Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][C:32]=4[Cl:34])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4Cl)cc3)cc2s1
Yield: 41.9 %

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2,4-dichloro-phenyl boronic acid (0.072 g, 0.38 mmol) to give the title compound (0.067 g, 0.13 mmol, 43%). LC/MS, Retention time=5.15 min; (m/z): calcd for C25H24Cl2N4OS: 499.5; found: 499.0.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.S(Cl)([Cl:25])=O>CN(C=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-phenoxybenzenesulfonic acid (3.14 g, 12.64 mmol) in thionyl chloride (9 ml) was refluxed for 4 h in presence of DMF (2 drops). After cooling to room temperature, diethyl ether (20 ml) was added and the resulting white solid was separated by filtration. The filtered solution was evaporated in vacuo to give 4-phenoxybenzenesulfonyl chloride as a brown oil which was used in the next step without further purification.
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br-:1].[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])([CH3:7])[CH3:8])=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (1.0 g, 2.52 mmol), 4-benzyloxyphenylacetic acid (0.61 g, 2.52 mmol), N-methylmorpholine (1.0 mL, 9.10 mmol), N,N′-dicyclohexylcarbodiimide (0.52 g, 2.52 mmol) and 1-hydroxybenzotriazole (0.34 g, 2.52 mmol) in anhydrous DMF (20 mL) is stirred under a nitrogen atmosphere at RT for 16 h. The reaction mixture is concentrated under vacuum and is purified by column chromatography (basic alumina, 0-3% MeOH in DCM) to afford the title compound as a white solid. M+ 540. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (1H, t), 8.07 (1H, t), 7.52 (2H, br), 7.41-7.28 (5H, m), 7.16 (2H, d), 7.09 (2H, br), 6.91 (2H, d), 5.05 (2H, s), 3.58-3.3.51 (2H, m), 3.40-3.25 (6H, m), 3.11-3.03 (2H, m), 3.02 (6H, s), 1.87-1.75 (2H, m).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[SiH:34]([CH3:36])[CH3:35].[CH:37](O)(C)C>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Si:34]([CH3:36])([CH3:37])[CH3:35])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCCCCCOc1ccc(-c2ncc(CCCCCCCC)cn2)cc1
Reactant: CC(C)O
Reactant: C[SiH](C)Cl
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCCCCCC[Si](C)(C)C)cc2)nc1

Procedure:
2 g (4.6 mmol) of 10-undecenyl 4-(5-octylpyrimidin-2-yl)phenyl ether, 6 g (63.4 mmol) of chlorodimethylsilane and 0.1 ml of a 0.1 molar solution of H2PtCl6 in isopropanol are heated at 100° C. for 8 h in a sealed glass tube. After opening the tube, the product is evaporated down, taken up in 10 ml of dry tetrahydrofuran and mixed with 50 ml of a 1 molar solution of methylmagnesium bromide in tetrahydrofuran. After heating for 2 hours under reflux, the mixture is hydrolyzed in a saturated aqueous NH4Cl solution and the aqueous solution is extracted repeatedly with diethyl ether. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and evaporated down in vacuo. After chromatographic purification (SiO2, CH2Cl2 /hexane 3/1) and recrystallization from methanol, 700 mg of colorless crystals are obtained.
Reaction SMILES: [O:1]=[CH:2][CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][C:11](=[N:15]O)[C:12](=O)[CH3:13].[ClH:17].C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C.CCCCCC>[Cl:17][CH2:10][C:11]1[N:15]=[C:2](/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[O:1][C:12]=1[CH3:13]
Reactant: Cl
Reactant: CC(=O)C(C)=NO
Reactant: CCOC(=O)C=CC=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1nc(CCl)c(C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 55 %

Procedure:
A mixture of ethyl 4-oxobutenate (25.31 g), 2,3-butanedione-2-oxime (20.02 g) and 4N hydrogenchloride-ethyl acetate solution (300 mL) was stirred at room temperature for 4 days. After concentration of the reaction mixture, diethyl ether was added to the residue, and the residue was decanted and washed. Tetrahydrofuran (300 mL) was added to the residue, and thionyl chloride (35.33 g) was further added. The mixture was heated under reflux for 2 hrs. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give from a fraction eluted with ethyl acetate-hexane (1:8, v/v), ethyl (2E)-3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-propenoate as colorless crystals (24.98 g, yield 55%). Recrystallization from hexane gave prism crystals. melting point: 53-54° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (obtained above), 4-amino-3-methoxybenzoic acid (585 mg, 3.5 mmol), isopropanol (10 ml), water (5 mL) and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give the product as white solid (396 mg). [M+H] calc'd for C22H26FN5O4, 444; found 444.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>CC1C=CC(C(C)C)=CC=1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: ClCCl
Product: CCCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in p-cymene (11 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine hydrochloride SLA 28178 (323 mg, 1.07 mmol) at RT followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1 h before addition of a new portion of SLA 28178 (323 mg, 1.07 mmol, done 3 times). After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 14.8 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.26 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum, to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 42 as a yellow solid (6 mg, 10% yield).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[C:9]([SH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)([O-])=O.C(OCC)(=O)C>[Fe].O>[NH2:5][C:8]1[C:9]([SH:18])=[N:10][CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1S
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(F)(F)F)cnc1S
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a mixture of 2.87 g of iron, 10 ml of acetic acid and 10 ml of water was added a mixture of 3.84 g of 3-nitro-5-(trifluoromethyl)pyridine-2-thiol and 10 ml of ethyl acetate at 70° C. over a period of 10 minutes. The reaction mixture was cooled down to room temperature, then, to the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure to obtain 3.1 g of 3-amino-5-(trifluoromethyl)pyridine-2-thiol.
Reaction SMILES: C(OC([N:8]1[C:12]([CH3:32])([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[NH2:8][C:12]([C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=2)=[CH:16][N:17]=1)([CH3:32])[CH2:11][OH:10]
Reactant: CCCCCCCCc1ccc(-c2cnc(C3(C)COC(C)(C)N3C(=O)OC(C)(C)C)[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCCCCCCc1ccc(-c2cnc(C(C)(N)CO)[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a flame dried round bottom flask equipped with a magnetic stirbar under an inert atmosphere was added 6 (973 mg, 2.07 mmol) followed by MeOH (20 mL) and p-TsOH.H2O (1.22 g, 6.42 mmol). This mixture was then heated to reflux, stirred 3 h, cooled to 0° C., and quenched by slow addition of sat. aq. NaHCO3 (20 mL). This solution was then diluted with EtOAc (30 mL) and the aqueous layer was discarded. The organic phase washed with sat. aq. NaHCO3 (1×20 mL), washed with 1M NaOH (1×20 mL), dried over sodium sulfate, and concentrated to an orange oil. To this oil was added Et2O which produced VPC24241 (408 mg, 60%) as a white precipitate which was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:22]1[N:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:23]=1[C:24]([NH:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:25]>O1CCCC1.CO>[Cl:44][C:41]1[CH:42]=[N:43][C:22]([N:11]2[CH2:12][CH:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:13])[CH2:10]2)=[C:23]([CH:40]=1)[C:24]([NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH2:29][CH2:28]1)=[O:25]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: Cc1cc(F)ccc1NC1CNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4C)C3)CC2)cc1
Temperature: 75 °C

Procedure:
To a solution of N-(4-fluoro-2-methylphenyl)azetidin-3-amine (D55) and triethylamine (0.14 ml, 1.04 mmol) in tetrahydrofuran/methanol (3 ml/1 ml) methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (253 mg, 0.693 mmol) was added and the resulting mixture was heated 24 h at 75° C. The residue obtained after solvent evaporation, was purified by Biotage SNAP-Si (10 g) cartridge eluting with eluting with a mixture dichloromethane/ethylacetate from 95/5 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D168) (105 mg).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([Br:25])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:25][C:19]1[C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:7]2[N:6]3[C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CN1CCNCC1
Product: CN1CCN(c2nnc3n2-c2cc([N+](=O)[O-])c(Br)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-9-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-bromo-9-nitro-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH:7](=O)[CH3:8].N1C=CC=CC=1.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>O.C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]1[S:6][CH:7]([CH3:8])[N:5]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC=O
Reactant: CNC(=S)NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CNC1=NN(C(=O)C(C)(C)C)C(C)S1

Procedure:
A 10.5 g. portion of 4-methylthiosemicarbazide was combined with 4.4 g. of acetaldehyde, and 7.9 g. of pyridine and 200 ml. of toluene were added. The mixture was stirred for a short time, and 12.1 g. of pivaloyl chloride was added slowly with agitation while the temperature of the mixture was held at 20°-25°. The mixture was then stirred at ambient temperature for 3 hours, and 50 ml. of water was added. The layers were separated, and the toluene layer was washed with water and was then concentrated under vacuum to obtain 21 g. of oil. The oil was dissolved in 25 ml. of hot nitromethane, filtered and cooled gradually to obtain a solid, which was washed with cold nitromethane and vacuum dried at 50° to obtain 14.8 g. of impure product, which was purified by slurrying it twice with 25 ml. portions of cold nitromethane and vacuum drying to obtain 8.3 g. of product, m.p. 102°-103°.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].[CH2:7]([OH:16])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OO)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl>[O:2]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]1[CH2:7][OH:16]
Reactant: O=C([O-])[O-]
Reactant: OC/C=C/c1ccccc1
Agent: CC(=O)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OCC1OC1c1ccccc1
Temperature: 17.5 °C
Reaction time: 2.5 h

Procedure:
Sodium carbonate (224 g) and trans-cinnamyl alcohol (200.0 g) were mixed with 2 L of methylene chloride, a slow nitrogen sweep was maintained through the vapor space of the flask and the mixture was cooled to 15-20° C. with a cold water bath. Peracetic acid solution (35%, 381.2 mL) was added over a 3 hour period, maintaining the internal temperature below 25° C. After the peracetic acid addition was complete, the mixture was stirred for 2-3 hours until complete, as shown by HPLC analysis. The mixture was cooled to 10° C. with an ice bath, and a solution of sodium sulfite (160 g) in 1200 ml water was added slowly over 90 minutes, keeping the temperature below 30° C. The phases were separated and the aqueous phase was extracted with methylene chloride (200 mL) to give a solution of the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8](=[O:25])[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][C:12]=1[O:23][CH3:24])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:6][O:7][C:8](=[O:25])[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][C:12]=1[O:23][CH3:24])=[CH2:1]
Reactant: COC(=O)C(=O)c1cc2c(cc1OC)CCC(=O)N2C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C(=O)OC)c1cc2c(cc1OC)CCC(=O)N2C
Temperature: -20 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A suspension of 3.1 g (0.0087 m) of methyl-triphenylphosphonium bromide in 100 ml of tetrahydrofuran was cooled to −20° C. To this suspension was added dropwise 3.5 ml (0.0087 m) of a 2.5 M solution of n-butyl lithium in tetrahydrofuran. The mixture was slowly. warmed to +5° C. at which time a yellow solution formed. The mixture was cooled to −20° C. and 2.2 g (0.0079 m) of (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-oxo-acetic acid methyl ester was added. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was filtered, and the filtrate evaporated to yield a brown oily residue. This material was chromatographed on 75 grams of silica using chloroform as the elutant. Appropriate fractions were combined and evaporated to yield 1.8 g (83%) of 2-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) acrylic acid methyl ester as an amorphous solid. 1H NMR (CDCl3) δ 2.58 (m, 2H), 2.82 (m, 2H), 3.15 (s, 3H), 3.70 (s, 6H), 5.70 (s, 1H), 6.25 (s, 1H), 6.65 (s, 1H), 6.80 (s, 1H). Mass spectrum: m/e=276 (p+1). TLC (5/1 methylene chloride/ethyl acetate) Rf=0.90.
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)[C:51]=1[C:52](O)=[O:53]>>[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)[C:51]=1[C:52]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:53]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1186050-58-7; 172 mg, 0.83 mmol) to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(C)(C)C.[CH:16]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[CH2:17].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1[CH:16]=[CH:17][C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:7][C:6]([OH:5])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
A mixture of 3-bromo-phenyl acetic acid tert-butyl ester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g, 20.80 mmol), diisopropylethylamine (3.63 g, 28.08 mmol), palladium acetate (107 mg, 0.478 mmol), and tritolylphosphine (475 mg, 1.56 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. The reaction was cooled to room temperature and ice water (50 mL) was added. EtOAc (50 mL) was added and the organic solution was washed with 5.5% HCl followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1 to 4:1) provided the title compound (1.95 g). MS 381 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].OC=[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].C([O-])(=O)C.[Na+]>Cl.O.CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:9]=[C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1=CO
Reactant: Nc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCCCC1=NNc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a cold (0° C.) solution of 4-chloroaniline (5.6 g, 44 mmol) in concentrated hydrochloric acid (5 mL) was added sodium nitrite (3.0 g, 44 mmol) dissolved in water (10 mL) portionwise over 20 minutes. The mixture was stirred at 0° C. for 30 minutes. In a separate flask, a cool solution of 2-(hydroxymethylene)cyclohexanone (Organic Syntheses, Collective Vol 4, 1963, pg. 536) (5.0 g, 40 mmol) in methanol (30 mL) was treated with a solution of sodium acetate (8.3 g, 101 mmol) in water (25 mL). The mixture was stirred at 0° C. for 20 minutes and the diazonium salt slurry was added. The combined mixture was stirred for 10-15 minutes, collected by filtration, triturated with ethanol, and collected by filtration to give cyclohexane-1,2-dione (4-chlorophenyl)hydrazone (4.6 g, 49% yield) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.93 (s, 1H), 7.29 (m, 4H), 2.55 (m, 2H), 2.40 (m, 2H), 1.84-1.75 (m, 4H).