Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:37].Br[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:40]4[N:45]=[CH:44][CH:43]=[CH:42][N:41]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:37]
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)sc2C)cc1C
Reactant: Brc1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)cc1C
Temperature: 100 °C
Yield: 41.5 %

Procedure:
3-[2-Methyl-4-(2-(5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiazol-4-yl)-propoxy)-phenyl]-propionic acid methyl ester (5.2 g, 6.92 mmol) is dissolved in anhydrous toluene (30 mL), degassed, and filled with nitrogen three times. [1,1′-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (330 mg, 0.346 mmol), 2-bromopyrimidine (2.24 g, 14 mmol), and sodium carbonate (3.71 g in 5 mL water, 35 mmol) are added, and the degassing procedure is repeated. The reaction is heated to 100° C. and monitored by HPLC. Upon complete consumption of starting material, the reaction is allowed to cool to room temperature and diluted with ethyl acetate. Celite is added and the mixture is filtered and rinsed with more ethyl acetate and water. The solution is further diluted with water and the two phases are separated. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester (1.3 g, 2.87 mmol) is obtained after column chromatography (65% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=[CH:10]1.O>CN(C)C=O>[Br:1][C:10]1[S:9][C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2c(cn1)-c1sccc1CCO2
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c(s1)-c1cnccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
N-Bromosuccinimide (0.237 g, 1.33 mmol) in dimethylformamide (4 mL) was added dropwise to a solution of 4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.250 g, 1.23 mmol) in dimethylformamide (4 mL, 100 mmol) at 0° C. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was mixed with 40 ml of water and extracted with 20 ml of ethylacetate twice. Combined organic extracts were washed with water and brine, and dried over MgSO4. The solvent was evaporated affording 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.227 g, 63%). 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.26 (d, J=5.4, 1H), 6.90 (d, J=5.5, 1H), 6.88 (s, 1H), 4.36 (t, J=4.7, 2H), 3.19 (t, J=4.8, 2H). MS (ESI+) 282.0
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:3]C1.Cl>C1COCC1.CO>[CH2:16]([O:15][C:6]1[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=1[CH:4]=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 96.6 %

Procedure:
A solution of 2-benzyloxy-5-methylsulphonylbenzaldehyde ethylene acetal (28.6 g) in THF (100 ml) and MeOH (100 ml) containing 2N HCl (50 ml) was stirred for 4 hours. The reaction mixture was concentrated to half its volume and water (100 ml) was added. The solid product was filtered and dried to give 2-benzyloxy-5-methylsulphonylbenzaldehyde yield 24 g m.p. 129° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([C:8](=[O:23])[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH2:19][CH2:20][CH2:21][N:22]=[C:11]23)=[CH:6][CH:5]=1.Cl>C(O)C>[OH:23][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:25][CH:24]=1)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]2[CH2:19][CH2:20][CH2:21][N:22]=[C:11]12
Reactant: O=C(CN1C2=NCCCN2c2ccccc21)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CN1C2=NCCCN2c2ccccc21)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
Add 0.35 g (9.3 mmol) of sodium borohydride in small portions, with vigorous stirring, to a suspension of 3.0 g (9.3 mmol) of 10-(4-chlorophenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole (obtained in Example 50) in 20 ml of ethanol. Maintain stirring for one hour and leave for 12 hours at room temperature. Acidify with hydrochloric acid, and evaporate the reaction mixture. Treat the residue with ammonium hydroxide and extract with chloroform. The organic phase obtained is passed over a column of alumina. Evaporate the solvent. The residue is the title compound.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Br:14][C:15]1[CH:23]=[CH:22][C:21]2[C:17](=[CH:18][N:19]([CH3:24])[N:20]=2)[C:16]=1[CH:25]=O>O1CCCC1.[Cl-].[NH4+]>[Br:14][C:15]1[CH:23]=[CH:22][C:21]2[C:17](=[CH:18][N:19]([CH3:24])[N:20]=2)[C:16]=1/[CH:25]=[CH:3]/[C:1]#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cn1cc2c(C=O)c(Br)ccc2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cc2c(/C=C/C#N)c(Br)ccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (88.0 μL, 0.544 mmol) in tetrahydrofuran (2 mL) was added 60% sodium hydride (20.1 mg, 0.502 mmol) under ice-cooling, and the mixture was stirred at 0° C. for 15 min. To the mixture was added a solution of 5-bromo-2-methyl-2H-indazole-4-carbaldehyde (100 mg, 0.418 mmol) in tetrahydrofuran (2 mL) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→80/20) to give the title compound (108 m yield 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH:7]([CH3:8])[CH2:6][NH:5][CH2:4]1.C([O:13][C:14]([C:16]1[CH2:17][N:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([F:26])=[C:21](Cl)[N:20]=2)=[O:15])C.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1([O:9][CH3:10])[CH:7]([CH3:8])[CH2:6][N:5]([C:21]2[N:20]=[C:19]3[C:24]([CH:25]=[C:16]([C:14]([OH:15])=[O:13])[CH2:17][N:18]3[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])=[CH:23][C:22]=2[F:26])[CH2:4]1
Reactant: COC1(OC)CNCC1C
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC1(OC)CN(c2nc3c(cc2F)C=C(C(=O)O)CN3c2ccc(F)cc2F)CC1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.132 g (0.91 mmol) of 3,3-dimethoxy-4-methylpyrrolidine (from Step 5 Example 183), 0.300 g (0.78 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, 12 mL of dry pyridine and 0.437 mL (3.1 mmol) of triethylamine. The reaction was stirred at room temperature for 15 hours, then the solvent was removed in a rotary evaporator. The residue was dissolved in methylene chloride and the product purified by column chromatography over silica gel, eluting with 0.5% increasing to 3% methanol/methylene chloride which was evaporated to afford 0.240 g of the title compound. This material was taken directly to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)CCOc1ccc(Br)cc1-2
Product: NC(=O)c1nc2n(c1-c1cn[nH]c1)CCOc1ccc(Br)cc1-2

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate similar to as described in Example 4 and triturated from water to give 86 mg of 10-bromo-3-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 5.5 mg of 10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 378 (M)+. NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 7.29 (dd, J=8.4, 2.1 Hz, 1H), 7.10-6.95 (m, 2H), 5.43 (s, 1H), 4.49-4.40 (m, 2H), 4.35-4.25 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][OH:8])[NH:5][C:4]1=[O:9])[CH3:2].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][O:8][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:5][C:4]1=[O:9])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@@H]1C(=O)N[C@@H]1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N[C@@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
187 mg of (±)-cis-3-ethyl-4-hydroxymethyl-2-azetidinone, 300 mg of imidazole, and 300 mg of t-butyldimethylsilyl chloride in 3 ml dry dimethylformamide (DMF) were stirred at room temperature for 2 hours. The mixture was concentrated to dryness and 25 ml of H2O:EtOAc (2:3) were added. The mixture was washed 3 times with 3 ml of H2O to remove DMF and imidazole and then dried over Na2SO4 and concentrated to yield the titled compound as white crystals. NMR (CDCl3): δ0.06 (6H, s), 0.89 (9H, s), 1.06 (3H, t), 1.48-1.88 (2H, m), 3.14 (1H, m), 3.56-3.90 (3H, m), 5.86 (1H, brs).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C1COCC1>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:20][C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1N
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2[nH]1
Temperature: 5 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
A mixture of 1,1'-carbonyldiimidazole (10.7 g) and THF (100 ml) was added to a mixture of 1,2-phenylenediamine (6.48 g) and THF (150 ml) which had been cooled to approximately 5° C. in an ice-water bath. The mixture was stirred at ambient temperature for 16 hours. The precipitate was filtered off giving 2,3-dihydrobenzimidazol-2-one (4.38 g, 55%), m.p. >290° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:30]([OH:32])=[O:31])[CH2:29][CH:28]=[CH:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][C:25]4([C:30]([OH:32])=[O:31])[CH2:29][CH:28]=[CH:27][CH2:26]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: NC1(C(=O)O)CC=CC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC=CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 1-aminocyclopent-3-ene carboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopent-3-ene-1-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 2.63 (d, 2H); 2.93 (d, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 5.68 (s, 2H); 7.21 (s, 1H); 7.27 (t, 1H); 7.50 (m, 2H); 8.45 (s, 1H); 8.50 (s, 1H); 10.09 (s, 1H); Mass Spectrum: (M+H)+ 443.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=1.[CH3:17][C:18]1([CH3:35])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:27][CH2:28]OS(C)(=O)=O)[C:19]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:35][C:18]1([CH3:17])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:27][CH2:28][N:14]2[CH2:15][CH2:16][C:11]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)=[CH:12][CH2:13]2)[C:19]1=[O:34]
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: CC1(C)C(=O)N(CCOS(C)(=O)=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C(=O)N(CCN2CC=C(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21
Reaction time: 3 h

Procedure:
4-(7-Fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (2.0 g, 9.26 mmols), 3,3-dimethyl-1-(2-methanesulfonyloxy-1-ethyl)-1,3-dihydro-2H-indol-2-one (2.623 g, 9.26 mmols), sodium carbonate (2.947 g,27.8 mmols),water (20 mls) combined and heated to 90 deg C. for 3 hours. Extracted into ethyl acetate (2×50 ml). Dried (MgSO4),filtered and concentrated in vacuo. The resultant solid was recrystallised from ethyl acetate and then converted to the hydrochloride salt (0.85 g).m.p 235-236 deg. C.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.F[C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=1>>[C:4]1(=[O:14])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][N:12]([C:21]3[CH:34]=[CH:33][C:24]([C:25]([CH:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=3)[CH:13]=2)[C:1](=[O:19])[C:2]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]cn1
Reactant: CC(CC(=O)O)C(=O)c1ccc(F)cc1
Product: CC(CC(=O)O)C(=O)c1ccc(-n2cnc(CCCN3C(=O)c4ccccc4C3=O)c2)cc1

Procedure:
Prepared by a method analogous to that of Example (a) from 2.6 g (10.2 mmol) of 4-(3-phthalimidopropyl)-imidazole and 2.2 g (10.5 mmol) of 3-(4-fluorobenzoyl)-butyric acid. 3.4 g (75%) of a brownish, viscous oil is obtained which is used without further purification for the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].Cl.C(N=C=NCCCN(C)C)C.O[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1.NCC1C=CC=CN=1>CN(C)C=O.O>[N:31]1[CH:32]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:33][NH:29][C:11]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)=[O:13]
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 4-[2-(methoxycarbonyl)ethyl]benzoic acid (200 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (221 mg), 1-hydroxybenzotriazole (169 mg) and 2-aminomethylpyridine (114 mg) in water bath, and the mixture was stirred for 24 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a preparative thin layer chromatography (dichloromethane:methanol=10:1, V/V) to give methyl 3-[4-(2-pyridylmethylcarbamoyl)phenyl]propionate (218 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[C:6](=[S:18])[NH:5][C:4](=[O:19])[CH:3]=1.[N:20]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:20][C:3]1[C:4](=[O:19])[NH:5][C:6](=[S:18])[N:7]([CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1nc2ccccc2[nH]1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(N)n(Cc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a suspension of 6-amino-1-(1H-benzimidazol-2-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.28 g, 1.0 mmol, obtained from Example 8(b)) in acetic acid (3 mL) was added, dropwise, a solution of sodium nitrite (0.080 g, 1.1 mmol) in H2O (0.5 mL). The reaction mixture was then stirred for an additional 40 minutes before sodium dithionite (0.36 g, 2.08 g) was added. The resulting mixture was stirred 15 minutes and then evaporated in vacuo. Water (50 mL) was added and the formed solid was collected by filtration, washed with water and dried which gave the title compound (0.19 g, 63%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
DIPEA (149.8 mg, 1.16 mmol) was added to a stirred solution of 2-fluoro-5-trifluoromethyl-benzoic acid (53.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123 mg, 0.64 mmol) at room temperature. After 2 minutes Biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.309 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 56 mg (42.3% yield) of biphenyl-4-carboxylicacid {2-[4-(2-fluoro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 99.19%, HPLC Purity: 98.21%. 1H NMR: (DMSO) δ 8.7 (t, 1H), 8.0-7.9 (d, 4H), 7.84-7.7 (q, 4H), 7.6 (t, 1H), 7.5 (t, 2H), 7.4 (t, 1H), 4.2 (dd, 2H), 3.8-3.6 (d, 4H), 3.6-3.4 (s, 2H), 3.3 (s, 2H).
Reaction SMILES: N1C=CC=C1.[H-].[Na+].Br[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:16]([C:20]([F:23])([F:22])[F:21])[O:17]2)=[CH:12][C:11]=1[Cl:29].C[O:31][CH2:32][CH2:33]OC>>[Cl:29][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[CH2:9][O:31][CH2:32][CH3:33])[O:17][CH:16]([C:20]([F:23])([F:22])[F:21])[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1cc[nH]c1
Product: CCOCc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of pyrrole (55 mg, 0.75 mmol) in 1.5 mL DME was added to a mixture of NaH (38 mg, 0.83 mmol) in I mL DME at 0° C. under argon. The mixture was stirred at 0° C. for 10 min and then warmed to 25° C. After 30 min, a solution of ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (300 mg, 0.75 mmol), from Example 162 Step 3, was dissolved in 2.5 mL DME was added dropwise. After 3 h, the reaction was filtered through a pad of Celite (1″) and washed with EtOAc (10 mL). The filtrate was concentrated to give a brown oil in 350 mg (100%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)[CH:17]=[CH:16][N:15]=1.[F:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH2:35])=[C:33]([O:41][CH3:42])[CH:32]=1>CC(O)CCC>[F:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH:35][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 24.27 g, 99.58 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 18.54 g, 99.58 mmol) in 2-pentanol (500 mL). The resulting mixture was stirred at 105° C. for 2.5 h. and then cooled to r.t. The resulting precipitate was collected by filtration, washed with 2-pentanol (50 mL) and dried under vacuum to give some of the desired product as a yellow solid. The filtrate was cooled and the resulting precipitate was collected by filtration and washed with 2-pentanol (10 mL). The two crops of product were combined and triturated with CH3CN to give a solid which was collected by filtration and dried under vacuum to give the title compound (37.4 g, 95%) as a yellow solid; 1H NMR: 3.92 (3H, s), 4.01 (3H, s), 7.13 (1H, dd), 7.27-7.36 (1H, m), 7.40-7.51 (2H, m), 7.59 (1H, d), 8.26 (1H, t), 8.35 (1H, d), 8.61 (1H, s), 8.85 (1H, d), 9.46 (1H, s); m/z: ES− M− 392.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][NH2:8])[CH:2]=1.CO[CH:12]=[CH:13][C:14]#[N:15].[O-]CC.[Na+]>C(O)C>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[CH:13][C:14]([NH2:15])=[N:8]2)[CH:2]=1
Reactant: Cc1cccc(NN)c1
Reactant: COC=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(-n2ccc(N)n2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
m-Tolylhydrazine (200 mg, 1.64 mmol), 3-methoxyacrylonitrile (0.137 mL, 1.64 mmol), and sodium ethoxide (111 mg, 1.64 mmol) were dissolved in ethanol (8 mL) and stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (ethyl acetate/hexanes, linear gradient) to afford 1-m-tolyl-1H-pyrazol-3-amine. MS ESI calc'd. for C10H12N3 [M+H]+ 174. found 174. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 5.69 (d, J=2.5 Hz, 1H), 5.01 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1>>[C:1]([C:5]1[CH:10]=[C:9]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:30])[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2cccc(Cl)c2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2cccc(Cl)c2)cc(C(C)(C)C)c1O
Temperature: 140 °C

Procedure:
A mixture of 1.50 g (0.0045 mole) of 2,6-di-tertiary-butyl-4-(3'-chloroanilino)phenol and 0.90 g (0.0090 mole) of succinic anhydride was heated under a nitrogen atmosphere at 140° C. for one hour. The resulting solid was recrystallized once from a mixture of ethanol and water and then twice from a mixture of ethyl acetate and hexane to hydroxyphenyl)-N-(3-chlorophenyl)carbamoyl]propionic acid, m.p. 204°-206° C. Analysis: Calculated for C24H30ClNO: % C, 66.7; % H, 7.0; % N, 3.2; Found: % C, 67.1; % H, 7.0; % N, 3.2.