Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:11]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH:7]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[N:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1.O>[Cl:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([N:23]3[CH2:24][CH2:25][N:20]([C:18]([NH:17][CH:7]4[CH2:6][CH:5]([OH:4])[C:11]5[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=5[CH2:9][CH2:8]4)=[O:19])[CH2:21][CH2:22]3)=[CH:27][CH:28]=[N:29]2)=[CH:34][CH:33]=1
Reactant: CC(=O)OC1CC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)CCc2ccc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCc2ccc(F)cc2C(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-[9-(acetyloxy)-2-fluoro-6,7,8,9-tetrahydro-5H-benzo[α]cyclohepten-7-yl]-4-(7-chloro-4-quinolinyl)-1-piperazinecarboxamide (30.0 mg, 0.0588 mmol) in THF:H2O (3:1, 2 mL) was added LiOH (8 mg). The reaction mixture was stirred at rt for 3 h, then THF was evaporated in vacuo. The reaction mixture was diluted with AcOEt (100 mL), washed with brine, and dried. Concentration followed by flash chromatography afforded the title product. LC-MS: 469 (M++1). δ 1H NMR (CDCl3) δ 8.70 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 7.05 (m, 2H), 6.85 (m, 2H), 4.95 (m, 1H), 4.35 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 3.15 (m, 1H), 2.60 (m, 1H), 2.20 (m, 2H), 1.8 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (52 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (153) (14.7 mg, yield: 66.4%, purity>90%) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26]3)[CH2:20][CH2:19]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)CC2)C1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-((3-methoxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (49 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (34 mg, 62%) as an off-white solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (br s, 1H), 8.47 (br s, 1H), 8.26 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.59 (br s, 1H), 7.51 (d, J=11.4 Hz, 1H), 4.50 (br s, 1H), 4.18 (d, J=19.4 Hz, 1H), 3.85-3.74 (m, 2H), 3.36 (s, 3H), 3.22-3.13 (m, 3H), 2.84 (s, 1H), 2.45-2.29 (m, 3H), 2.22-2.05 (m, 4H), 1.80-1.71 (m, 2H), 1.35-1.19 (m, 6H). ESI MS m/z 552 [C31H35ClFN3O3+H]+; HPLC>99% (AUC), tR=11.30 min.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=2)[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:27])[CH:20]=2)=[N:8]1.OO.[OH-].[Na+].O>C(O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:26]([NH:25][C:21]2[CH:20]=[C:19]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=4)[NH:7][N:8]=3)[CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:29]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3cccnc3)c1)nn2C1CCCCO1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4cccnc4)c3)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
Precursor, 1-perhydro-2H-pyran-2-yl-3-[3-(3-pyridylcarbonylamino) phenyl]-1H-indazole-5-carboxamide, was dissolved in ethanol (4 mL). Hydrogen peroxide (4 mL, 30% wt) was added to the solution followed by 0.200 mL of 6.0 N NaOH aqueous solution. The suspension turned white upon heating to 60° C. for 3.5 h. The reaction could not be driven to completion even after addition of excess reagent. The reaction mixture was neutralized. A white precipitate formed upon addition of water. The solid was collected by filtration and dried in a vacuum oven at 40° C. overnight. A suspension of this solid in 10 mL of toluene was cooled to 0° C. HCl gas was bubbled through the suspension for 10 min before stirring the flask content at room temperature for 2 hours. The desired product was purified using preparatory HPLC (0.049 g, 30% yield over 3 steps): 1H NMR (CD3OD) 9.2 (d, 1H), 8.77 (dd, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.39 (dt, 1H), 7.9–7.8 (m, 3H), 7.6–7.5 (m, 4H); ES-MS (m/z) 358 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd]>[N:11]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cc(-n2ccnc2)ccc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.8 %

Procedure:
To 1-(3-methyl-4-nitro-phenyl)-1H-imidazole (200 mg, 0.98 mmol) and 10% Palladium on carbon (35 mg) was added degassed methanol (3 mL). The suspension was flushed and evacuated with hydrogen/vacuum line. The suspension was allowed to stir at room temperature for 14 h under hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was filtered through a pad of celite and rinsed with methanol. Concentration of the filtrate gave the title compound (166 mg, 98%) which was used for the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (1H, s), 7.48 (1H, s), 7.16 (1H, narrow d, J=2.5 Hz), 7.09 (1H, dd, J=2.5, 8.4 Hz), 7.01 (1H, s), 6.67 (1H, d, J=8.4 Hz), 5.03 (2H, broad s), 2,10 (3H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([CH2:45][CH3:46])[CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18]2=[O:42])=[CH:14][CH:13]=1>C(Cl)Cl>[O:8]=[C:9]([CH2:45][CH3:46])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:42])=[CH:43][CH:44]=1
Reactant: CCC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
50 ml of trifluoroacetic acid were added to a solution of 19.3 g of 5-[4-(2-oxobutoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 94) in 100 ml of methylene chloride, and the mixture was stirred at room temperature for 1.5 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. Water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed by evaporation under reduced pressure, and the resulting residue was applied to a silica gel chromatography column, and eluted, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent. It was then recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 9.55 g of the title compound, melting at 141.5° to 145.7° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([Si:24]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:43][C:40]1[CH:39]=[CH:38][C:37]([Si:24]([C:31]2[CH:32]=[CH:33][C:34]([C:13]3[CH:12]=[CH:11][CH2:10][C:8]45[CH:9]=[CH:1][CH:2]=[CH:3][C:4]4=[CH:5][O:6][C:7]=35)=[CH:35][CH:36]=2)([C:21]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(Br)cc2)cc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(C3=C4OC=C5C=CC=CC54CC=C3)cc2)cc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of dibenzo[b,d]furan-4-ylboronic acid (2.60 g, 12.26 mmol), with bis(4-bromophenyl)diphenylsilane (12.12 g, 24.53 mmol), Pd(PPh3)4 (0.283 g, 0.245 mmol) and K2CO3 (5.08 g, 36.8 mmol) in toluene (200 mL) and water (50 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (9:1, v/v) as eluent to yield (4-bromophenyl)(4-(dibenzo[b,c]furan-4-yl)phenyl)diphenylsilane (3.14 g, 44%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[CH:15][CH:14]=4)=[C:4]([F:31])[CH:3]=1.O.[NH2:33]N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:33][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=4)=[C:4]([F:31])[CH:3]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2F)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, with compound C3-(4-chloro-2-fluorophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido-[2,3-b]indol-2-one and hydrazine monohydrate.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:10]1([CH:9]=[N:16][OH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: ON=CC1(Cl)C=CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-chlorosuccinimide (4.63 g, 34.7 mmol) was added to a solution of benzaldehyde oxime (3.5 g, 28.9 mmol) in DMF (30 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being pooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethylbenzene was obtained as a yellowish solid (4.28 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:30])[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[I:31].[Li+].[OH-]>C1COCC1.C(O)C>[I:31][C:7]1[CH:8]=[C:9]([N:12]([CH3:30])[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1I
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CN(C)c1ccc(OCC(=O)O)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A solution of (2-iodo-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (140 mg, 0.24 mmol) in THF (1.2 ml) and ethanol (1.2 ml) was treated at 0° C. with 1N LiOH (0.73 ml) and stirred for 3 h at RT. The reaction was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The product was crystallized from CH2Cl2 to give 79 mg of pure (2-iodo-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid, MS: 561.1 (M-H)−, MP: 172.5-173.0° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH:9]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([NH:15][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[S:14][C:10]=2[CH:9]=1
Reactant: Nc1nc2ccc(Cc3ccccn3)cc2s1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2ccc(Cc3ccccn3)cc2s1

Procedure:
A solution of 6-[(2-pyridyl)methyl]-2-aminobenzothiazole (1.3 g) and ethyl isocyanate (0.6 ml) in tetrahydrofuran (25 ml) was stirred at 60° C. for 4 hours. Evaporation of the solvent gave a residue which was crystallized from tetrahydrofuran. The crystal was collected by filtration to give 6-[(2-pyridyl)methyl]-2-(3-ethylureido)benzothiazole (0.68 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[N:10]=1>>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([NH:16][C:11]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:10]=2)[CH:22]=[CH:21][C:20]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1cccnc1
Product: COc1cc(Nc2nc(C)cc(Oc3cccnc3)n2)ccc1-n1cnc(C)c1
Yield: 53 %

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 3-hydroxy-pyridine and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 53% yield as a pale-yellow solid after purification by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3-oxo-2,3-dihydro-1H-indene-5-carboxylic acid (3 g, 17 mmol) in DCM (50 mL) and MeOH (10 mL) was added TMSCHN2 (17 mL, 34 mmol) dropwise and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient solvent system of 10:1 to 3:1 petroleum ether/EtOAc to give methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (2.0 g, 61%). MS ESI calcd for C11H10O3 [M+H]+ 191, found 191.
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[NH:4][C:3]1([CH2:28][O:29]C1CCCCO1)[CH2:20][O:21]C1CCCCO1.CO.Cl.C(=O)(O)[O-:40]>C(OCC)(=O)C>[OH:21][CH2:20][C:3]1([CH2:28][OH:29])[C:2](=[O:40])[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:17])([F:16])[F:18])[CH:8]=2)[C:5](=[O:19])[NH:4]1
Reactant: N#Cc1ccc(N2C(=N)C(COC3CCCCO3)(COC3CCCCO3)NC2=O)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C(=O)NC(CO)(CO)C2=O)cc1C(F)(F)F

Procedure:
300 mg of the product obtained in Stage 3 above is introduced into 3 ml of methanol and 1.5 ml of 2N hydrochloric acid and the whole is taken to reflux for one hour 30 minutes. It is returned to ambient temperature, poured into 5 ml of bicarbonate, extraction is carried out 4 times with ethyl acetate then the extracts are washed with a saturated sodium chloride solution and dried. 5 ml of methanol is added and purification is carried out on silica eluting with methylene chloride-methanol: 9-1. The residue is taken up in 20 ml of isopropanol under reflux then concentration is carried out and 225 mg of expected product (white crystals) is obtained. M.p.=207-208° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 66.3 %

Procedure:
2-Fluorobenzenesulfonyl chloride (0.5 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-amino-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 19, 0.53 g) in DCM (10 mL) and pyridine (20 mL) and the resultant mixture was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and the residue was treated with water, extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.574 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(=O)(=O)(O)[OH:16]>O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([C:7]([NH2:8])=[O:16])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cc([N+](=O)[O-])c(C#N)cc1C
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C(N)=O)cc1C
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a mixture of 4-methoxy-5-methyl-2-nitro-benzonitrile (8 g, 40 mmol) and water (50 ml) was added concentrated sulphuric acid (65 ml) and the mixture was stirred for 2.5 hours at 100-110° C. The mixture was allowed to stay overnight, filtered, washed with water and dried which gave the title compound (7 g, 83%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:16]([NH:26]C(=O)OC(C)(C)C)[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[N:4][C:5]([Br:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(Cl)Cl>C(Cl)Cl>[NH2:26][C@H:16]([C:3]1[N:4]=[C:5]([Br:15])[C:6]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])=[CH:7][C:2]=1[Br:1])[CH2:17][C:18]1[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)c(NC(=O)C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)c(NC(=O)C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-tert-butyl (1-(3,6-dibromo-5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (46C, 563 mg, 0.94 mmol) in 5 mL of methylene chloride was cooled down to 0° C. and to it was added 10 mL of 20% TFA/methylene chloride. The reaction was allowed to stir at room temperature for 1 hour and then concentrated to dryness to afford (S)—N-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-2,5-dibromopyridin-3-yl)-2,2,2-trifluoroacetamide as a TFA salt. 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (265 mg, 0.94 mmol), the amine (TFA salt from last step) and HATU (429 mg, 1.1 mmol) were dissolved in 10 mL DMF, cooled to 0° C., then N,N-diisopropylethylamine (0.84 mL, 4.7 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (sat'd aq.) and brine. After dried over MgSO4, it was filtered and concentrated to yield the title product. MS (m/z): 767.84 [M+H]+.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][C:12]=1[F:31]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:31]
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)c(F)c2)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1cc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)ccc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]>C1COCC1.C(OCC)(=O)C>[CH2:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([C:17]([NH2:19])=[O:18])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:4][CH:3]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]
Reactant: CCc1cccc(N=C=O)c1
Reactant: NC(=O)n1c(-c2ccc(N)cc2)cc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cccc(NC(=O)Nc2ccc(-c3cc4ccccc4n3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction mixture of 2-(4-amino-phenyl)-indole-1-carboxylic acid amide (125.5 mg, 0.5 mmol, 1 eq) and 3-ethylphenyl isocyanate (0.073 mL, 1 eq) in anhydrous THF (4 mL) was stirred at room temperature for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was triturated with EtOAC-Hex (1:1). 2-[4-({[(3-ethylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-1-carboxamide was obtained as white solid upon filtration in amount of 156 mg (78%).