-1-2 was added to this mixture at 0° C., which was stirred for 2 hours at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (37 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: BrCc1ccncc1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccncc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 4-bromomethyl-pyridine gave the title compound.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]1=[NH2+:23].[OH-].[Na+].CO[C:28](=O)[CH2:29][Cl:30]>CCO>[Cl:30][CH2:29][C:28]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1
Reactant: COC(=O)CCl
Reactant: Cc1cc(C)n(N)c(=[NH2+])n1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)n2nc(CCl)nc2n1
Temperature: 55 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A mixture of 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate (40 g, 0.1 mol) and NaOH (10 g, 0.2 mol) in 500 mL of EtOH was stirred at 50-60° C. for 1 hour. After chloroacetic acid methyl ester (16.6 g, 0.15 mol) was added, the resultant mixture was stirred at reflux for 4 hours. After being concentrated under reduce pressure, the residue was diluted with water (1000 mL) and extracted with CH2Cl2 (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=2/1) to give 2 g of 2-Chloromethyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine in 9% yield. 1H NMR (300 MHz, DMSO-d6): δ8.55 (s, 1H), 6.25 (s, 2H), 4.05 (s, 3H), 3.95 (s, 3H); LC-MS (MH+): m/z=196.9, tR (min, method A)=0.52
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: N#Cc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 36 %

Procedure:
Prepared from VII and 4-aminobenzonitrile. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 36%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3293, 2225, 2218, 1722, 1628, 1590, 1562, 1495, 1461, 1387, 1261, 1228, 1132, 966, 847, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 7.77 (m, 3H), 7.40 (d, 2H, J=9.0 Hz); HRMS calcd for C17H9N6S (M+H+): 329.0609, found 329.0612.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][CH:12](O)[CH:13]([CH3:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].BrC1C(C)=CC(C)=CC=1C.CN(C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:16][CH:13]([C:12]1[NH:1][C:2]2[C:3]([CH:11]=1)=[CH:4][C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=2)[CH2:14][CH3:15]
Reactant: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1N
Agent: [Pd]
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2[nH]1
Temperature: 160 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A mixture of 1-(2-amino-4-chloro-5-methoxyphenyl)-3-methylpentan-2-ol (602 mg), tetrakis(triphenylphosphine) palladium(0) (135 mg), potassium carbonate (646 mg), 2-bromomesitylene (0.420 mL), and N,N-dimethylformamide (11.7 mL) was stirred at 160° C. for 1 hour under microwave irradiation. To the reaction mixture were added ethyl acetate and water to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (514 mg). 1H-NMR (CDCl3) δ ppm: 0.91 (3H, t, J=7.4 Hz), 1.32 (3H, d, J=6.8 Hz), 1.55-1.80 (2H, m), 2.70-2.90 (1H, m), 3.91 (3H, s), 6.10-6.20 (1H, m), 7.05 (1H, s), 7.25-7.35 (1H, m), 7.50-8.00 (1H, br).
Reaction SMILES: [N+:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[C:9]([OH:11])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl>>[N+:1]([C:4]1[N:8]=[CH:7][N:6]2[C:5]=1[C:9](=[O:11])[N:6]1[CH:7]=[N:8][C:4]([N+:1]([O-:3])=[O:2])=[C:5]1[C:9]2=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)c1nc[nH]c1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c2c([N+](=O)[O-])ncn2c(=O)c2c([N+](=O)[O-])ncn12
Temperature: 120 °C
Yield: 107.3 %

Procedure:
An intimate mixture of 5-nitroimidazole-4-carboxylic acid (2.0 g) and phosphorus pentachloride (2.67 g) was stirred and heated in an oil bath at 120° C. for 1 hour. The resulting yellow slurry was evaporated at 60° C./0.1 nun Hg for 30 minutes, to give 1,6-dinitro-5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione (1.90 g) in the form of a yellow solid, m.p. 249°-251° C. (with decomposition). [νmax (KBr disc) 1750 cm-1 ; m/e 278 (M+)].
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][CH3:30])=[C:25]([N+:31]([O-])=O)[CH:24]=2)[CH2:17]1)([CH3:12])([CH3:11])[CH3:10].[CH2:36]([N:38]1[C:46]2[CH:45]=[CH:44][N:43]=[CH:42][C:41]=2[CH:40]=[C:39]1[CH:47]=O)[CH3:37].CO>O.C(O)C>[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C:23]2[CH:28]=[CH:27][C:26]3[N:29]([CH3:30])[C:47]([C:39]4[N:38]([CH2:36][CH3:37])[C:46]5[CH:45]=[CH:44][N:43]=[CH:42][C:41]=5[CH:40]=4)=[N:31][C:25]=3[CH:24]=2)=[O:34])[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CNc1ccc(C(=O)N2CCCC(NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reactant: CCn1c(C=O)cc2cnccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCn1c(-c2nc3cc(C(=O)N4CCCC(NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cnccc21
Temperature: 100 °C
Yield: 40 %

Procedure:
Sodium hydrosulfite (277.4 mg, 1.275 mmol) dissolved in water (1.5 mL) was added to a stirred solution of tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (143.2 mg, 0.378 mmol) and 1-ethyl-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (67.6 mg, 0.388 mmol) in ethanol (3.5 mL) at room temperature in a 5 ml microwave vial. The reaction mixture was then heated in a microwave for 5 hr at 100° C. Methanol was added to the reaction mixture and dried using Na2SO4. The reaction mixture was then filtered under gravity through a hydrophobic frit and the eluent collected and concentrated under vacuum. The crude product was dissolved in a minimum volume of DCM and purified using SP4 on a 25 g SNAP silica cartridge. The cartridge was eluted using a gradient of 0-100% 20% methanol in DCM/DCM. Appropriate fractions were collected and concentrated under vacuum to give the title compound as a yellow oil (76 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.[NH3:26].C(O)(C)C.O>CS(C)=O>[N+:23]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:26])[CH:3]=3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: N
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (1 g, 2.86 mmol) was dissolved in DMSO (15 mL) in a sealed reactor. After adding 2.0 M ammonia solution in isopropanol (15 mL, 30 mmol), the reaction mixture was stirred at 100° C. for 15 hours. After cooling to room temperature and adding water (70 mL), the reaction mixture was stirred at room temperature for 1 hour. Thus prepared solid was filtered, washed with water, and dried in the air. 6-(6-(3-Nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (850 mg) was yielded as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([S:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:14]=2)=[CH:21][CH:20]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1ccc(Sc2ccnc(Cl)c2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Sc3ccc(Cl)cc3)ccn2)n1
Yield: 47.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (7.01 mL, 4.91 mmol), 2-chloro-4-(4-chlorophenylthio)pyridine (1.38 g, 5.40 mmol), potassium phosphate (1.15 g, 5.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.112 g, 0.123 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethyl-9H-xanthene (0.0780 g, 0.135 mmol)were reacted in toluene (7 mL) and water (2 mL) to afford 4-(4-chlorophenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.781 g, 47.2% yield) as light yellow solid. 1H NMR (CDCl3) δ 8.09 (d, 1H), 7.45 (m, 2H), 7.38 (m, 2H), 6.57 (dd, 1H), 6.44 (s, 1H), 6.34 (d, 1H), 2.17 (d, 3H); Mass spectrum (esi) m/z=334 (100) (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CCCCCC.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-nitrobenzyl bromide (1.00 g, 4.63 mmol) and diethyl malonate (0.741 g, 4.63 mmol) in 30 ml of hexane was added potassium carbonate (0.640 g, 4.63 mmol) and 18-Crown-6 (0.012 g, 0.05 mmol). After stirred at 80° C. for 18 hours, the mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with water, then with brine, and concentrated under reduced pressure to obtain crude diethyl (2-nitrobenzyl)malonate.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:12]=2)[C:8]([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
A solution of and 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (73 mg, 0.2 mmol) and triphenylphosphine (79 mg, 0.3 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34 mmol). After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminopyridine (28.2 mg, 0.3 mmol) and pyridine (1 drop). The resulting reaction mixture was stirred at 25° C. for 48 h. The reaction mixture was then diluted with methylene chloride (50 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (2×25 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60Å, 25 cm×2 3cm ID, 50/50 heptane/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide (54.2 mg, 61.5%) as a white solid: mp 86-89° C.; EI-HRMS m/e calcd for C21H23F3N2O3S (M+) 440.1383, found 440.1381.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.COCCO.CCN(C(C)C)C(C)C>>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Temperature: 105 °C

Procedure:
The 6-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (0.025 g, 0.072 mmol) was combined with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.022 g, 0.14 mmol, from Example 176, Step 4) in 2-methoxyethanol (1.0 mL, 13 mmol) and DIPEA (0.037 g, 0.29 mmol) in a sealed tube. The reaction was heated to 105° C. in an oil bath for 18 hours. Without workup, the reaction was carried into the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Fc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1Cl
Yield: 41.8 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (82 mg, 42%). MS (ISP) 393.1 [(M+H)+]; mp 265° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[C:14]=[S:15])[CH2:3][CH2:2]1.[CH2:16]([NH2:18])[CH3:17].Cl.C(N)C>C[O-].[Na+]>[CH2:16]([NH:18][C:14]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[S:15])[CH3:17]
Reactant: S=C=Nc1ccccc1N1CCOCC1
Reactant: CCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCNC(=S)Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 2-morpholinophenyl isothiocyanate (3.3 g) with ethylamine generated from ethylamine hydrochloride (12.18 g) and sodium methoxide [generated from sodium (3.5 g) and methanol (100 ml)] gave 1-ethyl-3-(2-morpholinophenyl)thiourea (m.p. 118°-120° C.) which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[C:10]1([CH3:9])[CH:11]=[CH:12][CH:13]=[C:14]([C:2]2[C:7]([C:14]3[CH:15]=[C:10]([CH3:9])[CH:11]=[CH:12][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH:15]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(-c2nccnc2-c2cccc(C)c2)c1
Yield: 80 %

Procedure:
First, 2.39 g of 2,3-dichloropyrazine, 4.51 g of 3-methylphenyl boronic acid, 3.74 g of sodium carbonate, 0.17 g of bis(triphenylphosphine)palladium(II)dichloride (abbr.: Pd(PPh3)2Cl2), 15 mL of water, and 15 mL of acetonitrile were put in a round-bottomed flask with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 3 hours and 40 minutes to be heated. Then, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtrated. The solvent of this solution was distilled off to obtain 2,3-di-m-tolylpyradine (a white powder, yield: 80%). A synthetic scheme of Step 1 is represented by (E4-1) below.