Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:40][C:36]3[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3ccc(C)cn3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccc(C)cn3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (40.0 mg) obtained in Example 76-1 was dissolved in methanol (1.2 ml) and then added with 1-methylimidazol-2-aldehyde (11.9 mg) and sodium cyanoborohydride (11.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (42.5 mg) of the subject compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([C:24]4[CH:25]([CH2:31][CH3:32])[CH2:26][C:27](=[O:30])[NH:28][N:29]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH2:31]([CH:25]1[C:24]([C:22]2[CH:21]=[CH:20][C:18]3[N:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[O:16][C:17]=3[CH:23]=2)=[N:29][NH:28][C:27](=[O:30])[CH2:26]1)[CH3:32]
Reactant: [H][H]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1
Agent: [Pd]
Solvent: CO
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1

Procedure:
235 mg (552 μmol) 6-[2-(4-benzyloxy-phenyl)-benzoxazol-6-yl]-5-ethyl-4,5-dihydro-2H-pyridazin-3-one are hydrogenated together with 50 mg palladium on charcoal 10% and 50 ml of methanol at RT and 3.45 bar hydrogen pressure for 2.5 h, then the catalyst is filtered off and the filtrate is evaporated down completely i.V.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@H:13](O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:54])C(=O)C1>C(Cl)Cl>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@@H:13]([Cl:54])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of mixture of compound 2a (1.0 g, 2.67 mmol) and PPh3 (1.4 g, 5.34 mmol) in CH2Cl2 (15 mL) was added NCS (1.07 g, 8.01 mmol) portionwise at 0° C. Then the resulting mixture was stirred at rt for 1 h and poured into a silica gel column and eluted with EtOAc-hexanes (1:4) using pressure. The collected right fractions were combined, concentrated, and co-evaporated with CH2Cl2 several times and used next step (1.0 g, 95%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Br-:6].[K+:7].[Br:8]Br>O>[Br:6][C:2]([Br:8])([C:1]#[N:5])[C:3]#[N:4].[Br-:6].[K+:7]
Reactant: BrBr
Reactant: N#CCC#N
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CC(Br)(Br)C#N
Reaction time: 2 h

Procedure:
A mixture of 99 g of malononitrile and 75 g of potassium bromide in 900 ml of water was cooled to 5°-10° and 158 ml of bromine were slowly added at 5°-10° during 21/2 hours. After addition was completed, the mixture was stirred for 2 hours at 5°-10°, then was filtered. The collected solid was washed with 150 ml of ice-water and air-dried on the filter. A second crop was obtained by filtering the filtrate after a short quiescent period. The isolated solids were combined and dried to constant weight in a desiccator over phosphorus pentoxide (the presence of bromine vapors necessitated replenishing the phosphorus pentoxide) to give 337.5 g of the complex, which was used without further purification.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl.C(O)C>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnccc1O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl

Procedure:
4-Chloro-3-nitropyridine was prepared from 4-hydroxy-3-nitropyridine(25 g, 0.179M), phosphorus pentachloride(40 g, 0.192M) and 1 mL of phosphorous oxytrichloride. The mixture was heated at 120° for 1 hour. The reaction mixture was diluted with chlorform/ethanol mixture(9/1) and the precipitate was filtered to afford desired. (mp. 153-154° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11](Cl)=[O:12])[S:10][C:3]=12.[CH3:14][N:15]([CH3:17])[NH2:16]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:16][N:15]([CH3:17])[CH3:14])=[O:12])[S:10][C:3]=12
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Reactant: CN(C)N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride 20 (1 g, 4.33 mmol) (scheme 6) in DCM (22 mL), 1,1-dimethylhydrazine (0.33 mL, 4.33 mmol) was added in one portion and the mixture was stirred for 5 h. More 1,1-dimethylhydrazine (0.33 mL, 4.33 mmol) was added and the mixture was stirred overnight at room temperature. The crude was diluted with EtOAc, extracted with 1N HCl, the aqueous solution basified to pH˜11 by addition of 1N NaOH, extracted with EtOAc, the organic phase dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 237 (798 mg, 3.13 mmol, 72%) as a crude mixture that was used in the next step without further purification. MS (m/z): (M+1) 255.9 (100%), 257.9 (39%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:22][CH2:21]3)[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[ClH:4].[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([Cl:7])=[O:28])[CH2:24][CH2:25]3)[O:16][N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.24 mL) was added dropwise to a 0° C. solution of the compound prepared in Example 58 (615 mg) in dichloromethane (8 mL). The reaction was stirred at room temperature for 30 minutes and then concentrated to obtain the title compound (600 mg) having the following physical data. 1H NMR (DMSO-d6): δ 7.92-7.81 (m, 2H), 7.62-7.48 (m, 3H), 7.38 (s, 1H), 4.59 (s, 2H), 3.50-3.36 (m, 2H), 3.12-2.97 (m, 2H), 2.22-2.09 (m, 2H), 1.99-1.79 (m, 3H), 1.67-1.50 (m, 2H).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:30][CH:29]=[CH2:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: -60 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Anhydrous DMF solution (10 ml) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4.40 g, 16.2 mmol) was mixed with 60% sodium hydride (700 mg, 10 mmol) and stirred at roam temperature for 1 hour. The reaction solution was cooled to −60° C., mixed with allyl bromide (2.18 g, 18 mmol) and then returned to room temperature by further stirring for 1 hour. The reaction solution was mixed with ethyl acetate (150 ml), washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 4.32 g of the title compound as an oil (13.8 mmol, 87% in yield).
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.[CH2:13]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:14].[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[C:31]1([OH:34])[CH2:32][CH2:33][N:28]([CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:29][CH2:30]1)[CH3:14]
Reactant: CCOC(=O)C(C)C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)C1(O)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Yield: 74.8 %

Procedure:
125 ml of 1.6M butyllithium was added dropwise to a solution of 18.5 g (0.18 mole) of N-(1-methylethyl)-2-propanamine in 75 ml of tetrahydrofuran, cooled to a temperature of -70° C. The mixture was stirred for ten minutes at this temperature then 17.5 g ( 0.15 mole ) of 2-methyl-propanoic acid ethyl ester in solution in 70 ml of tetrahydrofuran was added, keeping the temperature at -70° C. After stirring for one hour at this temperature, a solution of 26 g (0.14 mole) of 1-phenylmethyl-4-piperidinone in 70 ml of tetrahydrofuran was added. The reaction medium was stirred for 1.5 h at a temperature of -70° C. and was then allowed to return to room temperature. After evaporating off the solvents under reduced pressure, the residue was poured into a saturated solution of ammonium chloride. The organic phase was extracted with ether, washed with water, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. After purification by distillation, 32 g (yield: 76%) of the desired product was obtained as an oil. B Pt=145°-150° C. (0.05 mm Hg, i.e. about 6.66 Pa)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)[CH2:26][CH:27]([N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(Nc2nc3n(n2)CCC(N2CCCC2)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.4 %

Procedure:
2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (50 mg, 0.107 mmol, from example 137) was added to a mixture of pyrrolidine (7.62 mg, 0.107 mmol), and sodium cyanoborohydride (1.0 M in THF, 428 μL, 0.428 mmol) in ethanol (0.535 mL). The mixture was stirred at rt for 48 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (24.8 mg, 35% yield) as a TFA salt. LC-MS (M+H)+ 522.4. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.80 (1 H, d, J=1.5 Hz), 7.35 (1 H, d, J=2.1 Hz), 6.98-7.22 (7 H, m), 4.96 (1 H, br. s.), 4.65-4.74 (1 H, m), 3.97-4.09 (1 H, m), 3.78-3.97 (5 H, m), 3.38 (1 H, br. s.), 2.92-3.02 (1 H, m), 2.84 (2 H, d, J=4.9 Hz), 2.36-2.53 (2 H, m), 2.03-2.31 (5 H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:30][NH:31][C:32]1[S:33][C:34]([S:38]([NH2:41])(=[O:40])=[O:39])=[C:35]([CH3:37])[N:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:41][S:38]([C:34]1[S:33][C:32]([N:31]([CH3:30])[C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:14][CH:13]=2)=[N:36][C:35]=1[CH3:37])(=[O:39])=[O:40]
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)Cc1ccc(-c2cc(F)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3cc(F)ccc3F)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At room temperature, 1.00 g (4.0 mmol) of (2′,5′-difluoro[1,1′-biphenyl]-4-yl)acetic acid and 0.54 g (4.0 mmol) of 1-hydroxy-1H-benzotriazole hydrate are initially charged in 15 ml of dimethylformamide. 0.84 g (4.0 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 0.77 g (4.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. Most of the dimethylformamide is removed at 50° C. under high vacuum, and the residue is stirred 3 times with in each case 50 ml of water and filtered off, stirred with 50 ml of isopropanol and filtered off once more. Removal of the solvent under reduced pressure gives the compound of Example 87 in the form of a slightly yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([N:14]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)=[N:15]1)=[O:13])[CH3:10].O>ClCCl>[CH2:9]([NH:11][C:12]([N:14]1[C:18]([CH3:19])=[C:17]([Br:1])[C:16]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:29])([F:30])[F:31])=[CH:23][N:22]=2)=[N:15]1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)c(Br)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
N-Bromosuccinimide (0.64 g, 3.6 mmol) was added to a solution of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (1.05 g, 3.0 mmol) in dichloromethane (20 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-4-bromo-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.86 g, yield: 67.0%). mp: 123-125° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.67 (s, 3H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 6.90-7.10 (m, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:44]/[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=4)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2ccccn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), [(2-pyridyl)methyl]triphenylphosphonium chloride (0.94 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)pyridine as colorless crystals (0.68 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=2)=[CH:24][C:6]=1[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: Cc1ccc(NC(=O)c2cccnc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (20 mg, 0.058 mmol) and nicotinoyl chloride hydrochloride (10 mg, 0.058 mmol) similar to Example 139 and isolated as a tan solid (13 mg, 47%). 1H NMR (DMSO-d6):
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1.N1C=CC=CC=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.Cl>CN(C=O)C>[CH:20]1([C:23]([N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([OH:13])[C:10]=3[CH2:11][CH2:12][C@@H:3]2[CH3:2])=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CCc2c(O)cccc2N1
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]1CCc2c(O)cccc2N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A 1000-mL round bottomed flask fitted with a nitrogen inlet, overhead stirrer, addition funnel, and thermocouple, was charged with (S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide (20 g, 82 mmol), followed by anhydrous DMF (109 mL), and pyridine (19.8 mL, 246 mmol). Cyclopropanecarbonyl chloride (7.43 mL, 82 mmol) was added dropwise over 30 minutes while holding temperature below 20° C. with a cool water bath. Following completion of the addition, the reaction mixture was stirred for 1.5 h at ambient temperature. The pot was cooled to 0° C. in an ice bath and 0.29 M aqueous HCl solution (315 mL) was added dropwise over 15 minutes. The slurry was stirred for 90 minutes in the ice bath before being filtered. The pot and filter cake were washed with 25 mL of ice water. The filter cake was dried under nitrogen on a Buchner funnel to afford (2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (17.16 g, 91%) as an off-white powder. MS (ES, m/z): 232 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[Cl:9])[NH2:5].[OH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[OH-].[K+]>CS(C)=O>[Cl:9][C:8]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]([NH2:5])=[CH:3][C:2]=1[N:17]1[CH:18]=[CH:19][C:14](=[O:13])[CH:15]=[CH:16]1
Reactant: Oc1ccncc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2ccc(=O)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 1.5 %

Procedure:
First, a mixture containing 14.3 g of 3,4-dichloro-6-nitroaniline, 9.01 g of 4-hydroxypyridine, 5.87 g of 86% potassium hydroxide, and 70 ml of dimethylsulfoxide was heated in an oil bath at 130° C. for 3.5 hours, and cooled. Ice water was added to the mixture and precipitated crystals were filtered. Then, 16.9 g of the resultant crude crystals were applied to a column containing 100 g of silica gel and eluted with 10% methanol in chloroform. The eluate was combined and evaporated. The residue was filtered to give 9.78 g of crude crystals of 4-chloro-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline (melting point: 288° to 291° C. (decomposition)). Then, 300 mg of the crude crystals were recrystallized with methanol to give 268 mg of crystals of 4-chloro-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CO
Product: COc1ccc2c(OC)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 285(MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].[CH3:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:16][O:15][CH3:14])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (1.62 g, 8.80 mmol, prepared using procedure in WO9849166), 2-bromoethyl methyl ether (1.23 g, 8.85 mmol) and cesium carbonate (2.90 g, 8.92 mmol) in N,N-dimethylformamide (20 ml) was stirred at 20° C. for 20 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (125 ml) and brine (100 ml). The phases were separated, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc/MeOH, 97:3) to afford the title compound of preparation 4 (831 mg, 3.43 mmol, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCCC2)c1C
Temperature: 80 °C
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.4 g, 0.0049 mole) in acetonitrile (10 mL), cesium carbonate (3.2 g, 0.0099 mole) and methyl iodide (3.5 g, 0.0024 mole) were added; resulting reaction mass was heated at 80° C. for 13 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (800 mg, 55%).