Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([OH:26])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([O:26][CH3:1])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(=O)O)N2C1=O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@@H]1CS[C@H]2C[C@@](Cc3ccccc3)(NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 25 °C

Procedure:
A total of 1.5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 250 mg of (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase:ethyl acetate:n-heptane=1:1.5).
Reaction SMILES: C([O:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=O)[C:8]=2[N:9]=1)C.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[C:8]2[NH:9][C:4](=[O:3])[N:5]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]=2[CH:13]=[CH:12][N:11]=1
Reactant: CCOc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1[nH]c2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-ethoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (763 mg) and phosphorus oxychloride (10 ml) was stirred at 100° C. for 5 hr, allowed to be cooled to room temperature, and concentrated under reduced pressure. To the residue was added toluene, and the mixture was again concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (437 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][C:11]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:18]2[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=2)[N:12]=1.O>CN(C)C=O>[N:3]1([CH2:9][CH2:10][C:11]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=3)[N:12]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Oily sodium hydride (60%, 0.044 g) was added to a solution of imidazole (0.075 g) in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.46 g) was added. The mixture was stirred at 80° C. for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (10/1, v/v) gave ethyl 2-[2-(1-imidazolyl)ethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.295 g, 66%) which was then recrystallized from ethyl acetate-hexane. Colorless prisms. mp. 173°-174° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:33]([C:32]4[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=4[O:30][CH3:29])=[O:34])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccccc1C(=O)N1CCC(N2N=C(c3ccc(OC)c4c3CC(C)(C)O4)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [O:1]1[CH:3]2[CH:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:5][CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]12.C([O-])([O-])=[O:21].[Na+].[Na+].[K+].[Br-]>CC(C)=O>[C:14]1([CH:4]2[CH2:5][CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]([OH:21])[CH:3]2[OH:1])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C2CCC(c3ccccc3)C3OC23)cc1
Reactant: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: OC1C(c2ccccc2)CCC(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,2-Epoxy-3,6-diphenylcyclohexane (32 mg, 0.13 mmol) was dissolved in acetone (10 mL). HClO4 (6%, 10 mL) was added and the mixture was stirred at room temperature for 24 hours. The reaction solution was neutralized with Na2CO3 and the reaction mixture was reduced to approximately half volume under reduced pressure. Extraction with CH2Cl2 and removal of the solvent yielded crude product (93% yield) as a white solid. Based upon the analyses of NMR spectra of crude and recrystallized product, reaction gave a single product. Recrystallization from hexane/CH2Cl2 gave pure product as a white crystalline solid: mp 134°-135° C.; IR (KBr) 3303, 3086, 3059, 3026, 2935, 2858, 1603, 1495, 1454, 1041, 760, 698 cm-1 ; 1H NMR (200 MHz, CDCl3) δ 7.20-7.60 (m, 10 H), 4.08 (t, J=9.8 Hz, 1 H), 3.95 (dd, J= 9.5, 5.5 Hz, 1 H), 3.56 (m, 1 H), 2.67 (ddd, J=11.7, 9.9, 4.3 Hz, 1 H), 1.65-2.39 (m, 6 H); 13C NMR (50 MHz, CDCl3) δ 142.3, 140.8, 129.7, 128.8, 128.4, 127.8, 126.9, 126.5, 76.8, 74.6, 50.6, 44.7, 29.9, 29.2; MS (EI) m/e (relative intensity) 268 (M+, 61.9), 250 (12.9), 237 (11.5), 219 (7.3), 146 (30.1), 131 (94.9), 117 (55.4), 104 (100.0), 91 (73.6), 77 (15.3); HRMS calcd. for C18H20O2 m/e 268.1463, found m/e 268.1464.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH3:17][O:18][C:19](=[O:36])[C@@H:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:21]1[C:32](=[O:35])[CH2:33][NH2:34]>CCCCCC.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:36])[C@@H:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:21]1[C:32](=[O:35])[CH2:33][NH:34][C:6](=[O:8])[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CC(=O)SC(Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CN
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CNC(=O)C(Cc1ccc(Cl)cc1)SC(C)=O
Yield: 53 %

Procedure:
Condensation of 2-acetylthio-3-(para-chlorophenyl)propanoic acid with N-glycyl-5-(ortho-hydroxyphenyl)proline methyl ester, obtained in accordance with the same protocols as those described in Preparation G, yields the expected product in the form of an oil after chromatography in an n-hexane/ethyl acetate mixture, 1:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[O:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:6]=1
Reactant: OC1CCOCC1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of (RS)-tert-butoxycarbonylamino-(3-hydroxy-phenyl)-acetic acid methyl ester (CAS 526217-60-7) in THF (10 ml) was treated under an argon atmosphere with tetrahydro-pyran-4-ol (0.24 ml), triphenylphosphine (649 mg) and di-tert-butyl azodicarboxylate (570 mg) and stirred at r.t. overnight. The reaction mixture was concentrated. The crude product was purified by column chromatography (silical gel; gradient: cyclohexane ->cyclohexane/EtOAc 1:1) to give (RS)-tert-butoxycarbonylamino-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid methyl ester (884 mg, 82%) as viscous light yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[C:17]([O:19][CH3:20])=[O:18])(=O)=O.[CH2:23](B(O)O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.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>[CH2:23]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)cnc12
Reactant: CCCCCCB(O)O
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: [Cs+]
Solvent: Cc1ccccc1
Product: CCCCCCc1cnc2c(C(=O)OC)cccc2c1
Temperature: 95 °C
Yield: 41 %

Procedure:
Methyl 3-(((trifluoromethyl)sulfonyl)oxy)quinoline-8-carboxylate (538 mg, 1.6 mmol), hexylboronic acid (415 mg, 3.2 mmol) and Cs2CO3 (779 mg, 2.4 mmol) were suspended in toluene (30 mL). The mixture was purged with nitrogen then tetrakis(triphenylphosphine)palladium (0) (55 mg, 0.05 mmol) was added. The reaction was sealed and heated at 95° C. for 16 h. The mixture was cooled and filtered through celite, rinsing with excess CH2Cl2. The filtrate was concentrated in vacuo. The resulting oil was purified on 40 g silica gel (19:1 CH2Cl2/methyl t-butyl ether) to afford 178 mg (41%) of methyl 3-hexylquinoline-8-carboxylate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[C:38]=3[F:39])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cccc(F)c1F
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluorophenyl)boronic acid gave 245. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.59 (s, 1H), 8.15-8.06 (m, 1H), 7.77 (s, 1H), 7.72-7.60 (m, 1H), 7.51-7.41 (m, 1H), 5.12-4.82 (m, 2H), 4.26-4.10 (m, 1H), 4.07-3.93 (m, 1H), 3.78 (s, 3H), 3.44-3.30 (m, 1H), 2.15 (ddd, J=11.7, 6.2, 3.5 Hz, 1H), 1.97-1.79 (m, 2H), 1.69 (d, J=13.1 Hz, 1H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O.C(=O)(O)[O-].[Na+].[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To piperidine-4-carboxylic acid (25 g) in THF (75 ml) there was added water (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2×150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated under vacuum. Yield: 48.5 g (96%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([Cu])#[N:10].[OH-].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: Brc1ccc(Br)nc1
Reactant: N#C[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Br)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A stirred solution of 2,5-dibromopyridine (39.465 g, 0.17 mol) in anhydrous NMP (100 mL) was treated with CuCN (14.42 g, 0.17 mol) for 20 hours at 110° C. under nitrogen. The reaction mixture was cooled to 40° C. and treated with aqueous sodium hydroxide (2M; 200 mL) and then with ethyl acetate (200 mL). The mixture was stirred for 1 hour and then filtered through Celite to remove the resulting precipitate. The retained solid was washed with aqueous sodium hydroxide (2M; 600 mL) and then with ethyl acetate (600 mL). The organic layers were combined and washed with aqueous ammonium hydroxide (5M; 800 mL), dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The involatile residue was purified by chromatography on silica gel [elution gradient 1% to 7% of ethyl acetate in hexanes] to give the title compound (8.538 g, 28%), as a colorless amorphous solid.
Reaction SMILES: [BH4-].[Na+].[CH:3]1[N:7]2[C:8]3[C:19](=[O:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[NH:10][C:11](=[O:12])[C:6]2=[N:5][CH:4]=1.C>CO.CN(C)C=O>[OH:20][CH:19]1[C:8]2[N:7]3[CH:3]=[CH:4][N:5]=[C:6]3[C:11](=[O:12])[NH:10][C:9]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(O)c1ccccc1-2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
0.86 g of sodium borohydride is added over 5 minutes to a stirred suspension of 2.4 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10-dione in 75 ml of methanol at a temperature between 25° C. and 35° C. After stirring for 30 minutes at 20° C., the insoluble material is isolated by filtration, washed with 10 ml of methanol and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (2.3 g) is dissolved in 100 ml of dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered and the filter is then washed with 20 ml of dimethylformamide. The filtrate and the washings are combined and 240 ml of distilled water are added. The solid is filtered off, washed twice with 40 ml in total of distilled water and with 20 ml of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1.9 g of 10-hydroxy-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, melting at 290° C. (decomposition) [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 5.65 (d, J=8.5 Hz, 1H: CH--O--); 6.17 (d, J=8.5 Hz, 1H: --OH); 7.33 and 7.41 (2dt, J=7.5 and 1 Hz, 1H each: --H7 and --H8); 7.57 and 7.77 (2dd, J=7.5 and 1 Hz, 1H each: --H6 and --H9); 7.58 and 7.93 (2s broad, 1H each: --H of the imidazole); 12.40 (cplx, 1H: --NH--)].
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:1]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=2)=[O:19])[CH:14]=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(N)c2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
Benzoyl chloride (7.5 g, 53 mmol) and 4-dimethylaminopyridine (1.0 g, 8.3 mmol) were added to a solution of 2-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 27 mmol) in N,N-dimethylacetamide (100 mL) and the mixture was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (40 mL) and 1N aqueous solution of sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water (100 mL) was added and neutralized with 2N-hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 2:1) to obtain 6.4 g of the title compound (19 mmol, yield 70%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[SiH](CC)(CC)CC>C(Cl)Cl>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:9]2[C:8]3[C:12](=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[NH:11][C:10]=2[CH3:14])=[CH:18][CH:17]=1
Reactant: Cc1cc2ccc(S(C)(=O)=O)cc2[nH]1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A solution of 6-methanesulfonyl-2-methyl-1H-indole (112 mg), prepared as described in Example 1 Step 3, in 9 ml CH2Cl2 was treated with p-bromo-benzaldehyde (100 mg) and 0.2 ml TMS-OTf. After cooling to 0° C., 0.26 ml of Et3SiH was added. The solution was stirred for 30 minutes followed by partitioning between EtOAc and water. Purification by TLC (2:1 hexane/EtOAc) gave 130 mg of 3-(4-bromo-benzyl)-6-methanesulfonyl-2-methyl-1H-indole 201, MS: 379 ([M+H]+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]2=[O:15].[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[NH:4]1[CH:3]=[CH:2][N:1]=[C:10]1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:15]
Reactant: CN1CCCNCC1
Reactant: O=C1Nc2ccccc2Cc2nccn21
Solvent: ClCCl
Product: CN1CCCN(C(=O)Nc2ccccc2Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 0.76 g of 11H-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one in 9 ml of methylene chloride was added at once 0.41 g of N-methylhomopiperazine and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. Recrystallization of the residue from methylene chloride-ether gave 1-[2-(2-imidazolylmethyl)phenylcarbamoyl]-4-methylhomopiperazine, the compound of formula VI wherein R1, R2, R4 -R7 are hydrogen, CnH2n is (CH2)3, R3 is methyl and Z is oxygen, melting at 139°-143°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:39])=[O:38]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(S(C)(=O)=O)C1
Reaction time: 18 h

Procedure:
The solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) and Et3N (58 μL, 0.42 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride (31 μL, 0.39 mmol). After 18 hours, the cloudy mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-95% EtOAc in hexanes to afford the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[CH3:29][O:30]C1C=C2C(=CC=1)NC(=O)C2>>[CH3:29][O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:28])/[C:19]/2=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 51 %

Procedure:
According to procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methoxyoxindole (11 mg, 0.068 mmol) to give the title compound as an orange solid (13.6 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 13.58 (br s, 1H), 10.45 (br s, 1H), 8.57 (d, J=6.0 Hz, 2H), 8.37 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J=16.6 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J=6.0 Hz, 2H), 7.57 (d, J=2.3 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 6.86 (dd, J=8.8, 2.5 Hz, 1H) 6.80 (d, J=8.3 Hz, 1H), 3.6 (s, 3H); MS ESI 395.2 [M+H]+, calcd for [C24H18N4O2+H]+ 395.14.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:26][CH:27]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 2 g (15 mmol) of 4 -tert-butylbenzoyl chloride with 2.9 g (15 mmol) of allyl 4-hydroxymethylbenzoate, 4 g (77% ) of allyl ester are obtained in the form of a colorless oil.