Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:22]=[CH2:23]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 75 °C
Reaction time: 60 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (2 g) in dimethylformamide (10 ml) at room temperature was added vinyltri-n-butyl tin (4.25 g) and tetra-kis-triphenylphosphinepalladium(0) (0.3 g). The mixture was heated at 75° C. for one hour and then cooled and left at room temperature for 60 hours. The reaction mixture was diluted with water and extracted with ether. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give the crude product as a black oil (6 g) which was purified by column chromatography on silica gel (200 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions gave the title compound as a buff solid, m.p. 186-70° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=O.[Cl-].[OH:31][NH3+:32].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[N:32][OH:31]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
27 g (65.1 mmol) of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 4.5 g (65.1 mmol) of hydroxylammonium chloride and 12.9 g (163 mmol) of pyridine. The reaction mixture is refluxed for 4 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 13.5 g of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone oxime as a beige solid with a melting point of 76-80° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 0.88 (t, 3H), 1.20-1.40 (m, 24H), 1.40-1.50 (m, 2H), 1.75-1.84 (m, 2H), 3.96-4.02 (m, 2H), 6.89(E)/6.95(Z) (d, 2H), 7.43(E)/7.52(Z) (d, 2H), 8.28(Z)/8.43(E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=7:3.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br>C(O)(=O)C.O>[Br:13][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COc1cccc(C(=O)O)c1F
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(C(=O)O)c1F
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To the suspension of 2-fluoro-3-methoxybenzoic acid (20 g, 118 mmol) in Acetic Acid (100 mL) and water (100 mL) at RT, bromine (12.05 mL, 235 mmol) was added dropwise. The reaction mixture was heated for 1 h at 60° C. The reaction was then cooled to RT and white precipitate was filtered. The solid was washed with excess water and dried to give 6-bromo-2-fluoro-3-methoxybenzoic acid (24.68 g, 99 mmol) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:16])[C:9]=2[Cl:15])[N:4]=1)[CH3:2].[H-].[Na+].C(C1C(C)=[C:29]([O:32][C:33](C2CC2)=[O:34])C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14][C:33]([O:32][CH3:29])=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:16])[C:9]=2[Cl:15])[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2ccc(F)c(Cl)c2c(O)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2ccc(F)c(Cl)c2c(OC(=O)OC)c1C
Reaction time: 1 h

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5-chloro-6-fluoroquinoline (1.5 g) prepared as described in Example 7 was dissolved in 70 ml of methanol. To this solution was added 30 ml of a 10% aqueous sodium hydroxide solution. The mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 1.17 g of 0.2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 15 ml of dimethyl formamide was suspended 40.1 mg of 60% sodium hydride. Separately, 200 mg of 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) prepared above was suspended in 2 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 78.5 mg of methyl chloroformate (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated, brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 218.8 mg of 2-ethyl-3-methyl-4-methoxycarbonyloxy-5-chloro-6-fluoroquinoline (compound 36). 1H-NMR data are shown in Table 3.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[NH:21][N:20]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Yield: 87.8 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.48 g) and hydrazine hydrate (0.508 g) in ethanol (10 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was washed with diisopropylether to give 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (2.15 g) as pale yellow crystals.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([O:7]C(=O)C2C=CC=CC=2)[C@@H:5]([CH2:16][O:17]C(=O)C2C=CC=CC=2)[O:4][C@H:3]1[N:26]1[CH:33]=[C:32]([I:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28].[OH-].[Na+]>CO.O>[F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:16][OH:17])[O:4][C@@H:3]1[N:26]1[CH:33]=[C:32]([I:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28]
Reactant: O=C(OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-5-iodouracil (4.7 g, 0.0081 mole) from Procedure 6 in 60 mL 50% MeOH/H2O is stirred at 25° C. maintained at pH 10.5 with 3N NaOH until complete dissolution of solid occurs. Progress of the hydrolysis is followed by HPLC (mobile phase=70% H2O/30% MeOH, flow rate=1 mL/min., wave length=282 nm UV detection, column=Whatman 10 ODS-3 reverse-phase 25 cm., injection volume=20 μl at ~0.5 mg/l concentration, α-IX=6.86 min., β-IX=7.98 min., and 5-iodouracil=4.5 min.). When the reaction is complete (16 hr.), 25 mL of water is added and the mixture is concentrated to approximately 30 mL. The clear aqueous concentrate is adjusted to pH 6.5 to 7.0 with 3N HCl. A solid forms, the mixture is stirred at 25° C. for 2 hrs., and at 0° to 5° C. for 5 hrs. The solid is collected by filtration, washed with 30 mL cold H2O and dried at 50° C./5 mm. The yield of product is 2.7 g (90%), mp 223°-226° [360 MHz NMR (CD3OD) 8.28, d, 1H; 6.16, dd, 1H; 5.04, m, 1H; 4.32, m, 1H; 3.95-3.7, m, 3H. Elemental analysis calculated: %C 29.05, %H 2.71, %N 7.53; Found: %C 28.86, %H 2.64, %N 7.50; IR (KBr) NH, OH 3400, 3200 cm-1 ; CO--NH--CO 1725, 1655 cm-1, C--O 1050 cm-1.]
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: COC(=O)CCCC[C@H](O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCC[C@@H](CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under an argon atmosphere, triethylamine (324 ml, 2.32 mmol) and methanesulfonyl chloride (132 ml, 1.70 mmol) were added to a solution of (6S)-(-)-methyl 6,8dihydroxyoctanoate (147 mg, 0.77 mmol) in dichloromethane (3.9 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (10 ml) and extracted with dichloromethane (10 ml). The extract was washed with 2 M hydrochloric acid (10 ml), saturated sodium bicarbonate solution (10 ml) and brine (10 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (6S)-(+)-methyl 6,8-bis(methylsulfonyloxy)octanoate (247 mg, 92% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]3[CH2:28][F:29])=[CH:10][CH:9]=2)[O:5][N:4]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:29][CH2:28][C@@H:15]1[C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:2][NH:1][S:30]([CH3:33])(=[O:32])=[O:31])[CH:7]=3)=[CH:13][CH:12]=2)[O:18][C:17]([CH3:19])([CH3:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CNS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a methylene chloride (10 ml) solution of (4S,5R)-tert-butyl 5-(4-(3-(aminomethyl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (270 mg, 0.66 mmol) that had been cooled to 0° C. is added mesyl chloride (83 mg, 0.73 mmol) and diisopropylethylamine (94 mg, 0.73 mmol) sequentially. The reaction is stirred at 0° C. for thirty minutes then quenched with water (2 ml). The quenched reaction is stirred for thirty minutes at room temperature. The organic phase is dried over sodium sulfate and concentrated to give the title compound (310 mg): m/z (Cl) 484 ([m+H]+.
Reaction SMILES: BrC[CH2:3][C:4]1[C:5]([CH3:20])=[N:6][N:7]([CH2:18][CH3:19])[C:8]=1[S:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:10]([S:9][C:8]2[N:7]([CH2:18][CH3:19])[N:6]=[C:5]([CH3:20])[C:4]=2[CH2:3][NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]([Cl:17])[CH:13]=1
Reactant: CCn1nc(C)c(CCBr)c1Sc1cc(Cl)cc(Cl)c1
Reactant: Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(CNc2cccnc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 7.5 %

Procedure:
A mixture of 227 mg of 4-bromoethyl-5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole, 62 mg of 3-aminopyridine and 36 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 15 minutes. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol for the elution to give 17 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-ylmethyl]-pyridin-3-yl-amine as a brown gum. 1H NMR (DMSO-d6) 1.19 (t, 3H), 2.27 (s, 3H), 4.05–4.11 (m, 4H), 6.03 (t, 1H), 6.87 (d, 1H), 6.99 (m, 1H), 7.04 (d, 2H), 7.44 (t, 1H), 7.72 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[C:40](=[O:41])[N:39]([CH2:42][C:43]3[O:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=3)[N:38]=[CH:37]2)[S:31][C:32]=1[C:33]([OH:35])=O.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[C:40](=[O:41])[N:39]([CH2:42][C:43]3[O:44][C:45]([C:48]([F:49])([F:51])[F:50])=[CH:46][CH:47]=3)[N:38]=[CH:37]2)[S:31][C:32]=1[C:33]([NH:59][CH2:58][C:54]1[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=1)=[O:35]
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 4-methyl-2-(5-oxo-1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 57% yield: mp 124-125° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 2H), 8.28 (s, 1H), 7.82-7.75 (m, 1H), 7.36 (s, 1H), 6.77-6.72 (m, 1H), 6.52 (t, J=5.5 Hz, 1H), 6.47-6.42 (m, 1H), 5.04 (s, 2H), 4.66-4.60 (m, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.6, 115.4, 150.9, 150.8, 149.7, 149.3, 149.2, 135.7, 131.4, 123.7, 121.8, 120.5, 116.9, 112.6, 112.5, 110.4, 42.1, 41.6, 17.2; MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][C:25]=3[O:27]C)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]>N1C=CC=CC=1.N.CO>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:25]([OH:27])=[CH:24][C:23]([O:29][CH3:30])=[CH:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COc1cc(OC)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: Cl
Agent: N
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 115 °C
Reaction time: 23 h
Yield: 68.5 %

Procedure:
Pyridine hydrochloride (2.33 g) was added in one portion to a stirred mixture of N-(3-chloro-4-fluorophenyl)-5,7-dimethoxyquinazolin-4-amine (6.4 g) in pyridine (75 ml) at room temperature. The reaction mixture was stirred at 115° C. under a nitrogen atmosphere for 23 hours and then the brown solution was cooled to room temperature and the yellow precipitate was filtered and washed with ice cold water to leave a light yellow solid. The solid was taken up in 7N ammonia in methanol and stirred at room temperature for 10 minutes. The solution was filtered and the filtrate was concentrated in vacuo to leave 4-[(3-chloro-4-fluorophenyl)-amino]-7-methoxyquinazolin-5-ol as a light brown solid (4.2 g, 68%); Mass spectrum MH+ 320.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([OH:9])(=O)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]([NH:22][CH:23]=[NH:24])[NH:20][N:21]=1.C(OC(=O)OCC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]2[N:22]=[CH:23][NH:24][C:6](=[O:9])[N:20]2[N:21]=1
Reactant: N=CNc1cc(-c2ccccc2Cl)n[nH]1
Reactant: CC(=O)O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: O=c1[nH]cnc2cc(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To an ethanolic solution of sodium ethoxide, generated by portionwise addition of sodium metal (4.2 g, 185 mmol) to stirred ethanol (250 ml), was added N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-formamidine, acetate salt (I-3A-9b; 5.2 g, 18.5 mmol) in one portion. Diethylcarbonate (17.8 ml, 148 mmol) was added, dropwise, and the mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction was concentrated, in vacuo, and then extracted with ethyl acetate from water after adjusting to pH 7 with 3 M aqueous HCL. The combined organic layers were washed with water and then brine, dried (MgSO4), filtered, and then concentrated, in vacuo, to one-third volume at which time a precipitate began to form. After stirring overnight, the product was collected by vacuum filtration and then dried, in vacuo, to afford I-3A-9c as a solid (2.61 g, 57%). A second crop of the intermediate was collected from the filtrate after standing an additional 24 hours (600 mg, 19%): +ESI MS (M+1) 247.1; 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.86-7.82 (m, 1H), 7.55-7.51 (m, 1H), 7.45-7.39 (m, 2H), 6.92 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].O>O1CCOCC1>[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][O:14][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1
Reactant: CC(C)(C)CO
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)COCc1ccc(C#N)cc1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3 mL, 6 mmol, 2M solution in THF) to a solution of 2,2-dimethyl-1-propanol (528 mg, 6 mmol) in anhydrous 1,4-dioxane. Stir until the suspension becomes homogenous. Then add a solution of 4-cyanobenzyl bromide (980 mg, 5 mmol) in anhydrous 1,4-dioxane (3 mL). Heat the mixture in a microwave oven at 100° C. for 30 min. Cool to room temperature, add water (50 mL) and extract with EtOAc (3×50 mL). Dry the combined organic extracts over MgSO4, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain the desired intermediate (811 mg, 80%).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1.C(N1CCC2C(C(N3CCC(C4C=CC=C(F)C=4C(F)(F)F)CC3)=O)=NNC=2C1)C>>[CH:30]1([CH2:33][N:22]2[CH2:23][CH2:24][C:25]3[C:17]([C:15]([N:12]4[CH2:11][CH2:10][CH:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[C:4]=5[C:26]([F:29])([F:27])[F:28])[CH2:14][CH2:13]4)=[O:16])=[N:18][NH:19][C:20]=3[CH2:21]2)[CH2:32][CH2:31]1
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Reactant: O=CC1CC1
Agent: CCN1CCc2c(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Product: O=C(c1n[nH]c2c1CCN(CC1CC1)C2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1

Procedure:
Following general procedure GP-G1, ((4-(3-fluoro-2-(trifluoro-methyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (30) and cyclopropane carbaldehyde were converted to (6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluormethyl)phenyl) piperidin-1-yl)methanone as a white solid (23 mg, 34%): 1H NMR (300 MHz, DMSO-d6) δ 12.74 (br s, 1H), 7.72-7.65 (m, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.34-7.27 (m, 1H), 4.92-4.63 (m, 2H), 3.59-3.53 (m, 2H), 3.32-3.09 (m, 2H), 2.90-2.39 (m, 7H), 1.81-1.62 (m, 4H), 0.92-0.85 (m, 1H), 0.52-0.48 (m, 2H), 0.14-0.10 (m, 2H); ESI MS m/z 451 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([OH:5])[CH3:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].[OH-].[Na+]>C1COCC1.CC(OC)(C)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][NH:1][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@@](O)(CN)c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-amino-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (34.7 g, 140 mmol) in THF (400 ml) was added 2-nitro-benzenesulfonyl chloride (34.9 g, 154 mmol) at 0-5° C. and afterwards 1N aqueous NaOH over a period of 0.5 h. The reaction mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with TBME and washed with water and NaH2PO4 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (toluene-EtOAc 3:1): Rf=0.51; UPLC RtH5=1.118 min; ESIMS: 450, 452 [(M+NHa)+]; 1H NMR (360 MHz, CDCl3): δ 7.98 (m, 1H), 7.81 (m, 1H), 7.65 (m, 2H), 7.59 (dd, 1H), 7.24 (m, 1H), 6.79 (dd, 1H), 5.60 (t, 1H), 4.16 (br s, 1H), 3.55 (dd, 1H), 3.44 (dd, 1H), 2.51 (s, 1H), 1.51 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C@H:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.[H-].[Na+].O1CCCC1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O>[CH3:23][S:20]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[C@@H:10]1[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:2](=[O:1])[N:11]1[S:43]([CH3:42])(=[O:45])=[O:44])[C:16]#[N:17])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-4-(2,5-Dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 11 mg, 0.29 mmol) and tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 10 min. Methanesulfonyl chloride (16 μL, 0.22 mol) is added, and the mixture is heated at 50° C. for 2 h. The mixture is cooled at room temperature, diluted with water (0.5 mL) and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 37 mg; ESI mass spectrum [M+H]+=568; Retention time HPLC: 0.81 min (005_CA01).