Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](C2C=CC=CC=2)[N:3]=1.ClC1C=C(Cl)N=CN=1.[CH2:23]([CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26]O)[CH3:24]>CC(C)CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([CH2:26][CH:25]([CH2:23][CH3:24])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CCCCC(CC)CO
Agent: Clc1cc(Cl)ncn1
Solvent: CC(C)CCO
Product: CCCCC(CC)Cc1cc(Cl)ncn1
Yield: 76.2 %

Procedure:
The compound is prepared analogously to the method described in Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloropyrimidine and 3-methylbutanol by 2-ethylhexanol. Yield: 76.2% of theory.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:19]=[C:18]([C:20](OCC)=[O:21])[N:17]([CH2:25][CH2:26][CH2:27][NH2:28])[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:14][C:15]1[CH:19]=[C:18]2[C:20](=[O:21])[NH:28][CH2:27][CH2:26][CH2:25][N:17]2[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)nn1CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1NCCCn2nc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Na2CO3 (25 g, 235.85 mmol) was added to a solution of ethyl 3-(benzyloxy)-1-[3-amino-propyl]-1H-pyrazole-5-carboxylate (5.5 g, 16.2 mmol) in water (150 mL). The mixture was stirred at room temperature for 18 hours and then extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in petroleum ether 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(benzyloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (4 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=O)[CH2:12][N:13]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:14][CH:15]=[CH2:16].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][N:13]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCN(CC(=O)Nc1ccc(OC)cc1Cl)CC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCN(CCNc1ccc(OC)cc1Cl)CC1CCCCC1

Procedure:
In a manner similar to Preparation 2 react N-(2-chloro-4-methoxyphenyl)-2-[cyclohexylmethyl(2-propenyl)-amino]acetamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:12][C:13]=2[O:14][CH3:15])OC1.[Cl:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>CO.[Cu-]=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:9]2[CH:8]=[C:13]([O:14][CH3:15])[N:12]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=2)[CH:27]=1
Reactant: CCOC(=O)c1ccc(B2OCC(C)(C)CO2)c(OC)n1
Reactant: Clc1c[nH]cn1
Agent: O=[Cu-]
Solvent: CO
Product: CCOC(=O)c1cc(-n2cnc(Cl)c2)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (49.8 mg, 0.068 mmol) was added to a solution of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (prepared in analogous fashion to methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30) in Preparation 10; 254 mg, 0.97 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (264 mg, 1.17 mmol), and potassium acetate (293 mg, 2.92 mmol) in 1,4-dioxane (8 mL). The reaction was stirred at 85° C. for 6 hours, whereupon it was allowed to cool to room temperature. Dichloromethane was added, and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to afford intermediate ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate. To a solution of ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate (crude) in methanol (50 mL) was added 4-chloro-1H-imidazole (C33) (100 mg, 0.97 mmol) and copper(I) oxide (14 mg, 0.098 mmol) and the reaction was stirred at ambient temperature overnight. The mixture was heated to 50° C. for 2 hours, and additional copper(I) oxide (14 mg, 0.098 mmol) was added. The reaction was heated to reflux for 2 hours and was then filtered through Celite. The Celite pad was washed with methanol, and the combined filtrate and washings were concentrated in vacuo. Purification was carried out twice via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane, then 0% to 40% ethyl acetate in heptane), affording the title compound as a white solid. Yield: 29.3 mg, 0.104 mmol, 11%. LCMS m/z 282.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (t, J=7.1 Hz, 3H), 4.14 (s, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.83 (m, 1H), 7.84 (d, J=7.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-bromo-2-methoxy-4-nitro-benzene (2.5 g, 10.8 mmol), Pd2(dba)3 (0.124 g, 0.215 mmol), NaOt-Bu (1.55 g, 16.2 mmol) and BINAP (0.202 g, 0.323 mmol) in toluene (20 mL) at 20° C. was added morpholine (1.5 mL, 17.2 mmol) over 10 min. The mixture was stirred at 80° C. for 3 h when TLC indicated no starting material remained. The mixture was evaporated under reduced pressure followed by the addition of H2O (50 mL). CH2Cl2 extraction (3×15 mL), followed by drying of the combined organic layers with MgSO4 afforded, after filtration and concentration, an orange oil. Chromatography on silica gel (97:3 CH2Cl2/MeOH) yielded pure compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:10][CH2:9][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:17]
Reactant: N#Cc1ccc(N(CCSc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(SCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A solution of 4-[{2-[(4-aminophenyl)thio]ethyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.038 g, 0.091 mmol; see Example 74A) in CH2Cl2 (4 mL) was treated under N2 with TEA (0.010 g, 0.099 mmol) and MsCl (0.011 g, 0.099 mmol) and stirred at rt. After 4 h, additional TEA (0.0046 g, 0.046 mmol) and MsCl (0.0052 g, 0.046 mmol) were added and stirred at rt. After 1 h, the mixture was concentrated in vacuo and the residue taken up in CHCl3 (4 mL) and heated at 70° C. for 2 h. Upon cooling, additional TEA (0.0046 g, 0.046 mmol) and MsCl (0.0052 g, 0.046 mmol) were added and heated at 70° C. for 12 h. Upon cooling, additional TEA (0.0092 g, 0.091 mmol) and MsCl (0.0104 g, 0.091 mmol) were added and heated at 70° C. for 4 h. The mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes gradient) to give the title compound (0.025 g, 55% yield): MS (ES) m/z 496 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.CC(C)C(O)=O.[CH3:32][C:33]([N:35]([CH3:37])[CH3:36])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]=[CH:32][CH2:33][N:35]([CH3:37])[CH3:36])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: NC(=O)c1ncn2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: CC(=O)N(C)C
Solvent: CC(C)C(=O)O
Product: CN(C)CC=NC(=O)c1ncn2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 115 °C

Procedure:
A mixture of 0.0047 mole 8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide and 3 ml of dimethyl acetamide dimethyl acetate was heated in an oil bath at a temperature of about 115° C. After cooling the crystals were collected on a glass filter and washed with dimethyl formamide (DMF) and ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH:20]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH:20]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCCCCCCCCCCC(CC(=O)OCc1ccccc1)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)CCCCCCCCCCCC(CC(=O)O)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of benzyl 3-(N-tertiarybutoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoate (2.85 g) in methanol (50 ml) was added 10% palladium on active carbon (0.5 g) and water (5 ml). The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent was removed under reduced pressure to give 3-(N-tertiarybutoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoic acid as an oil (2.31 g).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1cccc(F)c1-c1nc2c(Br)n[nH]c2c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3ccccc3c21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 50 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 890 mg of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline in 20 ml of DMF, 2.46 ml of N,N-diisopropylethylamine and 658 μl of 2-(trimethylsilyl)ethoxymethyl chloride. After 16 h at RT, the mixture is poured into 50 ml of ice-water. The aqueous phase is extracted with 3 times 50 ml of AcOEt and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and DCM (80/20 by vol.) then (50/50 by vol.), to give on one hand 498 mg of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline, in the form of a white gum, LC-MS-DAD-ELSD: 492 (+)=(M+H)(+), and on the other hand 200 mg of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white gum), LC-MS-DAD-ELSD: 492 (+)=(M+H)(+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([O:14]CC)=[CH2:13])=[CH:7][N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CC(OC)(C)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][N:6]=1)=[O:4]
Reactant: C=C(OCC)c1cnc(C(=O)OC)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)c1ncc(C(C)=O)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-5-(1-ethoxy-vinyl)-pyridine-2-carboxylic acid methyl ester (359 mg, 1.485 mmol) in THF (3.6 ml) was added para-toluenesulfonic acid monohydrate (565 mg, 2.97 mmol) and the mixture was stirred for 1 h. The reaction mixture was diluted with TBME and sat. aq. NaHCO3, the layers were separated and the aq. Phase was extracted with TBME. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 9:1 to 6/1) to provide the title compound as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([Cl:20])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([Cl:20])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:23])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(Cl)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, step a to d) in 2 mL DMF, under nitrogen, was added 0.104 g (0.46 mmol) N-iodosuccinimide, and the reaction was stirred at room temperature for 16 hours. 20 mL EtOAc was added and the mixture was washed with a 10% solution of Na2S2O3 (2×5 mL). The aqueous layers were combined and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with 10 mL saturated brine, and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1).
Reaction SMILES: C([O:5][CH2:6][CH:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19](=[O:31])[N:20]3[C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[C:15]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:14]=2)[CH2:8]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:15]1[N:14]=[C:13]([N:9]2[CH2:10][CH2:11][NH:12][CH:7]([CH2:6][OH:5])[CH2:8]2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:31])[N:20]2[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CC(C)(C)OCC1CN(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CCN1
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2c(-c3ccccc3Cl)nc(N3CCNC(CO)C3)cc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 mg of 7-[3-(tert-butoxymethyl)piperazin-1-yl]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one was added 1 mL of TFA. The mixture was stirred 2 h at rt, then concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 9:1 CH2Cl2-2M NH3 in MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:36])[CH2:13][N:14]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccccc3)sc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccccc3)sc2N1
Yield: 208 %

Procedure:
A suspension of 7.5 g of 5-(2-chlorophenyl)-7-(2-phenylethyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 175°-176° C. and 4.8 g of Lawesson reagent in 150 ml of toluene is stirred at 40°-45° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 9.8 g of 5-(2-chlorophenyl)-7-(2-phenylethyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[NH:17]1C=CN=[CH:18]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)=[O:6])[CH:1]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: CN(C)CCC(=O)c1c[nH]c2ccccc12
Product: O=C(CCn1ccnc1)c1c[nH]c2ccccc12

Procedure:
3-(Dimethylamino)-1-(1H-indol-3-yl)-1-propanone was converted to the methiodide (12.75 g) which was then reacted with imidazole (12.75 g) to give the title compound (4.67 g), m.p. 193°-197°; λmax (EtOH) 242.5 nm (ε11,130), λinf 257.5 nm (ε9,120), λmax 299 nm (ε12,420), identical with the material obtained in Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH2:29][O:30][CH:31]1[N:40](C(OCC)=O)[C:39]2[C:34](=CC=CC=2)[CH:33]=[CH:32]1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:8]([CH:22]([CH3:27])[CH3:23])[CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:39][N:40]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Solvent: CC#N
Product: CC(C)N(CCOc1ccccn1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Yield: 46.7 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.10 g) isopropyl-2-(pyridin-2-yloxy)-ethylamine (0.18 g) and EEDQ (0.136 g) in acetonitrile (2 ml) was stirred at reflux, under nitrogen, for 18 h. The solvent was evaporated and the residue was purified by flash chromatography on silica eluting with dichloromethane/methanol (98:2 then 96:4) to give the title compound as a pale yellow oil (0.033 g).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].O.[C:16](Cl)(=[O:18])[CH3:17].Cl>[OH-].[Na+].CCOCC.C(OCC)(=O)C>[C:16]([NH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C(=O)O)c1ccc2c(c1)CCO2
Reaction time: 0.33 h

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (10 mmole) is dissolved in 25 ml of water containing 20 mmole of sodium hydroxide. The temperature is maintained at 10° C. while 10.5 mmole of acetyl chloride in 10 ml of ether is added over a period of 10 minutes. The reaction mixture is stirred for 20 minutes. Ethyl acetate is added and the pH is adjusted to 2 with hydrochloric acid. The layers are separated, the organic layer is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:12][NH:11][C:10](=[O:13])[C:9]=3[CH3:14])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: CC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O
Product: CC1=C(c2ccc(-n3ccnc3)c([N+](=O)[O-])c2)CNC1=O

Procedure:
In a manner similar to that described in Preparation 10, 4-(4-fluoro-3-nitrophenyl)-1,5-dihydro-3-methyl-2H-pyrrol-2-one is reacted with imidazole to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl.CO>C(O)(=O)C>[C:14]1([CH:13]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 661.9 %

Procedure:
A mixture of 1.0 g (6.24 mmol) of tryptamine and 0.73 g (0.87 mmol) of benzaldehyde in 10 ml of acetic acid was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off, and the residue was made alkaline by the addition of a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure to give 1.82 g of a crude mixture. The resulting residue was subjected to column chromatography using 35 g of silica gel with a 9:1 by volume mixture of methylene chloride and methanol as the eluent, to yield 1.43 g (92%) of the title compound. The product was subsequently recrystallized from dichloroethane and hexane to yield 0.72 g of pale yellowish brown crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].IC.CN(C)[C:38](=O)[CH3:39]>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:38][CH3:39])[C:12]2[CH:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1ccc(Nc2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1ccc(N(CC)c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 56 %

Procedure:
Following general procedure G and using 4-[(7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 18, 0.15 g, 0.41 mmol), potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.94 g, 6 mmol) in 5 mL of anhydrous N,N-dimethylacetamide, the title compound (0.090 g, 56%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=8.9 Hz), 6.87 (d, 1H, J=2.2 Hz), 6.77 (d, 1H, J=2.2 Hz), 6.57 (d, 2H, J=9.1 Hz), 4.29 (q, 2H, J=7.1 Hz), 4.28 (s, 2H), 3.74 (q, 2H, J=7.0 Hz), 1.36 (t, 3H, J=7.1 Hz), 1.36 (s, 9H), 1.33(s, 6H), 1.26 (t, 3H, J=7.1 Hz)).