Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:12](=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccccc1C(F)(F)F
Yield: 52.8 %

Procedure:
Using the procedure of Step A of Example 6, 32.2 g of o-trifluoromethylaniline and 23.44 g of butyryl chloride were reacted to obtain 24.4 g of N-(2-trifluoromethylphenyl)-butanamide melting at 76° C which was used as is for the next step.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH2:35][CH2:36][O:37][CH3:38])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:41](O)C>O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH2:35][CH2:36][O:37][CH2:38][CH3:41])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCO
Reactant: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 90 %

Procedure:
A mixture of 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (1.3 g, 2.36 mmol) in ethanol (10 mL), tetrahydrofuran (20 mL) and an aqueous sodium hydroxide solution (10%, 6 mL) was heated at 50° C. for 5 h. The mixture was diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (900 mg, 90%): LC/MS m/e calcd for C24H28N2O3S [M+H]+ 425.57, observed 425.4.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:18]([O:26][CH2:27][CH:28]1[CH:33]=[CH:32][NH:31][CH2:30][CH2:29]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:18]([O:26][CH2:27][C:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=2)[CH2:30][CH:29]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCC1C=CNCC1)c1ccccc1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CC=C(COC(=O)c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
A suspension of 0.195 g (0.0010 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 5 ml of dimethylformamide was treated with 0.42 ml (0.0030 mol) of triethylamine and 0.365 g (0.0010 mol) of 1,2,3,4-tetrahydro-pyridin-4-ylmethyl benzoate and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed over silica gel with ethyl acetate as the eluent. 0.17 g (74%) of 1-(4-amino-2-methyl-pyrimidin-5-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-ylmethyl benzoate was obtained as a yellow oil. MS (ISP): me/e=339 (C19 H23N4O2+).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25](Br)[CH:26]=O)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]([NH2:40])=[S:39]>O1CCCC1.C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:39][CH:38]=[N:40][CH:26]=1)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C:19]2=[O:37])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: NC=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cncs3)CSC12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the epimeric bromoaldehydes) (2.34 g) and thioformamide (0.3 g) in dry tetrahydrofuran (23 cc) is stirred for 3 hours at 20° and then heated for 90 minutes at 50° C. The reaction mixture is diluted with ethyl acetate (160 cc) and washed with a saturated solution of sodium bicarbonate (100 cc) and then with a semi-saturated solution of sodium chloride (100 cc). After drying of the organic layer over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue obtained is subjected to chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.8 bar (80 kPa) with a 70/30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 16 to 25, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., and the residue is triturated in isopropyl ether (50 cc). After filtration and drying, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.85 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COC(COc1ccc(O)cc1)OC
Reactant: COc1ccc(N=C=O)cc1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)Oc2ccc(OCC(OC)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 4-Methoxyphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-4-methoxyphenylcarbamate as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:11][CH3:10])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (positive ion) m/z=202.0, 204.0 (M+H)+. Step C
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:26][C:27]#[CH:28])[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]3[N:22]=[N:23][N:24]=[C:16]3[C:15]=2[N:25]=1)[CH3:9].[OH:29][N:30]=[C:31](Cl)[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.ClN1C(=O)CCC1=O>C1COCC1>[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:26][C:27]2[O:29][N:30]=[C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH:28]=2)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]3[N:22]=[N:23][N:24]=[C:16]3[C:15]=2[N:25]=1)[CH3:9]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#CCn1c(COCC)nc2c1c(C)c(C)n1nnnc21
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1Cc1cc(-c2cccnc2)no1

Procedure:
In the presence of triethylamine (0.50 mL, 3.4 mmol), 8-(ethoxymethyl)-5,6-dimethyl-7-prop-2-ynyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine (0.442 g, 1.55 mmol) was reacted with N-hydroxypyridine-3-carboximidoyl chloride generated from 3-pyridinecarboxyaldehyde oxime (prepared as described in Part A of Example 5, 0.38 g, 3.11 mmol) and N-chlorosuccinimide (0.42 g, 3.11 mmol) in THF (5 mL) using the method described in Part B of Example 5. After purification by flash chromatography (silica gel, elution with 95:5 dichloromethane/methanol) and trituration in diethyl ether, the product 8-(ethoxymethyl)-5,6-dimethyl-7-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine was obtained (0.171 g) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CCO>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4])[CH3:18]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
To 100 mL of EtOH is added 28.9 g (0.1 mol) of 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone and 9.0 g (0.2 mol) of diethylamine. Reflux the reaction mixture and monitor by thin-layer chromatography. Upon completion of the reaction remove the solvent in vacuo and add 100 mL of 5% Na2CO3 solution and extract with Et2O. Dry the organic layer with Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]=2[CH:18]=1
Reactant: CC(C)N
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Reaction time: 4 h

Procedure:
(1R, 2S, 3S, 5S)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.00 g, 1.92 mmole) was refluxed in ethanol (10 mL) with isopropylamine (1.6 mL, Fluka) under nitrogen for 24 hours. A second portion of isopropylamine (0.80 mL) was added and reflux continued for an additional 4 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1 N sodium hydroxide (1.90 mL) was added, and volatiles were reevaporated. The residue was chromatographed on a silica gel column. Title compound was eluted with 10% methanol-ethyl acetate as a colorless glass. Concentration of an ethanol solution gave title compound as a off-white solid foam (360 mg, 46%). Such a sample was solidified by trituration with 95% water-5% methanol to give title compound as white powder (96%), m.p. 137-138° C.; 1H-NMR(DMSO-d6)δ 7.60 and 7.39 (both s, 2, aromatic CH), 6.64 (d, J=7.4 Hz, 1, NH), 5.14 (t, J=4.3 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.70 (d, J=3.5 Hz, 1, OH), 4.70-4.50 (m, 1, NCH), 4.50-4.30 (m, 1, OCH), 4.10-4.00 (m, 1, NCH of cyclopropylamino), 3.9-3.75 (m, 1, OCH), 3.70-3.50 (m, 2, OCH2), 2.20-1.80 (m, 3, CH2 and CH of cyclopentane), 1.24 (d, J=6.6 Hz, 6, 2 CH3); mass spectrum (CI): 374(M+1); [α 20 589-3.72°, [α]20 578-2.60°, [α]20 546-2.23°, [α]20 436-9.67°, [α]20 365-51.7 ° (c=0.269, methanol). [See Examples 16-18 and 20]
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][CH:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(O)Cc1ccc(N)cc1
Product: CC(=O)c1ccc(Nc2ccc(CC(C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and 1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)C1CC1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) cyclopropylcarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 387(M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:11]([N:9]1[C:8](=[O:15])[N:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:4]2=[N:10]1)[CH:12]([CH3:14])[CH3:13]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)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: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cc1
Temperature: 150 °C
Yield: 90.3 %

Procedure:
To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), 4-methoxyphenylboronic acid (0.026 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20° C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 14 mg of the title compound as a yellow solid. MS: [M+H]+=389.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]3[CH:11]=[CH:12][C:13]([C:15]([C:17]4[N:18]=[CH:19][N:20]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)=[O:16])=[CH:14][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3]1=[O:41].[CH3:42][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:16][C:15]([C:13]1[CH:12]=[CH:11][C:8]2[C:9]3[CH2:10][N:2]([CH3:1])[C:3](=[O:41])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:14]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:21]=1)[CH3:42]
Reactant: CN1Cc2c(ccc3cc(C(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc23)C1=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1Cc2c(ccc3cc(C(C)(O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc23)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methyl-7-[(1-trityl-1H-imidazol-4-yl)carbonyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (1.07 g) was dissolved in THF (22 mL) and cooled to 0° C., and then a solution (1.0 M: 3.0 mL) of methylmagnesium bromide in THF was added dropwise. The reaction mixture was stirred at room temperature for 1 hr. and a solution (1.0 M: 3.0 mL) of methylmagnesium bromide in THF was added. The mixture was further stirred at room temperature for 30 min., and 20% aqueous ammonium chloride solution was added to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: dichloromethane-methanol=100:1→40:1) to give 7-(1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)ethyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (1.00 g) as an amorphous solid. This amorphous solid was dissolved in 90% formic acid (9 mL) and THF (9 mL) and the solution was stirred with heating at 60° C. for 2 hrs. The reaction mixture was concentrated and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. Sodium chloride was added and the mixture was extracted three times with a mixed solution of ethyl acetate-THF (1:1) under salting out. The combined extracted layer was dried over anhydrous magnesium sulfate and concentrated. The residue was suspended in ethyl acetate, filtrated and recrystallized from ethanol-water to give the title compound (0.20 g) as pale-brown crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1
Reactant: Cc1nn(-c2ccccn2)cc1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccn2)cc1CCl
Temperature: 70 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethanol (3.00 g), thionyl chloride (2.5 mL) and toluene (50 mL) was stirred at 70° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-chloromethyl-3-methyl-1-(2-pyridyl)-1H-pyrazole (3.10 g, yield 94%) as a colorless oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=1[NH:24][CH:25]=[CH:26][N+:27]([O-:29])=[O:28])=O>C1C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][N:24]=[C:18]2[S:19][C:20]([CH2:22][CH3:23])=[CH:21][C:17]=12
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc2c(-c3ccccc3Cl)c([N+](=O)[O-])cnc2s1
Yield: 89.1 %

Procedure:
To a solution of DBU (5.1 g) in benzene (50 ml) was added dropwise a solution of 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene (5.1 g) in dioxanebenzene (1:1, 30 ml) over one hour with stirring under reflux. After refluxing for additional one hour, the mixture was washed with water and dried over MgSO4. The solvent was distilled off and to the residue was added isopropyl ether to obtain 4-(2-chlorophenyl)-2-ethyl-5-nitrothieno[2,3-b]pyridine as crystals (4.3 g, 89.0%). The crystals were recrystallized from isopropyl ether to obtain pale yellow prisms, mp: 72°-73° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(C(Cl)c2ccccc2)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(c2ccccc2)N2CCNCC2)cc1

Procedure:
For the preparation of the compound of Example 27, 4-(2-methoxyethoxy)benzophenone is obtained by reaction of 4-hydroxybenzophenone with 2-methoxyethyl chloride at 100° C. in the presence of sodium hydride in dimethylformamide. Further reaction takes place in accordance with Example 1-5. 4-(2-Methoxyethoxy)benzophenone is reduced to 4-(2-methoxyethoxy)benzhydrol using sodium borohydride. 4-(2-Methoxyethoxy)benzhydrol is reacted with thionyl chloride in chloroform to give 4-(2-methoxyethoxy)benzhydryl chloride. 4-(2-methoxyethoxy)benzhydryl chloride is reacted with piperazine in dimethylformamide in the presence of potassium carbonate to give 1-((4-(2-methoxyethoxy)phenyl)phenylmethyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[N:27]=[CH:28][S:29][C:30]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(=O)([O-])O.[Na+].ClCCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:30]2[S:29][CH:28]=[N:27][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: O=Cc1scnc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.2 g), 4-benzenesulfonylthiazole-5-carbaldehyde (0.23 g) and 1,2-dichloroethane (7.0 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (2.2 mL), trifluoroacetic acid (0.6 mL) and 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and diluted with saturated aqueous sodium hydrogen carbonate solution. The phases were separated and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:4 by volume) to afford the title compound as a white foam (0.20 g).
Reaction SMILES: C[Si]1(C)O[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.C[Si](C)(C)[O:17][C:18]1[CH:19]=[C:20]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][Si](C)(C)C>>[OH:17][C:18]1[CH:19]=[C:20]([CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=3[OH:3])=[CH:35][CH:36]=2)[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: Cc1ccc2c(c1)O[Si](C)(C)OC2=O
Reactant: C[Si](C)(C)Oc1ccc(CCc2ccc(N)cc2)cc1O[Si](C)(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CCc3ccc(O)c(O)c3)cc2)c(O)c1
Temperature: 180 °C
Yield: 48.2 %

Procedure:
A mixture of 2,2,7-trimethyl-4H-1,3,2-benzodioxasilin-4-one (2.0 g, 10 mmole) and 4-[2-[3,4-bis[(trimethylsilyl)oxy]phenyl]ethyl]benzenamine (3.0 g, 8 mmol) is heated under argon to 180° C. After three hours the mixture is cooled, triturated with pentane and filtered. The collected solid is rinsed several times with pentane and dried. Recrystallization from isopropanol gave the pure product (1.4 g), mp 201°-202° C.