Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:16]2[C@@H:12]([O:13][C:14](C)([CH3:17])[O:15]2)[O:11][C@@:10]1([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>CC(O)=O.OS(O)(=O)=O>[C:14]([O:13][CH:12]1[C@H:16]([O:35][C:33](=[O:34])[CH3:32])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:10]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH:19]([F:20])[F:21])[O:11]1)(=[O:15])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)O[C@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound (3aR,5R,6S,6aR)-6-(benzyloxy)-5-(benzyloxymethyl)-5-(difluoromethyl)-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole (1.0 g, 6.3 mmol) in Ac2O (2.5 mL) and AcOH (10 mL) was added H2SO4 (3 drops). The mixture was stirred at room temperature for 3 hrs. TLC showed the reaction was complete. The mixture was poured to water, extracted with EtOAc, dried (Na2SO4) and purified by silica gel chromatography [ethyl acetate:petroleum ether (1:3)] to afford compound 5 (1.0 g, crude) as a light-color oil. LC-MS (M+H)+=465.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Reaction time: 3 h
Yield: 32.3 %

Procedure:
N-(2-Aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 48 mg, 0.16 mmol) was stirred and dissolved in anhydrous DMF (2 ml) at ambient temperature. Potassium carbonate (23 mg, 0.16 mmol) was added followed by iodomethane (0.01 ml, 0.16 mmol) and the mixture stirred for 3 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate. The combined extracts were washed once with brine, dried over magnesium sulfate, filtered and the solvent evaporated to give the title compound as a colourless solid (16 mg, 32%); NMR Spectrum: (DMSO-d6) 1.70 (m, 4H), 1.96 (m, 2H), 2.18 (s, 3H), 2.85 (m, 2H), 3.03 (m, 1H), 4.84 (b, 2H), 6.57 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d, 1H), 7.36 (d, 2H), 7.99 (d, 2H), 9.54 (b, 1H); Mass Spectrum: M+H+ 310.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16]CC2C=CC=CC=2)[C:10]=1[C:24](=[O:26])[CH3:25])C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([CH:39]=O)[CH:33]=[CH:32]2>>[OH:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10]=1[C:24](=[O:26])[CH2:25][CH2:39][C:34]1[CH:33]=[CH:32][C:31]2[CH2:30][CH:29]([O:28][CH3:27])[CH2:38][CH2:37][C:36]=2[CH:35]=1
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Product: COC1CCc2cc(CCC(=O)c3c(O)cc(C)cc3O)ccc2C1

Procedure:
Intermediate 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treated with 6-methoxynaphthalene-2-carbaldehyde as described in Example 1, Part B. Subsequent catalytic hydrogenation as described in Example 1, Part C, provided 1-(2,6-dihydroxy-4-methyl-phenyl)-3-(6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one as a by-product. Further treatment of this by-product as described in Example 1, Part D and E, afforded the title compound. 1HNMR (300 MHz, CD3COCD3) δ 7.2-7.0(m, 2H), 6.95-6.85(m 3H), 6.6(s, 1H), 5.6(s, 1H), 5.27(d, J=7 Hz, 1H), 3.95-3.85(m, 1H), 3.75-3.55(m, 6H), 3.37(s, 3H), 3.3-3.2(m, 1H), 3.1-2.6(m, 8H), 2.05(s, 3H). MS: m/z (MH+) 499.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:9][CH:8]=2)=[O:27])[CH:22]=1
Reactant: NCCCCCc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(O)c1cccnc1
Product: O=C1CCC(c2ccc(CCCCCNC(=O)c3cccnc3)cc2)=NN1

Procedure:
By treating 6-[4-(5-aminopentyl)phenyl]-4,5-dihydropyridazin-3(2H)-one and nicotinic acid in the same manner as in Example 30, 6-[4-(5-(pyridin-3-ylcarbonylamino)pentyl)phenyl]-4,5-dihydropyridazin-3(2H)-one was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:16]([Cu])#[N:17]>CN(C=O)C.[C-]#N.[Na+]>[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[C:16]#[N:17])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(C(C)(C)C)c(Br)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)C)c(C#N)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
Methyl 3-bromo-4-tert-butyl-benzoate (2.26 g, 4.17 mmol) was dissolved in dry DMF (2.1 mL) before CuCN (821 mg, 9.17 mmol) and NaCN (1.0 mg, 0.021 mmol) were added. The mixture was flushed with nitrogen and was stirred at 110° C. for 24 h. The reaction mixture was diluted with ethyl acetate (70 mL) and was washed with water. The organics were dried over sodium sulfate and were evaporated to dryness. The crude material was purified by column chromatography eluting with 0-10% ethyl acetate in hexanes to give methyl 4-tert-butyl-3-cyano-benzoate (390 mg, 43%). ESI-MS m/z calc. 217.1, found 218.5 (M+1)+; Retention time: 2.07 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 8.31 (d, J=1.8 Hz, 1H), 8.16 (dd, J=8.4, 2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl.N>O=P(Cl)(Cl)Cl.C(O)(C)C>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([Br:19])[CH:21]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
A solution of 7-acetamido-6-nitro-3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl3 (250 mL) is heated under reflux for 2 h, the excess of POCl3 is removed under vacuum, and the residue is dissolved in CH2Cl2 and washed with aqueous Na2CO3 solution. Workup gives the crude 4-chloro derivative, which is coupled directly with 3-bromoaniline in isopropanol as above, and the resulting hydrochloride is converted directly to the free base, by treatment with aqueous NH3, to give 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (3.60 g, 45%). 1H NMR (DMSO) δ10.56 (1H, s), 10.29 (1H, s), 9.34 (1H, s), 8.70 (1H, s), 8.19 (1H, brs), 7.97 (1H, s), 7.88 (1H, d, J=6.0 Hz), 7.43-7.35 (2H, m), 2.13 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.98 mmol) in DMF (2 mL) was added TBDPS chloride (0.52 mL, 1.98 mmol) and imidazole (297 mg, 4.47 mmol) and the reaction stirred at RT for 16 h afterwhich time the reaction mixture was diluted with brine (10 mL), washed with CH2Cl2 (3×25 mL) and the organics combined and dried through a phase separation cartridge and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with EtOAc and increasing the polarity to 30% EtOAc/isohexane to obtain 4-(tert-butyl-diphenyl-silanyloxy)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (545 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1>C1COCC1>[CH3:17][N:16]([CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:18]=[CH:19][C:20]([F:21])=[C:2]([F:1])[CH:3]=2)[CH2:15][CH2:14]1)[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)=[S:31]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CNC1CCN(CCCCOc2ccc(F)c(F)c2)CC1
Solvent: C1CCOC1
Product: CN(C(=S)Nc1ccc(F)cc1)C1CCN(CCCCOc2ccc(F)c(F)c2)CC1

Procedure:
The condensation of 1.2 g (4 mmol) of 1-[4-(3,4-difluorophenoxy)butyl]-4-(methylamino)piperidine with 0.61 g (4 mmol) of 4-fluorophenyl isothiocyanate in THF according to the protocol of Example 1.1 gives 1.75 g (Yd: 95%) of a powder of formula 13.1
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:32][C:16]3[N:17]([CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[CH:18]=[C:19]([OH:22])[C:20](=[O:21])[C:15]=3[C:14]=2[CH2:33][N:34]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:35])=[CH:9][CH:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:43]([Cl:48])(=[O:47])[CH:44]([CH3:46])[CH3:45]>>[ClH:48].[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:32][C:16]3[N:17]([CH2:23][C:24]4[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=4[F:30])[CH:18]=[C:19]([O:22][C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[C:20](=[O:21])[C:15]=3[C:14]=2[CH2:33][N:34]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:35])=[CH:11][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)C(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)c(O)cn3Cc2c(F)cccc2F)cc1
Product: CC(C)C(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)c(OC(=O)C(C)C)cn3Cc2c(F)cccc2F)cc1
Product: Cl

Procedure:
The compound obtained in Example 9 was subjected to a similar procedure as in Example 10, using isobutyryl chloride instead of isopropyl chloride, and the titled compound was obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:11]([CH2:21][CH2:22][CH3:23])[C:10]([O:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=1.[F:28][C:29]([F:37])([F:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].O>O1CCCC1>[F:28][C:29]([F:37])([F:36])[C:30]([C:7]1[CH:8]=[CH:9][C:10]([O:24][CH2:25][O:26][CH3:27])=[C:11]([CH2:21][CH2:22][CH3:23])[C:12]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)([OH:31])[C:32]([F:35])([F:34])[F:33]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1COC1CCCCO1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Under an argon atmosphere, n-butyl lithium (1.58 mol/L hexane solution 1.55 mL, 2.45 mmol) was dropped at −78° C. into a solution of 2-(6-bromo-3-(methoxymethoxy)-2-propylbenzyloxy)tetrahydro-2H-pyrane (725 mg, 1.75 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at the same temperature for 15 minutes and then stirred at the elevated temperature of −45° C. for 1.5 hours. A tetrahydrofuran (4 mL) solution of hexafluoroacetone was dropped at −78° C., and the mixture was stirred at 0° C. for 5 hours and then stirred at room temperature for 12 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (728 mg, 90%) was obtained as colorless oil.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+:26]>[Ag].O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[K+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 85 °C

Procedure:
Using the apparatus shown in FIG. 7, particulate organic silver salt 6-1 was prepared in the following manner. Into a tank (501) containing 83.5 g of behenic acid and 1583.5 g of pure water with stirring at 85° C., 147.7 ml of 1.5N aqueous KOH solution was added in 5 min. and reacted further for 60 min. to obtain a potassium behenate solution. Finally, water was added to make the total amount to 2000 ml. To a tank (502), 2000 ml of aqueous solution containing 37.6 g of silver nitrate was added and maintained at 10° C. In FIG. 7, the numeral 33 designates the mixing device, as shown in FIG. 1(a). To the mixing device (33) in which a supply tube and a discharge tube each had an inside diameter of 4 mm, the foregoing potassium behenate solution and aqueous silver nitrate solution were supplied at a flow rate of 750 ml/min and allowed to undergo nucleation. During the nucleation, the silver potential was continuously measured by a sensor (508). The acceptable pH range was set within±0.05 and a switching valve was operated to allow solution to discharge through pass (511) outside of a tank (504) until the pH fell within the foregoing range. A steady state was attained 15 sec. from the start of addition and the switching valve (510) was concurrently operated to introduce formed nucleus particles into a tank (504). Further, when the total amount of formed nucleus particles reached 1500 ml, the switching valve (510) was operated to allow solution to discharge through the pass (511) outside of the tank (504). In FIG. 7, the numeral 508 designates a sensor for detecting various conditions such as temperature, silver potential, pH and pAg; the numeral 509 designates a control means constituted of a computer; the numerals 512 and 513 designate a flowmeter and a pump, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]1([O:40][CH3:41])[C:34](=[CH:36][CH:37]=[CH:38][CH:39]=1)[OH:35].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:40][CH3:41])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.4 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of guaiacol and 20 ml of dry dimethylformamide is stirred at room temperature for 23 hours, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate, there is obtained o-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 205°-206°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>O>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1
Reactant: COc1ccc(COc2cc(Br)cc(Nc3cccnc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: O
Product: Oc1cc(Br)cc(Nc2cccnc2)c1
Reaction time: 1.67 h
Yield: 50.2 %

Procedure:
[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (26.7 g, 69.2 mmol) was dissolved in thioanisole (62 mL, 529 mmol). Trifluoroacetic acid (81 mL, 1.06 mol) was added slowly with the temperature held between 20 and 25° C. over a period of 100 min. The solution was left to stand at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and concentrated to a small volume (˜30 mL). To the residue were added TBME (250 mL), water (300 mL) and methanol (30 mL). The organic layer was extracted with a mixture of 4N hydrochloric acid and methanol. The combined aqueous layers were diluted with methanol (100 mL), washed with methylene chloride (3×150 mL) and neutralized with 4N NaOH (440 mL) to pH 7. The precipitated white solid was collected, washed with cold water (2×10 mL) and dried in a vacuum oven overnight at 60° C. 3-Bromo-5-(pyridin-3-ylamino)-phenol (9.21 g, 50%) was obtained as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](Cl)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][N:23]=[CH:22]1.C(N(CC)CC)C.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:29][CH2:28][CH2:27][CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Chlorobenzenesulphonamido)benzoyl chloride (3.40 g) was added in portions to a stirred mixture of 3-imidazol-1-ylpropylamine (1.29 g), triethylamine (1.04 g) and dimethylformamide (25 ml) at room temperature. The temperature of the mixture rose to 33° C.; the mixture was then stirred at room temperature for 4 hours before pouring into water (500 ml). The aqueous solution was decanted from the crude product which had precipitated as a gum. This gummy material was dissolved in dichloromethane (50 ml), the solution was dried over magnesium sulphate and the solution was evaporated. The crude product was recrystallised from ethyl acetate to give 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide, in the form of a white solid, m.p. 175°-177° C. (yield: 2.1 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C1C=CC=CC=1.C(N(CC)CC)C>[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:16])=[CH:13][CH:12]=1
Reactant: Nc1ccc(C(=O)Cl)cc1
Reactant: CSCC[C@H](N)C(=O)O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(=O)c1ccc(N)cc1)C(=O)O

Procedure:
In an Erlenmeyer flask, 1.35 g of para-aminobenzoic acid chloride are dissolved in 20 ml benzene in the presence of 2.8 ml triethylamine. 1.49 g L-methionine is added progressively and the resultant mixture is filtered. After evaporation of the filtrate to dryness under vacuum (15 mm Hg), the residue is dissolved in N hydrochloric acid and extracted with chloroform. The chloroformic solution is successively washed with several ml of 10% aqueous HKCO3 solution and with water. It is then collected, dried over magnesium sulfate and evaporated. The product obtained is precipitated in cyclohexane and filtered. After recrystallization in a (1:1) mixture of 95 alcohol-water, 1.95 g of white crystals are isolated. M.p.: 172° C.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:40][CH:41]=1>>[ClH:34].[ClH:34].[ClH:34].[ClH:34].[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:13][CH2:14]1)[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:40][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(NCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN(Cc3ccccc3)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cn2)cc(OC)c1OC
Product: Cl

Procedure:
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a tetrahydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:31]([CH:28]([N:27]([CH2:20][C:18]1[S:19][C:12]2[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=2[C:17]=1[CH3:22])[CH3:26])[CH2:29][OH:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNC(CO)Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(CO)Cc2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 10 h
Yield: 76.3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), 2-(methylamino)-3-phenylpropan-1-ol (Tetrahedron 2001, 57, 3425)(33 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 10 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (52 mg) as a white solid.