Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:4][C:3]1=[O:13].C(N(CC)CC)C.[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:38][CH2:39][CH2:40]Br)[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]>C(C(C)=O)C(C)C>[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:38][CH2:39][CH2:40][CH:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:5]43[O:4][C:3](=[O:13])[N:2]([CH3:1])[C:6]4=[CH2:7])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc2c(c1)N(CCCBr)c1ccccc1S2
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=C1N(C)C(=O)OC12CCNCC2CCCN1c2ccccc2Sc2ccc(C(C)=O)cc21
Reaction time: 6 h
Yield: 84.5 %

Procedure:
A mixture containing 7.3 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 9 ml of anhydrous triethylamine, 22.0 g of 3-(2-acetyl-10H-phenothiazin-10-yl)-propyl bromide and 80 ml of methyl isobutyl ketone is refluxed under argon while stirring for 6 hours. After cooling down the organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained is purified by chromatography on a silica gel column by using first chloroform and then ethyl acetate as eluating agent. After combining the ethyl acetate eluate is evaporated under reduced pressure and the residue is recrystallized from ethanol to give the title compound in 84.5% yield, m.p.: 105°-106° C.
Reaction SMILES: Cl[C:2]([C:4]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([CH3:22])[CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([C:4]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:3])=[C:17]([CH3:22])[CH:16]=1
Reactant: CCOC(=O)C1(C(=O)Cl)CCCC1
Reactant: Cc1cc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CCCC1
Yield: 35 %

Procedure:
Ethyl 1-chlorocarbonylcyclopentanecarboxylate (3.10 grams, 0.02 mole) prepared in Example XX, 4-bromo-2-methylaniline (2.82 grams, 0.02 mole) and triethylamine (1.53 grams, 0.02 mole) were reacted in tetrahydrofuran (200 milliliters) under conditions similar to those described in Example I to give 2.40 grams (0.007 mole) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopentanecarboxylate which, after recrystallization from hexane, had a melting point of 64° C.-67° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C@@H:14]([CH3:19])[CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[C:32]1([C@H:38]2[CH2:42][O:41][C:40](=[O:43])[NH:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O1CCNC1=O>O1CCCC1>[C:32]1([C@H:38]2[CH2:42][O:41][C:40](=[O:43])[N:39]2[C:16](=[O:18])[CH2:15][C@@H:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:19])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Triethylamine (1.3 mL, 9.1 mmol) was added to (S)-3-phenylbutyric acid (1.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. followed by the dropwise addition of pivaloyl chloride (0.83 ml, 6.7 mmol) to give a white solid. The reaction was allowed to warm to room temperature for 10 minutes then cooled back down to −78° C. In a separate flask, n-butyllithium (4.6 mL, 11.6 mmol, 2.5 M F in hexanes) was added to (S)-(+)-4-phenyl-2-oxazolidinone (2.0 g, 12.2 mmol) in anhydrous tetrahydrofuran at −78° C. and allowed to stir for 10 minutes. The lithiated oxazolidinone was transfered via cannula to the mixed anhydride at −78° C. and stirring continued for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over sodium sulfate. The crude product was purified by chromatography over silica gel eluted with 2:3 ethyl acetate/hexanes and the resulting solid was recrystallized from ethyl acetate/hexanes to afford (S)-4-phenyl-3-((S)-3-phenyl-butyryl)-oxazolidin-2-one (1.63 g, 88% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1)[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([CH3:25])=[N:22][C:21]=2[C:26](O)=[O:27])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:26]([C:21]1[N:22]=[C:23]([CH3:25])[S:24][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[O:27])[CH3:2]
Reactant: CCOC(=O)CC1COCCN1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: CCOC(=O)CC1COCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Yield: 66 %

Procedure:
The title compound (1.48 g, 66%) was prepared from (RS)-morpholin-3-yl-acetic acid ethyl ester, D43 (1.37 g, 5.8 mmol) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (1.00 g, 5.8 mmol) according to a procedure similar to that described for D16.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:8]=2[C:3]=1[C:4](=O)[CH2:5][CH2:6]3.C[O:18]C1C=CC=C2C=1CCCC2=O>>[OH:18][C:10]1[C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:8]=2[C:3]([CH2:4][CH2:5][CH2:6]3)=[CH:2][CH:11]=1
Reactant: COc1cccc2c1CCCC2=O
Reactant: O=C1CCN2CCCCc3ccc(O)c1c32
Product: Oc1ccc2c3c1CCCCN3CCC2

Procedure:
The title compound was synthesized in a similar manner as 11-hydroxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinolone starting from 5-methoxytetralone: 1H NMR (DMSO-d6) δ 8.69 (s, 1H), 6.55 (d, 1H); 6.27 (d, 1H), 3.05-3.02 (m, 2H), 2.92-2.89 (m, 2H), 2.68-2.64 (m, 2H), 2.54 (t, 2H), 1.69-1.60 (m, 4H), 1.45-1.37 (m, 2H); MS expected 204 (C13H18NO, M+1), found 204.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:13]([C:18]([O:20]C)=O)[C:14]([O:16][CH3:17])=[O:15])[CH:10]([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8].[F:22][C:23]1[C:24]([C:30](=[NH:32])[NH2:31])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=1>O1CCOCC1>[F:12][CH:10]([F:11])[C:9]1([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:18](=[O:20])[NH:32][C:30]([C:24]2[C:23]([F:22])=[CH:28][C:27]([F:29])=[CH:26][N:25]=2)=[N:31]1
Reactant: N=C(N)c1ncc(F)cc1F
Reactant: COC(=O)C(C(=O)OC)=C(c1ccc(F)c(F)c1)C(F)F
Solvent: C1COCCO1
Product: COC(=O)C1C(=O)NC(c2ncc(F)cc2F)=NC1(c1ccc(F)c(F)c1)C(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Titanium tetrachloride (11.4 mL, 104.1 mmol) in dichloromethane (28 mL) was added dropwise to a flask containing tetrahydrofuran (205 mL) under a nitrogen atmosphere, cooled in icebath. Then 1-(3,4-difluorophenyl)-2,2-difluoro-ethanone (10 g, 52 mmol) and dimethyl malonate (5.93 mL, 52 mmol) were added both at once. The resulting mixture was stirred under nitrogen atmosphere for 60 minutes while cooling was continued. Then, pyridine (16.8 mL, 208 mmol) in tetrahydrofuran (37 mL) was added to the mixture and this was allowed to warm to room temperature and stirred overnight. Next, distilled water (40 mL) and diethylether (40 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted with diethylether (2×40 mL). The combined organics were washed with brine (60 mL), NaHCO3 (60 mL) (aq/sat) and again with brine (60 mL). The organic layer was dried on MgSO4, filtered and concentrated under reduced pressure yielding dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (15.6 g) as a clear oil. Dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (5 g) was dissolved in 1,4-dioxane (25 mL) and treated with 3,5-difluoropyridine-2-carboximidamide (3.1 g, 19.6 mmol). The resulting mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate-heptane 0:100 to 50:50) yielding methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate (5.45 g) as a yellow solid which was used as such. Methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate was treated with phosphorus oxychloride (10 mL, 107.6 mmol) and the mixture was stirred at reflux for 2 hours.
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.ClC1C(=O)C(C#N)=C(C#N)C(=[O:25])C=1Cl>O1CCCC1.O>[C:1]1(=[O:25])[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: c1ccc2c(c1)c1c3n2CCCC3CCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC2CCCn3c2c1c1ccccc13
Temperature: 0 °C

Procedure:
7.2 g (0.034 mol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazole prepared according to A. S. Baily et al. J. C. S. Perkin I (1980) 97, were dissolved in 300 ml of tetrahydrofuran. The mixture was diluted with 30 ml of water and cooled to 0° C. A solution of 17.0 g (0.075 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of tetrahydrofuran was added dropwise in 10 minutes while stirring thoroughly at a reaction temperature between 0° and 5° C. The reaction mixture was stirred for 1 hour and evaporated in vacuum. The residue was extracted with methylene chloride. The methylene chloride solution was washed with 200 ml of 0.5N sodium hydroxide solution and evaporated in vacuum. The residue was chromatographed over 500 g of silicagel using ethyl acetate as an eluent. After evaporating the good fraction, the desired ketone was obtained in a yield of 4.6 g (60%) having a melting-point of 172°-173° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.79 g, 4.34 mmol) in acetonitrile (9.5 mL) was treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol) and acetonitrile (9.5 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 3.96 mmol) in acetonitrile (9.5 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.86 g, 59%) as a light, brown solid: HR-ES-MS m/z calculated for C18H20NO4F3 [M+H]+ 372.1417, observed 372.1418; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.29-1.55 (m, 1H), 1.56-1.68 (m, 1H), 1.73-1.90 (m, 1H), 3.66 (s, 3H), 4.19 (d, J=18.1 Hz, 1H), 4.26 (d, J=18.1 Hz, 1H), 4.75 (dd, J=11.4, 4.6 Hz, 1H), 4.95 (s, 1H), 7.64-7.78 (m, 4H).
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1)[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27](Cl)=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.CO>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:4]4[N:5]=[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:7](=[O:9])[NH:8][C:3]4=[N:1][N:2]=3)[CH2:25][CH2:26]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Reactant: NNc1nnc(-c2ccccc2)c(=O)[nH]1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C2(c3nnc4[nH]c(=O)c(-c5ccccc5)nn34)CC2)cc1
Yield: 70.6 %

Procedure:
To a solution of 3-hydrazino-6-phenyl-1,2,4-triazin-5(4H)-one (40.0 mg, 0.197 mmol) in pyridine (0.5 mL) was added 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (0.062 g, 0.30 mmol) and the resulting mixture was irradiated under microwave at 150° C. for 15 min. The reaction mixture was diluted with methanol and purified by RP-HPLC to afford the desired product (50 mg, 70%). Analytical LCMS: (M+H)+=360.2.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>C(Cl)(Cl)Cl>[CH2:10]([N:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: OCCNCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: OCCN(CCO)Cc1ccccc1
Reaction time: 5 h
Yield: 79.5 %

Procedure:
Diisopropylethylamine (2.99 mL, 17.1 mmol) and benzyl bromide (1.36 mL, 11.4 mmol) were added to a chloroform (46 mL) solution of diethanolamine (1.80 g, 17.1 mmol), and the solution was stirred for 5 hours under heat and reflux. The reaction solution was washed with water, saturated sodium bicarbonate water, and saturated brine, dried over magnesium sulfate, and evaporated after filtration. The resulting residue was purified by silica gel column chromatography (methanol/chloroform=0/100 to 12/88) to give N-benzyldiethanolamine (1.77 g, 79.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1Cl
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.75 g), 2-(2,4-dichlorobenzyl)-3-oxopentanoic acid methyl ester (1.3 g), polyphosphoric acid (5 mL) and dioxane (25 mL) was heated at 120° C. for 17 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and this mixture washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a brown oil, 1.7 μg.
Reaction SMILES: [CH2:1]1[CH2:6]CC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(O)C>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH:1]([O:34][C:33](=[O:35])[CH2:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22])=[CH:37][CH:36]=1)([CH3:6])[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)OC(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
A solution of DCC (2.06 g; 10 mmol) in EtOAc (10 ml) was added with stirring, at 0° C. to a mixture of the compound of example 1f (2.78 g; 9 mmol) and propane-2-ol (2 ml) in EtOAc (20 ml). DMAP (1.1 g; 9 mmol) was added after 10 min and stirring continued for 2 h at 0° C. The reaction mixture was stored in a freezer overnight. The precipitated DCU was filtered and the filtrate was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5% CH3CN in CHCl3) to obtain the title compound. Yield, 3.0 g (94.9%); mp, 62-64° C. (EtOAc-PE 60-80° C.); analysis: C18H25NO6 requires C, 61.53; H, 7.17; N, 3.99. found: C, 61.94; H, 7.19; N, 3.95%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[OH:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]2[N:24]=[CH:25][NH:26][C:22]=2[CH:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]([NH:8][C:6]2[N:7]=[C:2]([N:26]3[C:22]4[CH:21]=[C:20]([CH2:19][OH:18])[CH:28]=[CH:27][C:23]=4[N:24]=[CH:25]3)[CH:3]=[N:4][CH:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: OCc1ccc2nc[nH]c2c1
Reactant: CC(Nc1cncc(Cl)n1)c1ccc(F)cc1
Product: CC(Nc1cncc(-n2cnc3ccc(CO)cc32)n1)c1ccc(F)cc1
Yield: 8.1 %

Procedure:
In a procedure analogous to Example 3, reaction of 6-chloro-N-[1-(4-fluorophenyl)ethyl]pyrazin-2-amine (1.80 g, 7.15 mmol) and 5-hydroxymethyl benzimidazole (1.26 g, 8.5 mmol) furnished the two products which were separated by column chromatography using dichloromethane-methanol (98:2-92:8) as eluant. From the less polar fractions was obtained [1-(6-{[1-(4-fluorophenyl)ethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]methanol as a pale yellow solid (210 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1.CS(O[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][N:42]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:43][C@H:44]([OH:56])[C:45]2[C:53]3[S:52][C:51](=[O:54])[NH:50][C:49]=3[C:48]([OH:55])=[CH:47][CH:46]=2)=[CH:37][CH:36]=1)(=O)=O>C(#N)C>[OH:56][C@H:44]([C:45]1[C:53]2[S:52][C:51](=[O:54])[NH:50][C:49]=2[C:48]([OH:55])=[CH:47][CH:46]=1)[CH2:43][N:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[C:9]([CH3:8])[S:13][CH:12]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:40][CH:39]=1)[C:57](=[O:58])[O:59][C:60]([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 80 °C

Procedure:
Triethylamine (0.25 mL) was added to a solution of (5-methylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 104, step b) (0.195 g) in acetonitrile (2.5 mL). This solution was added to a solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.5 g) in acetonitrile (2.5 mL). The resulting mixture was heated at 80° C. for 48 hours. The reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a cream solid. Yield 0.33 g.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:18])[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[Cl-].[Zn+2:20].[Cl-]>CO.O>[Zn:20].[CH3:2][C:3]1([CH3:18])[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: [Zn+2]
Agent: CC1(C)C=C(OS(C)(=O)=O)c2ccccc2N1
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: [Zn]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of 13.2 g. of (2,2-dimethyl-1,2-dihydroquinoline-4-yl)-methylsulfonic acid sodium salt in 10 ml of methanol 2.7 g of zinc chloride are added. The solution is stirred at room temperature of 2 hours, whereupon it is diluted with 40 ml of water. The solution is then evaporated in vacuo on water bath. 9.9 g (87%) of (2,2-dimethyl-1,2-dihydroquinoline-4-yl)-methylsulfonic acid zinc salt are obtained, melting at 98° to 100° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([C:14]#[N:15])[CH:8]=2)[CH:6]=1.[H][H]>N.CO.[Ni+2]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][NH2:15])[CH:8]=2)[CH:6]=1
Reactant: [H][H]
Reactant: Cc1cn(-c2ccc(N)c(C#N)c2)cn1
Agent: [Ni+2]
Agent: N
Solvent: CO
Product: Cc1cn(-c2ccc(N)c(CN)c2)cn1
Yield: 81.6 %

Procedure:
To 4-(4-methyl-1H-imidazol-1-yl)-2-cyanoaniline (15.5 g; 78.2 mmol) dissolved in 10% NH3/methanol was added Raney-Nichel (5 g), the resulting mixture was hydrogenated at 60° C., at an hydrogen pressure of 60 bar, for 24 hours. The nitrogen purged reaction mixture was filtered on celite, the cake was washed with methanol and the combined filtrate and washings evaporated. The residue was purified by column chromatography over silica gel (DCM/MeOH/2M NH3, 85:10:5) evaporation of the combined appropriate fractions afforded the pure titled product as yellow-orange solid (12.9 g, 82%). C11H14N4, MW: 202.26; 1H-NMR (300 MHz, d6-DMSO) ppm: 2.13 (s, 3H), 5.24 (s, 2H), 6.67 (d, 1H), 7.08 (dd, 1H), 7.17 (t, 1H), 7.23 (d, 1H), 7.81 (d, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C>C(O)(=O)C.C(OCC)C>[BrH:48].[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCC1CCNCC1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h

Procedure:
In 2 ml of acetic acid is dissolved 0.7 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(RS)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 2 hours. The reaction solution is diluted with 100 ml of ethyl ether, and after the mixture is allowed to stand, the supernatant layer is removed by decantation. The precipitate is rinsed with 50 ml of ethyl ether and dried to give 3(RS)-[5-(4-piperidyl)-1(RS)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid.hydrobromide. This product is dissolved in 20 ml of 1N aqueous sodium hydroxide, and the solution is allowed to stand at room temperature for 1 hour, made acidic with 2 ml of acetic acid and purified by XAD-2 column chromatography (methanol:water=1:1). The effluent is concentrated under reduced pressure, and the crystals, which separate out, are rinsed with 50 ml of acetone and collected by filtration to give 0.22 g of 3(RS)-[5-(4-piperidyl)-1(RS)-carboxypentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-acetic acid as colorless prisms. m.p. 240°-260° C. (decomp.).