Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)C>O1CCCC1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH:24]([N:26]([CH3:27])[CH3:28])[CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 11 h
Yield: 33 %

Procedure:
To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (78 mg) in tetrahydrofuran (6.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.82 ml), followed by stirring at room temperature for 11 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (2 ml) and hexane (2 ml) were added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (34.9 mg, 33%) as pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Product: CCCCNc1nc(N)c2[nH]cnc2n1

Procedure:
2-Chloroadenine (6.0 g, 35.4 mmol) and butylamine (30 ml) were placed in an autoclave (200 ml), and the content of the autoclave was allowed to react at 130° C. for 150 hours. The reaction solution was concentrated under reduced pressure, and water was poured into the residue to precipitate a solid. The precipitated solid was sequentially washed with methylene chloride and methanol. Thus, 2.08 g of the title compound was obtained as a yellowish orange powdery solid (yield: 30%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[F:31][C:15]([F:14])([F:32])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([N:1]3[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)=[O:29])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (0.65 g, 3.5 mmol), 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid (0.80 g, 2.9 mmol), triethylamine (0.82 mL, 5.8 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.4 g, 3.2 mmol) were mixed in dry methylene chloride (10 mL). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (20% EtOAc/hexanes to 40% EtOAc/hexanes) to give 0.975 g of the desired product. MS (M+H) 442.1.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:25]3[CH2:26][CH2:27][CH2:28][CH:23]([C:22]([F:30])([F:29])[F:21])[CH2:24]3)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)(F)C1CCCNC1
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCCCN1CCN(C(=O)c2ccc(CN3CCCC(C(F)(F)F)C3)cc2)CC1

Procedure:
Prepared from the product of Example 13 and 3-trifluoromethylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(CC1CCC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g, 0.49 mmol) and lithium hydroxide monohydrate (0.206 g, 4.9 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid (0.106 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.18 (s, 1H); 3.98 (q, 2H); 3.51 (t, 1H); 2.15-2.28 (m, 2H); 1.55-2.15 (m, 7H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18])[C:3]([O:5]CC)=[O:4].Cl>[OH-].[K+]>[O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:22])[C:17]([OH:19])=[O:18])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)CCCCCCCCC(=O)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(=O)CCCCCCCCC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A suspension of 350 mg (1.11 mmole) of diethyl 2,11-dioxododecanedioate in 10 ml of 5% potassium hydroxide solution was stirred at room temperature for 2 hours, by which time all of the material had gone into solution. The aqueous solution was acidified with concentrated HCl, and the product was extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate and filtered. Concentration of the filtrate gave 250 mg of residue, which solidified. This material was used directly in the next reaction without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[NH:9][CH:10]=1)=[O:5])C.CO.[OH-].[Na+].[OH-].[Na+]>>[C:20]([N:17]1[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12][S:11][C:8]2[NH:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:19][CH2:18]1)([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: CCOC(=O)c1c[nH]c(SCCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCSc2nc(C(=O)O)c[nH]2)CC1

Procedure:
6-2 (162.5 mg, 0.42 mmol) was dissolved in 3 mL MeOH NaOH (1N, 0.5 mL, 0.5 mmol) was added; after 6 h additional NaOH (1N, 1 mL, 1 mmol) was added; after 1 day additional NaOH (1N, 1 mL, 1 mmol) was added. After three more days the mixture was heated at 50° for 6 h, then concentrated. The residue was taken up in water, pH adjusted to 5 with 5% KHSO4, extracted 3× with EtOAc, the combined organic extracts were washed with brine, dried (MgSO4), and concentrated providing acid 6-3. Rf 0.39 (9:1:1 CH2Cl2 /MeOH/HOAc);
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=3)[N:12]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:11]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1.O>[CH:4]1([C:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=3)[N:12]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)CCn1c(-c2ccccc2CNCCN(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Lithium hydroxide monohydrate (1 eq) was added to a solution of methyl 3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in a mixture THF:H2O (4:1, 0.1 M). The mixture stirred at RT for 1 h. The reaction was quenched with 1 N HCl and the solvent evaporated in vacuo. The residue was washed with the minimum amount of Et2O and the solid residue filtered to obtain the title compound (82%); MS (ES+) m/z 506 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC.CCOC(C)=O.CCO>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:3]=[C:2]([C:30]3[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=3)[N:7]=1)[CH2:9]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(-c2ccccc2)cc(N2CC3CCC(C2)O3)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccc(-c2nc(-c3ccccc3)cc(N3CC4CCC(C3)O4)n2)cc1
Yield: 75.6 %

Procedure:
A mixture of 3-(2-chloro-6-phenylpyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (500 mg, 1.66 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (545 mg, 2.49 mmol), Pd(PPh3)4 (20 mg), and 2M aqueous Na2CO3 (1.25 mL) in 1:1 toluene:EtOH (8 mL) was heated in a microwave at 120° C. for 20 min. The reaction was repeated with 386 mg of 3-(2-chloro-6-phenylpyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. The reaction mixtures were combined, diluted with EtOAc and washed with H2O then brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give an orange oil. Silica gel chromatography (hexane/EtOAc) gave 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl)aniline as a white solid (450 mg).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20]C)=O)[C:7]2[CH:8]=[N:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[CH:12]=1.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:18]([NH:22][CH2:23][C:24]2[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])=[O:20])[C:7]2[CH:8]=[N:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[CH:12]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
Aqueous NaOH (0.68 g, 17.18 mmol) was added to a solution of methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (3.7 g, 11.45 mmol) in EtOH (40 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and the residue acidified using 1N HCl solution. The resulting precipitate was filtered and dried under vacuum. This crude acid (3.2 g, 10.3 mmol) was then dissolved in DMSO (20 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (3.15 g, 20.77 mmol) added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (8.1 g, 15.5 mmol) was added and left to stir overnight. After completion of the reaction, reaction mass was poured into ice to obtain solid which was filtered and washed with acetonitrile then ether to provide the desired 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (2.6 g, 56.5%). LCMS: 443.05 (M+1)+; HPLC: 95.00% (@ 254 nm) (Rt; 7.195); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.61 (t, 1H, J=4.8 Hz), 8.36 (s, 1H), 8.19 (s, 1H), 7.70 (s, 1H), 5.88 (s, 1H), 5.23-5.20 (m, 1H), 4.33 (d, 2H, J=4.8 Hz), 2.20 (s, 3H), 2.12 (s, 3H), 1.98 (m, 2H), 1.97-1.90 (m, 2H), 1.87-1.86 (m, 2H), 1.73-1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](NN)=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(O)(=O)C>S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: NNc1nc(F)c(F)cc1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Cl)cnc1F
Yield: 86.5 %

Procedure:
17.9 g of the compound obtained in Step 2 was added to a mixture of 360 ml of acetic acid and 135 ml of water, and 450 ml of 10% aqueous copper sulfate was added dropwise thereto. The resulting mixture was refluxed for 24 hours while removing water using a Dean-Stark trap, to obtain 12.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)(O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(O)CCN(c3ccc(Cl)nn3)CC2)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(C2=CCN(c3ccc(Cl)nn3)CC2)c1
Reaction time: 6 h
Yield: 64 %

Procedure:
A mixture of 4 parts of 1-(6-chloro-3-pyridazinyl)-4-(3-methoxyphenyl)-4-piperidinol, 80 parts of ethanol and 50 parts of a hydrochloric acid solution 6N was stirred for 6 hours at reflux temperature. The reaction mixture was evaporated. Water was added and the whole was treated with concentrate ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.5 parts (64%) of 3-chloro-6-[3,6-dihydro-4-(3-methoxyphenyl)-1(2H)-pyridinyl]pyridazine; mp. 126.4° C. (compound 235).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: NCc1cccc(F)c1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: O[C@H](CNCc1cccc(F)c1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 3-fluorobenzylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS=96%, [M+H]+=411.
Reaction SMILES: [I:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Ni].C(OCC)(=O)C>[NH2:12][C:11]1[C:2]([I:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1I
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1I
Yield: 86.3 %

Procedure:
A mixture of methyl 2-iodo-3-nitrobenzoate (77.0 g, 251 mmol) and a catalytic amount of Raney nickel in ethyl acetate (100 mL) was stirred under hydrogen atmosphere at room temperature for 2 days, and filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10) to give the title compound (60.0 g, yield 86%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21](COCC[Si](C)(C)C)[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3[nH]ccc23)cn1
Reaction time: 16 h
Yield: 26 %

Procedure:
Ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (20 mg, 0.0000452 mol) was stirred in 1 mL TFA for 1 hour. Then excess TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing 0.5 mL NH4OH. Evaporation of the volatiles was followed by purification by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford ethyl 3-methyl-3-[4-(1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butanoate, trifluoroacetate salt (5 mg, 26%). 1H NMR (400 MHz, d6-DMSO): δ 12.19 (s, 1H), 8.61 (br s, 1H), 8.34-8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), 7.02 (br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H), 1.02 (t, 3H); MS(ES): 313 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9](=S)[NH:10][C:11]2[NH:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:33])[C:31]=1[F:32])[CH2:27][NH2:28].Cl.C(N=C=NCCCN(C)C)C>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6](/[N:8]=[C:9](/[NH:28][CH2:27][C:26]2[CH:29]=[C:30]([F:33])[C:31]([F:32])=[C:24]([F:23])[CH:25]=2)\[NH:10][C:11]2[NH:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCc1cc(F)c(F)c(F)c1
Reactant: O=C(NC(=S)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: O=C(/N=C(/NCc1cc(F)c(F)c(F)c1)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-N-((3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamothioyl)benzamide (500 mg, 1.43 mmol) was dissolved in methanol (5 mL) and 3,4,5-trifluorobenzylamine (462 mg, 2.87 mmol) was added followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (550 mg, 2.87 mmol). The reaction was stirred at 50° C. for 30 minutes. The crude mixture was then partitioned between water and ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate, then purified by chromatography (gradient: 95:5 hexanes:EtOAc to 7:3 hexanes:EtOAc). (Z)-4-Chloro-N-(((3,4,5-trifluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)benzamide was obtained as a solid (221 mg, 32% yield). MS (ES+) 475.8.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1([CH3:36])[CH2:10][CH2:9][C:8]2[C:11]([CH3:35])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.[OH-].[Na+]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][C:12]2[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]3[O:6][C:5]([CH3:36])([CH2:4][C:3]([OH:37])=[O:2])[CH2:10][CH2:9][C:8]=3[C:11]=2[CH3:35])=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCCCOc2c(C)c(C)c3c(c2C)CCC(C)(CC(=O)OC)O3)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCCCOc2c(C)c(C)c3c(c2C)CCC(C)(CC(=O)O)O3)ccc(C(C)=O)c1O
Yield: 59.6 %

Procedure:
A 0.669 g sample of the methyl ester from Example 20 was saponified with sodium hydroxide using the procedure described in Example 17. The crude acid product was chromatographed on 30 g of silica gel. Elution with 2:1 hexane-ethyl acetate afforded 0.386 g (59.6%) of racemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid as a yellow glass.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[Br:13]Br>ClC(Cl)C>[Br:13][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12]
Reactant: BrBr
Reactant: Cc1cccc2c1NC(=O)C2=O
Solvent: CC(Cl)Cl
Product: O=C1Nc2c(CBr)cccc2C1=O

Procedure:
The 7-methylisatin (16.1 g, 0.1 mole) is suspended in dichloroethane (2000 ml) and the suspension is heated and irradiated with a high intensity light source to the reflux point. Bromine (24.3 g, 0.15 mole) is added dropwise over a one hour period.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:14][CH2:15][CH2:16][O:17]1)[CH2:13][Br:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC)C1(C)OCCO1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1(CBr)OCCO1

Procedure:
A solution of bromine (14.72 g) in chloroform (30 ml) was added to a stirred solution of ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 20 g) in chloroform (200 ml) at ambient temperature and stirred at the same temperature for an hour. To the resultant solution was added 5% sodium thiosulfate aqueous solution (100 ml) and stirred at ambient temperature for 10 minutes. The organic layer was separated, washed with 5% sodium thiosulfate aqueous solution (100 ml), water (100 ml), a sodium bicarbonate saturated aqueous solution and sodium chloride saturated solution in turn and then dried over magnesium sulfate. The solution was evaporated in vacuo and the remaining oil (33.4 g) was distilled under reduced pressure to give an oil of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyrate (syn isomer), bp 0.95 mm/Hg 115°-118° C. (Yield: quantitative).