Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([NH:39][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 17 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as described in Example 164B (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.035 g, 17%). 1H NMR (300 MHz, CDCl3) δ 9.45 (br, 1H), 8.77 (s, 1H), 7.80 (s, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.35 (m, 2H), 7.28 (s, 1H), 7.21 (s, 1H), 6.31 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.91 (s, 3H); LC-MS (ESI) m/z 505 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCCc1cc(Cl)cc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1cc(Cl)cc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl) phenoxy)chroman-4-carboxylic acid (60.0 mg, 0.115 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (230 μl, 0.115 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (62.0 mg, 0.114 mmol, 99.1% yield) as a solid. MS (apci) m/z=521.9 (M+2H-Na)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]2)=[C:21]([CH3:41])[CH:20]=1>>[NH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:22]2[C:21]([CH3:41])=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)=[C:24]([O:25][CH3:26])[CH:23]=2)[CH2:28][CH2:29]1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) tert-butyl 1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-ylcarbamate (INTERMEDIATE 29).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:33])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (106 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (114 mg, 57%) as a white powder.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[C:15](Br)=[N:14][C:13]([Br:17])=[CH:12][N:11]=1.O>O1CCCC1>[Br:17][C:13]1[N:14]=[C:15]([O:8][CH2:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)[C:10]([NH2:9])=[N:11][CH:12]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(Br)nc1OCC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Sodium hydride (0.96 g, 23.7 mmol) was added in portions to a solution of cyclobutanemethanol (2.2 mL, 23.7 mmol) in tetrahydrofuran (30 mL) at 0° C., the reaction mixture was stirred at room temperature for 45 minutes. A solution of 2-amino-3,5-dibromopyrazine (3.0 g, 11.9 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was heated at 50° C. for 16 hours. The reaction mixture was cooled to room temperature and water (2 mL) was added, the whole was then concentrated in vacuo to give a brown oil. The crude product was purified by flash column chromatography (100% dichloromethane) to give 5-bromo-3-cyclobutylmethoxy-pyrazin-2-ylamine as a pale yellow solid, 3.19 g (100% yield). LC@215 nm; Rt 2.11: 93%, m/z (ES+): 259 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN1CCCC1
Yield: 95 %

Procedure:
Pyrrolidine, 71.1 g, was added to 86.1 g of methyl acrylate at 20° C. and reacted for 24 hours. Purification by vacuum distillation yielded 149 g of methyl 3-(1-pyrrolidinyl)propionate, designated [B-17] (boiling point: 74° C./800 Pa, yield: 95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([F:7])=[C:5]([CH:8]=[O:9])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[K+].[K+]>CC(C)=O.O.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:6]([F:7])=[C:5]([C:8]([OH:17])=[O:9])[C:4]([C:10]([F:13])([F:11])[F:12])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1F
Reaction time: 8 h
Yield: 200.2 %

Procedure:
A solution of 1-methyl-3-trifluoromethyl-5-fluoro-pyrazole-4-carboxaldehyde (9.8 g) in acetone (60 mL) was stirred rapidly at RT while a solution of potassium dichromate dihydrate (5.6 g) in water (38 mL) and sulfuric acid (4.6 mL) was added. The mixture was stirred rapidly overnight then diluted with water (150 mL). The mixture was extracted with CH2Cl2 (6 ×75 mL). The combined organic solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo leaving a light yellow solid (7.2 g). The solid was recrystallized from EtOAc/hexane to give the desired compound as white crystals (3.8 g). m.p. 165-166° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: CCCN1C(=O)Cc2cc(N3C[C@@H](CN)OC3=O)cc(F)c21
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC)OC3=O)cc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.038 ml, 0.480 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.135 g, 0.320 mmol) and diisopropylethylamine (0.235 ml, 1.28 mmol) in dichloromethane (3 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as an off white solid. HPLC r.t. 4.40 min; 1H NMR (300 MHz, CDCl3) 7.30 (m, 1H), 7.21 (m, 1H), 5.10 (t, 1H), 4.77 (m, 1H), 4.02 (t, J=9 Hz, 1H), 3.77-3.82 (m, 3H), 3.68 (s, 3H), 3.57 (s, 2H), 3.49-3.63 (m, 2H), 1.69 (m, 2H), 0.95 (t, J=7.5 Hz, 3H); MS for C17H20F2N3O5 m/z 366.1 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:13][C:12]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:8]=[CH:7][N:6]=1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:13][C:12]=2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)CCSc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC(C)=O)c2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(SCCC(=O)O)nc(-c2ccc(F)cc2)c1-c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
50 ml of HCl 10% are added to ethyl 3-[5-(2-acetylaminopyridin-4-yl)-4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-ylsulfanyl]propionate (0.67 mmol/0.297 g), and the mixture is stirred at room temperature for 6 h. The mixture is then slowly neutralized using 2N NaOH, resulting in the precipitation of 3-[5-(2-aminopyridin-4-yl)-4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-ylsulfanyl]propionic acid as a whitish powder. The precipitate is filtered off with suction, washed with a little ice-cold water and dried over P2O5.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[C:16]([NH:17]C(=O)OC(C)(C)C)=[CH:15][N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[C:16]([NH2:17])=[C:15]([F:34])[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2nn(-c3ccccc3)cc2NC(=O)OC(C)(C)C)cc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Nc2nn(-c3ccccc3)c(F)c2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-{[4-(acetylamino)benzoyl]amino}-1-phenyl-1H-pyrazol-4-yl)carbamate (15 mg, 0.034 mmol) in methylene chloride (1 mL) and dimethylformamide (1 mL) was added selectfluor (24 mg, 0.069 mmol) and the resulting solution was stirred overnight at rt. The reaction was evaporated to dryness and purified by reverse phase LC to give the desired product as white solid. ESIMS calcd 454.18 (M++H), found 454.2 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([OH:32])=[CH:4][N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][C:36]=1[O:43][CH3:44])=[N:3][CH:4]=[C:5]2[OH:32])(=[O:14])=[O:13]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(O)c3c2)c(OC)c1
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: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OC)ncc(O)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-hydroxy-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE WWW) (0.263 g, 0.535 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (0.136 g, 0.802 mmol), tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.053 mmol), and potassium carbonate (0.369 g, 2.67 mmol). Dioxane (2.67 ml) and Water (0.891 ml) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(4-fluoro-2-methoxyphenyl)-4-hydroxy-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 582.2 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21
Yield: 84 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 84% of theory, C25H24N6O3 (456.5) ##EQU24##
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=[CH:7][C:6]1=2>C1(C)C=CC=CC=1>[OH:4][C:5]1([CH3:1])[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: O=C1CCCc2nc(OCc3ccccc3)ccc21
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Product: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 92 %

Procedure:
Methylmagnesium bromide (3.0M in diethyl ether, 47 ml) was added dropwise to a solution of 5,6,7,8-tetrahydro-5-oxo-2(phenylmethoxy)quinoline (29.6 g) and toluene (1 l) at 0° C. The reaction mixture was allowed to warm to room temperature, with stirring. The redaction mixture was then quenched with saturated ammonium chloride solution, the layers were separate, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to provide 31.7 g (92.0%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:16]([O-])=O)[CH:5]=1)[CH3:2].[H][H]>CO.[Pd]>[NH2:16][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([O:14][CH3:15])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 92.5 %

Procedure:
A mixture of methyl 4-ethoxy-5-methoxy-2-nitrobenzoate (8.38 g, 32.8 mmol) and Pd/C (10%, 0.85 g) in MeOH (20 mL) was stirred under 1 atmosphere of hydrogen at room temperature for 6 hours. The reaction mixture was filtered with Celite and washed with MeOH. The filtration was concentrated under reduced pressure to give methyl 2-amino-4-ethoxy-5-methoxybenzoate as solid (6.832 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), 6.13 (s, 1H), 5.56 (br, 2H), 4.08 (q, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 1.48 (t, 3H); LC-MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](O)[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([Cl:20])[C:6]=2[CH:17]=1
Reactant: OC1c2ccccc2C=Cc2ccc(Br)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1c2ccccc2C=Cc2ccc(Br)cc21

Procedure:
663 milligrams (2.31 millimoles) of 3-bromo-5H-dibenzo[a,d]cyclohepten-5-ol, 825 milligrams (6.94 millimoles) of thionyl chloride and 10 milliliters of benzene were mixed together and refluxed for 1.5 hours and the solvent removed in vacuo to obtain a 3-bromo-5-chloro-5H-dibenzo[a,d]-cycloheptene product as residue. The residue was dissolved in 10 milliliters of dimethylformamide and 1.74 milliliters (1.29 grams, 10.0 millimoles) of ethyl diisopropyl amine and 500 milligrams (2.31 millimoles) of cinnamoylpiperazine added thereto and the resulting mixture stirred overnight to obtain a 1-(3-bromo-5H-dibenzo[a,d]cyclohepten-5-yl)-4-cinnamoylpiperazine compound in the reaction mixture. It was recovered as residue by vaporizing the solvent in vacuo, the residue then was dissolved in ethyl acetate, the ethyl acetate solution washed with three 50 milliliter portions of water and with one 100 milliliter portion of brine, and then dried over potassium carbonate. After removing the drying agent, the solvent was evaporated in vacuo from the dried solution to obtain 1.07 grams (95 percent yield) of the cinnamoylpiperazine compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[CH3:19][Mg]Cl.S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([CH3:19])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:7]2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cl)cc2)OC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
Over a period of 30 minutes a solution of 130 g of 2-(4-chlorobenzoyl)benzoic acid in 300 ml of anhydrous tetrahydrofuran was added drop-wise under nitrogen to 900 ml of a stirred 3M solution of methylmagnesium chloride in anhydrous tetrahydrofuran. After the addition the reaction mixture was kept at reflux temperature for 1 hour. Afterwards it was cooled in an ice bath to room temperature and 1 L of an aqueous 2N sulfuric acid solution was added slowly, followed by 600 ml of toluene. The organic layer was separated and washed with brine, dried and evaporated in vacuo. Bulb to bulb destination (0.1 mm Hg/160° C.) afforded 60 g of 3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone as a yellow oil. M.S. (C.I.) (M/Z): 260 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[NH:15][C:14](=[O:16])[CH2:13][O:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[CH2:3]([CH:10]1[N:15]([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:14](=[O:16])[CH2:13][O:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COCC(Cc2ccccc2)N1
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COCC(Cc2ccccc2)N1C(CCN1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% NaH (80 mg, 2 mmol) in dry dimethylformamide (8 ml) was added 5-benzyl-3-morpholinone (880 mg, 2 mmol). The mixture was stirred at room temperature for 1 hour. To this were added 4-(3-chloro-3-phenylpropyl)morpholine (480 mg, 2 mmol) and dry dimethylforamide (1 ml). The mixture was then stirred overnight at 60° C. The stirred mixture was placed under reduced pressure to evaporate the solvent. Water was added to the residue, and extraction with ethyl acetate was performed. The extract was washed with a saturated aqueous brine and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to remove the solvent. The oily residue was placed on silica gel column and eluated with ethyl acetate/methanol (20/1) to yield the desired diastereomer A (168 mg, 21.3%) and diastereomer B (156 mg, 19.8%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([CH2:15][CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:1][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([CH2:15][CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: NCCCO
Reactant: CCC(Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCC(Oc1cccc(CNCCCO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
tert-Butyl 2-(3-formylphenoxy)butyrate (105.1 mg, 0.42 mmol) was dissolved in chloroform (10 ml) at room temperature, and thereto were added 3-amino-1-propanol (0.04 ml, 0.47 mmol), sodium triacetoxyborohydride (134.6 mg, 0.63 mmol) and acetic acid (0.03 ml, 0.51 mmol) in sequential order at the same temperature, and then stirred at room temperature for 24 hours. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution and thereafter extracted by chloroform, to obtain an organic layer. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressured. The resultant substance was purified by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained as a colorless oil (43.3 mg, 33.3%).