Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20]([C:22](=O)[CH3:23])[CH:21]=1>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20](/[C:22](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:23])[CH:21]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(N)(=O)=O)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(N)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 40.5 %

Procedure:
3-(hydrazinecarbonyl)benzenesulfonamide (50 mg, 0.232 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.6 mg, 0.232 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)benzenesulfonamide (36 mg, 0.094 mmol, 40.4% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.34 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.73 (t, 1H, J=8.0 Hz), 7.64 (m, 1H), 7.51 (bs, 2H), 7.32 (dd, 1H, J=2.4 & 8.4 Hz), 6.92 (d, 1H, J=8.4 Hz), 2.49 (s, 3H). Mass [M+H]+: 368.0
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]1[CH:23]([CH2:24][OH:25])[CH2:22][CH:21]([NH2:26])[CH2:20]1.[OH-].[Na+]>C(N(CC)CC)C.C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:26][C@H:21]2[CH2:20][CH2:19][C@@H:23]([CH2:24][OH:25])[CH2:22]2)[N:3]=1
Reactant: NC1CCC(CO)C1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(N[C@H]2CC[C@@H](CO)C2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (530 mg, 2.00 mmol) from Example 4, 3-aminocyclopentyl-1-methanol (276 mg, 24 mmol), triethylamine (1.12 g, 10.98 mmol), and ethanol (20 mL) was stirred at reflux for 5 hours. An additional amount of triethylamine (1.17 g) was then added and the solution was refluxed for 8 additional hours. The solution was allowed to cool to room temperature and 2 mL of 1 N NaOH was added. The solution was concentrated and the residues were placed on silica gel column which was eluted with 10% methanol-chloroform (0.36 g, 52%). Recrystallization of such a sample from ethanolacetonitrile gave title compound as white powder, m.p. 177-180° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
4 g (20 mmol) of ortho-bromonitrobenzene, 842 mg (1.2 mmol) of bis(triphenyl-phosphine)palladium(II) chloride and 230 mg (1.2 mmol) of copper(I) iodide were, under argon, initially charged in 40 ml of triethylamine. At room temperature, 2.95 g (30 mmol) of trimethylsilylacetylene were then added dropwise over a period of 10 min, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into 50 ml of water and extracted three times with in each case 50 ml of diethyl ether, and the extracts were dried over sodium sulphate and concentrated. Column-chromatographic purification on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 3:1) gave 4.2 g (96% of theory) of trimethyl-(2-nitrophenyl-ethynyl)silane [log P (pH 2.3)=4.12].
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][N:23]=1)([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=O)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][N:23]=1)([C:3]1[NH:34][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CSc1ccc(C(C)(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(C)(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 145.1 %

Procedure:
To a solution of 5-methyl-5-[5-(methylsulfanyl)pyridin-2-yl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (60.7 mg) in acetic acid (1 mL) was added ammonium acetate (181 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (84.0 mg, yield 82%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]([CH3:23])[CH3:22])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.CC1([CH2+])C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:39]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:40]=[CH:41][N:42]=3)=[CH:34][CH:33]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]([CH3:23])[CH3:22])[C:5]2[C:10]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:39]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:40]=[CH:41][N:42]=4)=[CH:36][CH:37]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CC(C)Oc1nc(Cl)nc2c1c(I)cn2COCC[Si](C)(C)C
Reactant: [CH2+]C1(C)OB(c2ccc(-c3nccn3COCC[Si](C)(C)C)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1nc(Cl)nc2c1c(-c1ccc(-c3nccn3COCC[Si](C)(C)C)cc1)cn2COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-isopropoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (4,5,5-trimethyl-2-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)-1,3,2-dioxaborolan-4-yl)methylium (1.2 equiv) and tripotassium phosphate trihydrate (3 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.09 M) was added palladium 1,1-bis(diphenylphosphion)-ferrocene dichloride (0.2 equiv). The reaction mixture was stirred at 100° C. for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a red solid. MS (ESI) m/z 614.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].S(=O)(=O)(O)O.[CH3:35][C:36]([CH3:38])=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH:36]([CH3:38])[CH3:35])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N(c2ccc3c(c2)C(C)(C)OC3(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a solution of 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.1 g, 0.32 mmol) and sodiumcyanoborohydride (0.12 g, 1.92 mmol) in 2 mL of acetone and 2 mL of acetic acid, sodiumcyanoborohydride (0.1 g, 1.58 mmol) was added followed by a drop of sulfuric acid. After half an hour at room temperature, another drop of sulfuric acid was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was taken up in ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography on silica gel, using 5% ethyl acetate in hexane as the eluent, to afford the title compound (0.007 g, <10%). 1H NMR (300 MHz, CDCl3): δ 7.83 (d, 2H, J=9.0 Hz), 7.14 (d, 1H, J=7.9 Hz), 7.00 (dd, 1H, J=7.8, 1.8 Hz), 6.81 (d, 1H, J=1.7 Hz), 6.52 (d, 2H, J=9.2 Hz), 4.39 (heptet, 1H, J=6.6 Hz), 4.30 (q, 2H, J=7.11 Hz) 1.56 (s, 6H), 1.51 (s, 6H), 1.34 (t, 3H, J=7.1 Hz), 1.17 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:14].[K+]>[OH-].[K+].O.OCC(CO)O>[OH:14][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCC(O)CO
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
4-Isopropyl-benzoic acid (5.00 g, 30.0 mmol) was dissolved in 20 mL of 10% potassium hydroxide in water solution. To this solution was added 480 mL of 0.2 N aqueous potassium hydroxide solution, followed by a solution of potassium permanganate (9.65 g, 60.0 mmol) in 500 mL of water. The mixture was stirred at 70° C. for one hour. To the reaction mixture was added a few drops of glycerol, and the resulting mixture was cooled to 0° C. Solid residues were removed by filtration, and the filtrate was acidified to pH 1 and extracted twice with ether. The ether extracts were combined, rinsed once with brine and dried over magnesium sulfate and concentrated in vacuo. The concentrate was washed with carbon tetrachloride and recrystallized from water to give 2.2 g (12.2 mmol) of 4-(1-hydroxy-1-methyl-ethyl)-benzoic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@:25]([CH3:47])([C:43](OC)=[O:44])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+]>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH2:43][OH:44])([CH3:47])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (3S,5R,6S)-methyl 1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carboxylate (450 mg, 0.640 mmol; Example 248, Step A) at 0° C. in THF (4 mL) under a nitrogen atmosphere was added dropwise lithium triethylborohydride (1.60 mL, 1.60 mmol, 1M solution in THF). The reaction was stirred at 0° C. for 1 hour and then it was quenched with methanol (0.2 mL) and treated with Oxone® (2 KHSO5.KHSO4. K2SO4, DuPont, Wilmington, Del.) (1.18 g, 1.92 mmol) in water (50 mL). The mixture was stirred for 1 hour and then extracted with ethyl acetate (100 mL). The separated organic layer was washed with Na2S2O3 (50 mL, saturated aqueous solution) and then dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (SiO2, hexanes:EtOAc, 1:0 to 7:3) gave the title compound. Mass Spectrum (ESI) m/z=674.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13]#[N:14].F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:13]#[N:14])=[C:2]([NH:1][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[S:6][C:5]=2[CH:7]=1
Reactant: COc1ccc2c(C#N)c(N)sc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: COc1ccc2c(C#N)c(Nc3cc(F)ccc3[N+](=O)[O-])sc2c1
Yield: 29 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-methoxybenzo[b]thiophene-3-carbonitrile (5.2 g) and 2,4-difluoro-nitrobenzene (4.0 g), 6-methoxy-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (2.5 g) was obtained.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[Na+].CN(C=O)C.[Br:13][C:14]1[C:15]([C:26]#[N:27])=[N:16][N:17]([CH2:24][CH3:25])[C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22]Cl>O>[C:1]([O:4][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1[N:17]([CH2:24][CH3:25])[N:16]=[C:15]([C:26]#[N:27])[C:14]=1[Br:13])(=[O:3])[CH3:2]
Reactant: CCn1nc(C#N)c(Br)c1CCCCCl
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C#N)c(Br)c1CCCCOC(C)=O
Temperature: 100 °C
Yield: 80.5 %

Procedure:
Potassium acetate (1.69 g, 17.2 mmol), sodium iodide (255 mg, 1.7 mmol), and DMF (17 mL) were added to 4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.0 g, 3.4 mmol, prepared as described in Parts A-E of Example 19), and the reaction was heated at 100° C. for two hours under a nitrogen atmosphere and allowed to cool to ambient temperature. Water was added, and the resulting mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with hexanes/ethyl acetate in a gradient from 90:10 to 60:40) to provide 0.86 g of 4-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)butyl acetate.
Reaction SMILES: FC1C=CC=CC=1C1C=CN(C)N=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:22]1[CH:23]=[N:24][N:25]([CH3:26])[C:21]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14]
Reactant: BrBr
Reactant: Cn1nccc1-c1ccccc1F
Agent: Cn1ccc(-c2ccccc2F)n1
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Br)c1-c1ccccc1F
Reaction time: 0.83 h
Yield: 27.6 %

Procedure:
To a solution of a mixture of 3-(2-fluorophenyl)-1-methyl-1H-pyrazole and 5-(2-fluorophenyl)-1-methyl-1H-pyrazole (6.77 g, 38.4 mmol, 1.0 eq.) in chloroform (10 mL) under nitrogen at 0° C. was added a solution of bromine (2.0 mL, 39.0 mmol, 1.0 eq.) in chloroform (5 mL) over 10 min. After 50 min, the reaction mixture was diluted with chloroform and washed with saturated aqueous NaHCO3 (3×), dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (10:1) as eluent afforded 4-bromo-5-(2-fluorophenyl)-1-methyl-1H-pyrazole as a white solid (2.70 g, 28% yield), a mixture (0.65 g, 7% yield) and 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole as a white solid (5.94 g, 61% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C)C=O>[C:10]1([CH:9]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CCCC1=O

Procedure:
1-Phenylethyl-2-pyrrolidone is prepared from 2-pyrrolidone and 2-bromoethylbenzene in N,N-dimethylformamide in the presence of sodium hydride (M. Matsukawa et al. NeuroToxicology 2004, 25, 293-302).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8]O)[NH2:7].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17]>CO>[CH2:20]([O:19][C:15]([C:16]1[N:7]=[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[NH:8][CH:17]=1)=[O:18])[CH3:21]
Reactant: C#CC(=O)OCC
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Solvent: CO
Product: CCOC(=O)c1c[nH]c(-c2cccc(C(F)(F)F)c2)n1
Temperature: 200 °C
Yield: 22.4 %

Procedure:
A mixture of 3-trifluoromethylbenzamidoxime (19.89 g, 0.0974 mol) and ethyl propiolate (9.60 g, 0.0974 mol) in 100 mL methanol was refluxed overnight. The reaction was cooled and concentrated in vacuo and trace methanol removed by azeotroping with toluene (2×100 mL). The remaining residue was heated at 200° C. for 6 h in diphenyl ether (50 mL) before cooling and diluting with cold methanol (200 mL). The solid precipitate was filtered off and sucked dry on a glass frit to give 6.2 g of the title compound as a solid.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[N:16]1([C:2]2[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1oc(Br)nc1C(F)(F)F
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: CCOC(=O)c1oc(N2CCCCC2)nc1C(F)(F)F
Temperature: 120 °C
Yield: 88 %

Procedure:
To a solution of ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) (0.85 mL) in α,α,α-trifluorotoluene (10 mL) at RT was added piperidine (1.1 mL). The reaction mixture was heated at 120° C. for 20 min by microwave then cooled to RT and diluted with EtOAc (100 mL). The organic solution was washed with H2O (2×100 mL), saturated NH4Cl (1×100 mL), brine (1×100 mL), dried over Na2SO4, filtered, and concentrated to give ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A-3) as a yellow solid (1.28 g, 88% yield). LCMS (ESI) calcd for [M+1]+ 293.1. found 293.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 339) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.575 g, 18%). mp 137-139° C. 1H NMR (300 MHz, DMSO d6) δ 0.81 (d, J=7 Hz, 6H), 1.49 (m, 2H), 1.57 (m, 1H), 4.42 (t, J=7 Hz, 2H), 7.44-7.65 (m, 5H), 7.76 (m, 1H), 7.84 (m, 2H), 7.94 (m, 2H), 8.20 (s, 1H). MS (DCI/NH3) m/z 448 (M+H)+, 465 (M+NH4)+. Anal. calc. for C21H22ClN3O4S: C, 56.31; H, 4.95; N, 9.38. Found C, 56.02; H, 4.82; N, 9.31.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=CC(N)=CC=1>C(O)(=O)C>[F:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(F)cc1
Yield: 64 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (76 mg, 0.33 mmol), triethyl orthoformate (0.66 ml), 4-fluoroaniline (0.058 mg, 0.61 mmol), and acetic acid (0.08 ml) were used to give 68.5 mg (0.021 mmol, 64% yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:18][CH2:17][C:16]#[N:19])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC#N
Reactant: NCC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: N#CCCNCC1CCN(Cc2ccccc2)CC1
Yield: 102.2 %

Procedure:
A mixture of 1-(phenylmethyl)-4-piperidinemethanamine (0.076 mol) and acrylonitrile (0.076 mol) in ethanol (250 ml) was stirred and refluxed for 4 hours. The solvent was evaporated, yielding 20.0 g (102.4%, crude residue, used in next reaction step, without further purification) of 3-[[[1-(phenylmethyl)-4-piperidinyl]methyl]-amino]-propanenitrile (interm. 14).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[C:15]([F:22])[CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C>[NH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH2:23][N:13]2[C:14]3[C:19](=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[F:22])[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[N:12]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1

Procedure:
5-Chloro-N-[1-[(3-cyanophenyl)methyl]-7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 45) (600 mg, 1.26 mmol) was dissolved in THF (13 mL) and stirred in an ice bath. The solution was then treated dropwise with lithium aluminium hydride (1M in diethyl ether) (0.881 mL, 0.881 mmol) and stirred under nitrogen overnight. Further six portions of lithium aluminium hydride (1M in diethyl ether, 0.126 mL at a time) were added dropwise to the reaction and stirred for another day. The reaction was quenched with 2M NaOH solution (4 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) before being dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was dissolved in methanol and loaded onto a methanol conditioned sulfonic acid cartridge (SCX-2) 50 g. The cartridge was washed with methanol and eluted with 2M ammonia in methanol. Ammoniacal fractions were evaporated to give a brown gum (100 mg). The aqueous layer was back extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous magnesium sulphate before being evaporated in vacuo to give a brown gum (60 mg). The aqueous layer was back extracted with chloroform-isopropanol 3:1 (100 mL). The organic layer was dried over anhydrous magnesium sulphate before being evaporated in vacuo to a further 40 mg. The solids in the aqueous layer were collected by filtration. The solid was dissolved in methanol and filtered to remove any insoluble material. The filtrate was evaporated in vacuo to a further batch of 300 mg. The combined batches were dissolved in methanol and loaded onto a methanol pre-conditioned 50 g sulfonic acid (SCX-2) cartridge. The cartridge was washed with methanol and then eluted with 2M ammonia in methanol. Ammoniacal fractions were evaporated in vacuo to give the title compound as a brown gum (220 mg) LCMS (System A) RT=0.81 min, ES+ve m/z 481/483 (M+H)+.