Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH2:23])[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:14])=[O:13].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH:23][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:13])=[O:14]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Cl)C[C@@H]21
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N1C[C@H]2CC[C@H](Nc3ccc(C(F)(F)F)cn3)[C@H]2C1
Temperature: 86 °C

Procedure:
(3aR,4S,6aS)-2-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-amine (70 mg, 0.190 mmol) from Step B of Example 284, 2-bromo-5-(trifluoromethyl)pyridine (42.9 mg, 0.190 mmol), and triethylamine (0.079 mL, 0.569 mmol) were combined in ethanol (0.6 mL). The reaction was heated at 86° C. for 5 days and the solvent was evaporated in vacuo. The resultant material was purified using a 12 g silica gel cartridge with a gradient of 0-0.8% methanol (2 N ammonia)/dichloromethane over 20 minutes to give crude product. It was further purified by loading it onto 2×0.25 mm preparative thin-layer chromatography plate and eluted with 30% acetone/hexanes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50-8.52 (bs, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.03 (s, 1H), 7.96-7.98 (m, 1H), 7.75-7.78 (m, 1H), 7.54-7.59 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 4.30-4.42 (m, 1H), 3.89 (dd, J=10.2, 2.7 Hz, 1H), 3.57 (dd, J=10.2, 7.0 Hz, 1H), 3.43 (dd, J=9.9, 6.7 Hz, 1H), 3.39 (dd, J=10.0, 2.9 Hz, 1H), 2.68 (d, J=3.5 Hz, 2H), 2.13-2.20 (m, 1H), 1.90-1.97 (m, 1H), 1.59-1.66 (m, 1H), 1.40-1.48 (m, 1H); MS (ESI+) m/z 514 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F

Procedure:
To a solution of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (2.00 mmol) in 8 mL toluene is added 1-amino-2-(isopropylsulphonyl)benzene (2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and cesium carbonate (2.20 mmol). The mixture is purged with nitrogen, and can be subjected to microwaves at 100° C. until formation of 2-chloro-5-trifluoromethyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine. The reaction mixture can then be concentrated and purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(F)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-fluoro-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (DMSO-d6): 10.97 (s, 1H), 8.94 (d, J=2.7, 1H), 8.36-8.32 (m, 1H), 8.02-7.98 (m, 1H), 7.78-7.75 (m, 1H), 7.73-7.72 (m, 1H), 7.70 (d, J=1.5, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: CC(C)c1ccc(N)c(C(F)(F)F)c1
Yield: 97.4 %

Procedure:
330 g of 2-nitro-5-isopropylbenzotrifluoride in 1,200 ml of methanol are initially introduced into a hydrogenation apparatus, and 30 g of Raney nickel are added. After the system has been flushed with hydrogen, a hydrogenation is carried out at 25°-45° C. under a pressure of 30 bar of hydrogen. After the hydrogen absorption is complete, the solution is filtered to separate off the catalyst. After the solvent has been distilled off, the product is distilled. 280 g of 2-amino-5-isopropylbenzotrifluoride (boiling point: 95°-8° C./18 mbar, nD20 : 1.4810) are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(c1)NC(=O)CC2
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A solution of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (310 mg, 1.90 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (666 mg, 2.28 mmol) in DMF (3.0 mL) is treated with Cs2CO3 (1.25 g, 3.80 mmol). The resulting suspension is heated at 60° C. for 5 hours and then quenched with water dropwise. The mixture is extracted with EtOAc (40 mL×3) and the combined organics are dried (Na2SO4), concentrated to a suspension. It is then filtered and the solid is rinsed with EtOAc (2 mL) and dried under vacuum to obtain pure product (233 mg, 29%).
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[Cl:22])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[Cl:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4]([NH:40][CH3:39])=[O:23])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-N-methyl 3-pyridin-3-yl-acrylamide CCXXIV was prepared from 3-(3-chloro-1H-indazol-5-yl)-3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[NH:5][N:4]=1.[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+].C(O)(=O)C.N1CCCCC1>ClCCl.O>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1
Reactant: C/C([O-])=C/C#N
Reactant: COc1n[nH]c2ccc(C=O)cc12
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12

Procedure:
A mixture of 300 mg (1.704 mmol) 3-methoxy-1H-indazole-5-carbaldehyde (Example 7A), 151 mg (1.442 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 93 μl (1.639 mmol) acetic acid and 11 mg (0.131 mmol) piperidine in dry dichloromethane (10 ml) was refluxed overnight employing a water separator. Upon cooling, a precipitate was formed which was removed by filtration. The filtrate thus obtained was concentrated, and the residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to afford 43 mg (10% of th.) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Reactant: CC(=O)OCC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and acetic acid chlorocarbonyl-methyl ester the title compound was obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:3]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1
Reactant: CCCc1nn(C)c2c(Cl)nc(CCC(=O)OC)nc12
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(=O)OC)nc12
Yield: 105.3 %

Procedure:
3 g of methyl 3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionate and 1.9 g of 3-chloro-4-methoxybenzylamine (“A”) in 50 ml of dimethylformamide (DMF) are stirred at 60° for 12 hours in the presence of potassium carbonate. After filtration, the solvent is removed and the mixture is worked up in the customary manner. 4.6 g of methyl 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionate are obtained as a colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([CH:20]=[CH:21][CH3:22])=[CH:18][CH:19]=3)=[C:11]([F:23])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([CH2:20][CH2:21][CH3:22])=[CH:18][CH:19]=3)=[C:11]([F:23])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)s1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)s1

Procedure:
3.10 g (8.73 mmol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)-5-propenylthiophene are hydrogenated in 100 ml of THF, in the presence of Pd/C (5% of Pd) at atmospheric pressure and room temperature. The reaction solution is evaporated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(4′-ethyl-3-fluorobiphenyl-4-yl)-5-propylthiophene as a colourless solid (m.p. 41° C.).
Reaction SMILES: O=O.[C:3]([NH:11][C:12](=[CH:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-]>>[C:3]([NH:11][CH:12]([CH2:17][N:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Agent: O=O
Agent: [Cl-]
Product: COC(=O)C(CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Reaction time: 20 h

Procedure:
With exclusion of oxygen, an autoclave was charged with 1 g (2.68 mmol) of methyl 2-benzoylamino-3-diphenylaminoacrylate and 40 mg (0.042 mmol) of tris(triphenylphosphine)rhodium(l) chloride. After purging with argon, 40 ml of oxygen-free methanol were added. The autoclave was sealed gas-tight and the solution was hydrogenated at RT for 20 hours (h). The autoclave was decompressed and purged with nitrogen. The solvent was evaporated off under reduced pressure and the residue was chromatographed through a column filled with silica gel 60 (eluent: 1:1 ethyl acetate/heptane). After the solvents had been evaporated off under reduced pressure, a white solid remained, which was utilized for the formulation of a method and as a system test for the determination of the enantiomeric purity by HPLC on chiral phase.
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:3]=1[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[N:9]=1)=[O:7].N1C2C(=CN=CC=2)C=[CH:25][C:24]=1C(O)=O.O.ON1C2C=CC=CC=2N=N1.NC1C=CC=C(F)C=1CN>CN(C=O)C>[C:19]1([C@@H:18]2[CH2:3][C@H:4]2[NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][CH:14]=3)[N:9]=2)=[O:7])[CH:20]=[CH:21][CH:2]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: Nc1cccc(F)c1CNC(=O)c1ccc2cnccc2n1
Agent: NCc1c(N)cccc1F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Compound #16 N-(2-amino-6-fluorobenzyl)-2-[1,6]naphthyridinecarboxamide To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-amino-6-fluorobenzylamine (60.0 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.0 mg, 94%): m.p. 165 (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([C:12]([C:14]2[CH:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)=[O:13])[CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].C(O)(C)C.Cl>[Zn+2].[Br-].[Br-].CCOC(C)=O.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]2[N:25]=[N:26][NH:27][N:9]=2)=[C:4]([C:12]([C:14]2[CH:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)=[O:13])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1OCc1nn[nH]n1
Yield: 111.2 %

Procedure:
[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]-acetonitrile (38 mg) was added NaN3 (66 mg), ZnBr2 (59 mg), isopropanol (1.3 mL) and water (1.6 mL), and the reaction mixture was heated to reflux for 1 h. The mixture was added 3% HCl (1 mL) and EtOAc (4 mL) and stirred until two clear phases appeared. The aqueous phase was added 3% HCl until pH<1 and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated to give 47 mg white foam: LC/MS (an10n8): Rt 2.93, m/z 243.0 [M−H]−; 1H NMR (CDCl3): δ 5.69 (s, 2H), 7.13 (d, J=8.6 Hz, 1H), 7.39-7.45 (m, 1H), 7.49-7.56 (m, 2H), 7.62-7.71 (m, 2H), 7.71-7.79 (m, 1H), 8.13 (s, 1H), 8.45 (s, 1H); 13C NMR (CDCl3): δ 63.3, 115.6, 117.7, 120.3, 124.5, 128.6, 130.0, 131.2, 132.0, 132.9, 136.3, 139.1, 143.5, 154.7, 188.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[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.C[N:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:22][NH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: Cn1cc(B(O)O)cn1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3cn[nH]c3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and N-methyl-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-7-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:21]([O-:23])=[O:22])=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[C:6]([OH:8])[CH:7]=1.[F:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][CH2:25][F:24])[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: OCCF
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1OCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrophenol (0.35 g), 2-fluoroethanol (71 mg) and triphenylphosphine (0.31 g) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 0.68 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/1) to give 2-chloro-4-(2-fluoroethoxy)-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (0.24 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution were added methanol (3 mL) and nickel(II) bromide (7 mg). To the mixture was added sodium borohydride (70 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−1/1) to give the title compound (0.2 g).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH2:6]=[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[CH3:8].ClC(Cl)C.ICI>[Cl-].[NH4+]>[CH3:6][C:7]1([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)[CH2:1][CH2:8]1
Reactant: C=C(C)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc2cc(C3(C)CC3)ccc2c1
Temperature: 25 °C
Yield: 151.5 %

Procedure:
Diethylzinc (1.0 M in Hexane)(6.30 ml, 6.30 mmol) was added to a solution of methyl 6-(prop-1-en-2-yl)-2-naphthoate (0.57 g, 2.5 mmol).in dichloroethane at 0° C. Diiodomethane (1.01 ml, 12.6 mmol) was then added dropwise to the mixture solution and the resultant mixture was stirred at 60° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (30 mL), and the mixture was extracted with CH2Cl2 (30 ml×3). The combined organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), and the organic layer was dried over Na2SO4. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate-hexane (1:20) to give 0.91 g of the title compound as white solid. 1H NMR (270 MHz, CDCl3) ppm 0.75-0.95 (2H, m), 0.95-1.13 (2H, m), 1.52 (3H, s), 3.97 (3H, s), 7.41 (1H, d, J=9.9 Hz), 7.74 (1H, s), 7.82 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=8.6 Hz), 8.04 (1H, d, J=8.6 Hz), 8.56 (1H, s). MS (ESI) m/z: not observed M+ peak.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(O)(=O)C>CO.ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([OH:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNc2ccc(F)cc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cnc2ccc(F)cc2n1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.00 g, 24.1 mmol, 1.0 eq), sodium hydroxide (1.93 g, 48.2 mmol, 2.0 eq) and of 3% hydrogen peroxide solution (50 mL) is refluxed for 2 hours, then it is acidified by slow addition of acetic acid. The resulting mixture is cooled to room temperature, the precipitated solid is collected by filtration, washed with ice-water, and dried under vacuum to give a crude that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1, v/v) to afford 7-fluoro-quinoxalin-2-ol as a yellow solid (2.60 g, 69% yield).
Reaction SMILES: [C:1]([C:4]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([N:8](CC)CC)=[O:7])(=O)[CH3:2].[NH2:19]N>O>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]2[C:4]=1[C:1]([CH3:2])=[N:19][NH:8][C:6]2=[O:7]
Reactant: NN
Reactant: CCN(CC)C(=O)c1cccc(OC)c1C(C)=O
Solvent: O
Product: COc1cccc2c(=O)[nH]nc(C)c12
Yield: 64 %

Procedure:
To 0.37 g (1.48 mmol) of 2-acetyl-3-methoxy-N,N-diethylbenzamide* in 5 ml of water was added 5 ml of anhydrous hydrazine. This was heated at reflux for four hours, cooled and the resulting solid filtered and washed with water to provide 0.18 g (64%) of the desired product; mp 257°-260°.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccccc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.1 mL, 35.3 mmol), pyridine (3.80 mL, 47.0 mmol) and 2-chloroaniline (3.00 g, 23.52 mmol). The reaction mixture was heated for 6 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chlorophenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=256.1 (M+1).
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.O[C:29]1([C:53]2[C:61]([OH:62])=[CH:60][C:56]3[O:57][CH2:58][O:59][C:55]=3[CH:54]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH2:38][CH2:39][CH2:40][N:41]2[C:49](=[O:50])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]2=[O:51])[C:30]1=[O:52]>>[OH:62][C:61]1[C:53]([CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH2:38][CH2:39][CH2:40][N:41]3[C:49](=[O:50])[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:42]3=[O:51])[C:30]2=[O:52])=[CH:54][C:55]2[O:59][CH2:58][O:57][C:56]=2[CH:60]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{3-[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (94%): 1H NMR (300 MHz, CDCl3,) δ 7.81-7.78 (m, 2H), 7.70-7.67 (m, 2H), 7.32-7.27 (m, 2H), 7.12-7.07 (m, 1H), 6.90-6.87 (m, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 5.86 (dd, 2H), 4.82 (s, 1H), 3.96-3.66 (m, 4H), 2.17-2.04 (m, 2H); MS (ES+) m/z 457.0 (M+1).