Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][NH:12][C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1.Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(Cl)c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccncc2)Cc2cccnc2N1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17 %

Procedure:
Sodium hydride (50% dispersion in oil) (364 mg, 7.6 mmole), previously washed in hexanes, was added to a solution of 1-(3-chlorophenyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (500 mg, 1.9 mmole) in tetrahydrofuran (100 ml). The suspension was stirred for 5 minutes at room temperature and 4-chloromethylpyridine hydrochloride was added. The suspension was refluxed for 18 hours. The solvents were removed and H2O was added to the residue. The residue was extracted twice with ethyl acetate (2×25 ml). The organic phases were combined and the solvents removed. The residue was purified with preparative thin-layer chromatography (ethyl acetate as the eluent) yielding 116 mg (0.33 mmole, 17% yield) of 1-(3-chlorophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (mp 132°-134° C.), as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[CH:3]=1.[O:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][C:28](Cl)=[O:29])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:16][C:28](=[O:29])[CH2:27][C:20]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=2[O:17][CH3:18])[CH:3]=1
Reactant: N#Cc1c(N)cc(N)nc1-c1ccccc1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.8 %

Procedure:
To a solution of 50 mg (0.24 mmol) of 4,6-diamino-2-phenyl-nicotinonitrile in 2 mL of CH2Cl2 was added 150 mg (0.70 mmol) of (2,5-dimethoxyphenyl)acetyl chloride (Example 68A), then 100 μL (1.23 mmol) of pyridine. The mixture was stirred at ambient temperature for 10 minutes then the solvent was removed under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, then extracted with 1 M HCl(aq.) (2×5 mL), saturated NaHCO3(aq) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 40% ethyl acetate:hexanes to provide 11 mg (12%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.43 (m, 1H), 7.75 (m, 2H), 7.51 (m, 4H), 6.99 (m, 2H), 6.91 (m, 1H), 6.81 (m, 2H), 3.69 (m, 8H); MS (ESI) m/e 389 (M+H)+, 387 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]([F:27])([F:26])[C:5]([F:25])([F:24])[O:6][C:7]([F:23])([F:22])[C:8]([F:21])([F:20])[O:9][C:10]([F:19])([F:18])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:30]([C:38]1[CH:39]=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:30]([C:38]1[CH:43]=[N:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:20])([F:21])[C:7]([F:22])([F:23])[O:6][C:5]([F:24])([F:25])[C:4]([F:26])([F:27])[O:3][C:2]([F:28])([F:29])[F:1])([F:19])[F:18])=[CH:46][CH:45]=2)=[N:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy) 1-bromobutane (20.9 g, 38.5 mol; prepared from 1,4-dibromobutane and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10.0 g, 0.35 mol). The resulting product was further purified by recrystallization from ethanol and subsequent Kugelrohr distillation to provide a yield of 17.5 g (b.p. 195°-220° C. at 0.1 torr).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([O-:16])=O)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]2[N:27]=[C:28]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])[NH:29][C:25]=2[CH:24]=1>>[OH:35][CH:32]([CH2:33][OH:34])[CH2:31][NH:30][C:28]1[NH:27][C:26]2[CH:36]=[CH:37][C:23]([NH:22][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:21])=[CH:20][CH:19]=4)=[CH:18][CH:17]=3)=[CH:24][C:25]=2[N:29]=1
Reactant: Nc1ccc2nc(NCC(O)CO)[nH]c2c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)[O-])cc2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)Nc3ccc4[nH]c(NCC(O)CO)nc4c3)cc2)cc1

Procedure:
Compound 440 was prepared from 4-(4-dimethylaminobenzamido)benzoate and 5-amino-2-(2,3-dihydroxypropylamino)benzimidazole by standard conditions. [M+H]+ calcd for C26H28N6O4: 489.22; found: 489.01.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH2:27]>C(O)C>[CH3:13][CH:12]([NH:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH:12]([CH3:13])[CH2:11][C:10]([CH:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH:6]=[CH:7][CH:2]1[CH3:1])=[O:14])[CH2:11][C:10](=[O:14])[CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][CH:2]1[CH3:1]
Reactant: CC=CC(=O)C1C(C)C=CCC1(C)C
Reactant: NCCCNCCCNCCCN
Solvent: CCO
Product: CC(CC(=O)C1C(C)C=CCC1(C)C)NCCCNCCCNCCCNC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. stirred solution of 96 g (0.50 mol) of 1-(2,6,6-trimethyl-cyclohex-3-enyl)-but-2-en-1-one (δ-damascone) in 250 mL of ethanol is added 47 g (0.25 mol) of N1-[3-(3-Amino-propylamino)-propyl]-propane-1,3-diamine. The reaction is allowed to warm to room temperature. After stirring for 24 h, the ethanol is concentrated by rotary evaporation to give 3-[3-(3-{3-[1-methyl-3-oxo-3-(2,6,6-trimethyl-cyclohex-3-enyl)-propylamino]-propylamino}-propylamino)-propylamino]-1-(2,6,6-trimethyl-cyclohex-3-enyl)-butan-1-one (bis-Michael adduct 14) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:24][CH2:25][CH2:26][OH:27])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[O:24][CH2:25][CH2:26][OH:27])[NH:11][N:10]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1OCCO
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a solution of 31.3 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazol-5-carboxylic acid ethyl ester obtained by Example 349 in 0.7 mL of tetrahydrofuran were added 0.3 mL of ethanol and 0.2 mL of 5N sodium hydroxide aqueous solution, and stirred at 70° C. for 1 hour and 20 minutes. After cooling on ice, the solution was neutralized with 2N hydrochloric acid under ice cooling, and the precipitated crystals were collected by filtration, and dried under reduced pressure, to afford 25 mg of the title compound as yellow crude crystals.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)C>[F:22][C:17]1[CH:16]=[C:3]2[C:2](=[C:19]([F:20])[C:18]=1[F:21])[N:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: COc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (0.4 g), p-anisidine (0.15 g) and ethanol (4 ml) is stirred at room temperature for 30 minutes. After the reaction, the solvent is distilled off under reduced pressure. To the residue is added anhydrous dioxane (10 ml) and thereto is further added portionwise 60% sodium hydride (60 mg). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into saturated aqueous ammonium chloride, and the mixture is extracted with dichloromethane to give ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A 1 M solution of borane-tetrahydrofuran complex (30 ml) was added dropwise to a stirred solution of 2-phenoxybenzoic acid (5.35 g) in dry THF (50 ml), cooled to 0° C. (effervescence). Following the addition, the mixture was stirred at 0° C. for 15 minutes, then at room temperature for 1.5 hours. It was poured into water and extracted with ether. The extracts were washed successively with water, aqueous sodium bicarbonate, aqueous sodium carbonate, then dried and concentrated under reduced pressure to give 2-phenoxybenzyl alcohol (4.83 g, 97%) as a colourless oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([NH:31][C:32]1[C:33]([S:41][CH3:42])=[N:34][C:35]([CH3:40])=[CH:36][C:37]=1[S:38][CH3:39])=[O:30]>CN(C=O)C.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:28][C:29]([NH:31][C:32]2[C:33]([S:41][CH3:42])=[N:34][C:35]([CH3:40])=[CH:36][C:37]=2[S:38][CH3:39])=[O:30])[CH2:17][CH2:16]1)(=[O:12])=[O:11]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: O=S(=O)(CCN1CCNCC1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCS(=O)(=O)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a solution of 1-[2-(benzimidazol-2-ylsulfonyl)ethyl]piperazine (17 mg, 0.058 mmol) in DMF (0.1 ml) were added potassium carbonate (16.0 mg, 0.116 mmol) and 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (18.6 mg, 0.058 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=5:1) to provide 19.8 mg (yield 64%) of the desired compound as pale yellow oil. IR (neat) cm−1: 3345, 1672, 1565, 1420, 1124. 1H-NMR (CD3OD) δ: 2.43 (3H, s), 2.47 (3H, s), 2.48 (3H, s), 3.00 (2H, br. d, J=12.9 Hz), 3.12 (2H, t, J=10.7 Hz), 3.34 (2H, s), 3.58-3.78 (8H, m), 6.85 (1H, s), 7.12-7.18 (2H, m), 7.43-7.48 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][OH:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCC(OCCO)CC1COc1c(F)ccc(F)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
A solution of 2-[10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethanol (1.09 g, 2.54 mmol) in CH2Cl2 (25 mL) at 0° C. was treated with Et3N (0.37 mL) and MsCl (0.65 mL), the reaction mixture was slowly warmed to room temperature. After 14 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to afford the title compound (1.24 g, 97%): 1H NMR (CDCl3 400 MHz) δ 7.58 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.07 (m, 1H), 6.40 (m, 1H), 5.23 (dd, J=2.9, 11.7 Hz, 1H), 4.37 (dd, J=3.7, 4.4 Hz, 2H), 4.11 (d, J=11.7 Hz, 1H), 3.72 (m, 2H), 3.58 (m, 1H), 3.13 (s, 1H), 3.01 (m, 1H), 2.40 (m, 2H), 1.87 (m, 2H), 1.56 (ddd, J=1.6, 14.7, 14.7 Hz, 1H), 1.14 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:19]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:18]([NH2:28])[N:17]([C:29]3[CH:34]=[C:33]([C:35](=[O:40])[NH:36][CH:37]4[CH2:39][CH2:38]4)[CH:32]=[CH:31][C:30]=3[CH3:41])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:28][C:18]1[N:17]([C:29]2[CH:34]=[C:33]([CH:32]=[CH:31][C:30]=2[CH3:41])[C:35]([NH:36][CH:37]2[CH2:38][CH2:39]2)=[O:40])[N:16]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:19]=1[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)c2ccccc2)c1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1nc(OC2CCNCC2)c(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of 4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester 8 (5.0 mg, 0.0089 mmol) in dichloromethane (2.0 ml) was added trifluoroacetic acid (0.5 ml). The mixture was stirred at room temperature for 3 h. Volatiles were removed in vacuo and the residue was washed with ether and a small amount of EtOAc to give the desired 3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide, trifluoroacetate salt 9 as a white solid (3.0 mg, 59%). HPLC (4 minute 10-90 gradient) tR 1.75 min; MS m/z 460.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=4.0, 1 H), 8.33 (bs, 2 H), 7.90 (d, J=8.0, 1 H), 7.83 (s, 1 H), 7.62 (d, J=7.0, 2 H), 7.44-7.52 (m, 4 H), 7.03 (bs, 2 H), 4.82 (m, 1 H), 2.97 (m, 2 H), 2.85 (m, 1 H), 2.73 (m, 2 H), 2.27 (s, 3 H), 1.91 (m, 2 H), 1.73 (m, 2 H), 0.71 (m, 2 H), 0.57 (m, 2 H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:20])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:12]>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:20])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 11.1 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-l -(2,6-dichloro-3-pyridinyl)-2-propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 EtOAc:Hex gave 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH+: 384.2.
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[I:11][C:3]1[CH:4]=[CH:5][C:6]([S:7]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:1][CH:2]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C

Procedure:
Pipsyl chloride (1.21 g, 4.0 mmol) was dissolved in THF (12 mL) and 4-methylpiperazine (1.1 mL, 12.2 mmol) was added dropwise. The resulting suspension was allowed to stir at RT over night. Filtration and washing with THF afforded crop 1 of compound 58. The mother liquors were concentrated, taken up in CH2Cl2, washed with H2O and brine, then dried over Na2SO4 to afford a second crop of compound 58.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]1.[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:19]#[N:20])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]1
Reactant: N#C[Cu]
Reactant: FC(F)(F)c1cc(I)n(-c2cccc(Cl)c2Cl)n1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Temperature: 200 °C
Yield: 59.5 %

Procedure:
To a stirred solution of 1-(2,3-dichlorophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (11.1 g, 27.58 mmol, 1.0 eq) in NMP (50 mL) was added CuCN (2.39 g, 27.58 mmol, 1.0 eq.) and heated to 200° C. for 2 h. The reaction mixture was passed through a celite pad and washed with excess of ethyl acetate. The filtrate was washed with water and the ethyl acetate layer was separated, dried (Na2SO4), and the solvent evaporated. The resulting residue was purified by CC using ethyl acetate/PE (1:9) to get 1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (5.02 g, crude, yellow solid).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]1=[O:13].CN(C=O)C.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:4]1[C:3](=[O:13])[N:2]([CH3:1])[C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Cn1c(=O)c(=O)[nH]c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Cl)nc2ccccc21

Procedure:
A mixture of 56.1 g. (0.32 m.) of 1,4-dihydro-1-methylquinoxalin-2,3-dione, 10 ml. of DMF, 50 ml. (0.67 m.) of thionyl chloride and 1 l. of toluene was refluxed for 1 hour, cooled, and stripped, finally under high vcuum to a crude dark solid, m.p. 124°-130° C. of sufficient purity to use in the next step.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[CH2:18]1[CH2:22][C:21]2([CH2:29][C:27](=O)[O:26][C:24](=[O:25])[CH2:23]2)[CH2:20][CH2:19]1>O1CCOCC1>[N:8]1[C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=[CH:16][C:7]=1[CH2:6][CH2:5][CH2:4][C:3]1[N:17]=[C:27]([CH2:29][C:21]2([CH2:23][C:24]([OH:26])=[O:25])[CH2:22][CH2:18][CH2:19][CH2:20]2)[O:1][N:2]=1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Solvent: C1COCCO1
Product: O=C(O)CC1(Cc2nc(CCCc3ccc4c(n3)NCCC4)no2)CCCC1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 3,3-tetramethyleneglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting mixture was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.68 (8H, m); 1.95 (2H, p); 2.13 (2H, p); 2.45 (2H, s); 2.80 (6H, m); 3.15 (2H, s); 3.50 (2H, t); 6.63 (1H, d);
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[NH:4]1.[C:17]([CH2:19][C:20](O)=[O:21])#[N:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:20](=[O:21])[CH2:19][C:17]#[N:18]
Reactant: CC1(C)N[C@H](CF)[C@@H](c2ccc(I)cc2)O1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of (4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-oxazolidine (3.5 g, 10.50 mmol), 2-cyanoacetic acid (1.34 g, 15.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.11 g, 15.8 mmol) in dimethylformamide (21 mL) is added triethylamine (2.12 g, 21 mmol) and stirred at room temperature for overnight. The mixture is partitioned between ethylacetate and brine. The organic solution is separated, dried over MgSO4, filtered and evaporated to give a yellow residue, which is purified on silica gel column using heptane to neat ethylacetate to give the title compound (2.75 g): 1HNMR (DMSO-d6): 1.48 (s, 3H), 1.53 (s, 3H), 3.96-4.24 (m, 2H), 4.47-4.84 (m, 3H), 5.11 (d, 1H), 7.31 (d, 2H), 7.77 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.I[CH3:18]>>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[N:9]=[C:8]([S:12][CH3:18])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1
Reactant: CI
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Product: CSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 89 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with iodomethane to give the title compound in 89% yield.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH2:2]1.[CH3:10]O>[Pd].C>[S:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: CO
Reactant: O=C([O-])C1=CCCSC1
Agent: [Pd]
Product: COC(=O)C1=CC=CSC1
Yield: 96 %

Procedure:
A solution of 832 mg (4.37 mmole) of 5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide from part D in methanol (40 mL) was hydrogenated in the presence of 400 mg (50% wt) of 10% Pd/charcoal for 4 hrs. at room temperature and 50 psig of H2. The catalyst was removed by vacuum filtration through a short plug of packed celite and the solvent removed in vacuo to give 802 mg (96%) of methyl 2H-thiopyran-3-carboxylate, 1,1-dioxide as a white solid; mass spectrum m/z=193 (CI,M+H) Part F: Preparation of 2H-thiopyran-3-carboxylate, 1,1-dioxide.
Reaction SMILES: [NH2:1]N.C[N:4]([CH:6]=[C:7]1[C:15](=O)[CH2:14][CH2:13][C:12]2[N:11]([CH3:17])[N:10]=[CH:9][C:8]1=2)C.C>CO>[CH3:17][N:11]1[C:12]2[CH2:13][CH2:14][C:15]3[NH:1][N:4]=[CH:6][C:7]=3[C:8]=2[CH:9]=[N:10]1
Reactant: CN(C)C=C1C(=O)CCc2c1cnn2C
Reactant: NN
Solvent: CO
Product: Cn1ncc2c1CCc1[nH]ncc1-2
Yield: 74 %

Procedure:
Hydrazine (1.00 ml) was added dropwise to a solution of 4.1 g of 4-[(dimethylamino)methylene]-1,4,6,7-tetrahydro-1-methyl-5H-indazol-5-one in 100 ml of methanol. The solution was heated at reflux for 30 minutes and treated with a small amount of activated charcoal. The mixture was gravity-filtered and the filtrate was concentrated in vacuo. The residue was flash chromatograhed (10% methanol in dichloromethane) on silica gel to provide an amber syrup. The syrup was triturated with ether to afford 3,4,5,6-tetrahydro-3-methylbenzo[1,2-c:4,3-c']dipyrazole as tan crystals (74% yield). Recrystallization from toluene gave a solid melting at about 150°-156° C.