Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:46])[C@@H:4]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:29][CH3:30])=[CH:15][C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C:18]=3[CH:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C.C1COCC1>[C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:29][CH3:30])=[CH:15][C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C:18]=3[CH:17]=2)=[CH:8][CH:7]=1)[C:3]([OH:46])=[O:2])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC(=Cc1ccc2c(c1)Cc1ccccc1-2)COc1ccc(C[C@H](Nc2ccccc2C(=O)c2ccccc2)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(=Cc1ccc2c(c1)Cc1ccccc1-2)COc1ccc(C[C@H](Nc2ccccc2C(=O)c2ccccc2)C(=O)O)cc1
Temperature: 5 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
(S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-ethyl-3-(9H-fluoren-2-yl)-allyloxy]-phenyl}-propionic acid methyl ester (example 5) (700 mg, 1.15 mmol) was dissolved in a mixture of ethanol (20 ml) and THF (20 ml). 1N NaOH (10 ml) was added and the mixture was stirred for 16 h at 5° C. The mixture was concentrated in vacuo. 1N HCl and ethyl acetate (10 ml) was added. The aqueous phase was isolated and extracted with ethyl acetate (×2) The organic layers were combined, washed with water, dried (MgSO4) and evaporated to give 500 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[S:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:14][C:8]=3[CH:7]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2s1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-hydroxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (260 mg, 0.612 mmol) in CH2Cl2 (20 mL) at RT is treated with Et3N (0.40 mL) and methanesulfonyl chloride (140 mg, 1.22 mmol). The mixture is stirred for 30 min and quenched with water (1.0 mL). The organic layer is concentrated and purified using silica gel column chromatography (25% EtOAc/Hex) to afford the title compound (190 mg, 62%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:38][CH2:37]3)=[CH:28][CH:27]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17]C)=[O:16])=[O:12])=[N:7][N:8]=1>C1COCC1.O>[Br:3][C:4]1[N:5]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:38][CH2:37]3)=[CH:28][CH:27]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([OH:17])=[O:16])=[O:12])=[N:7][N:8]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to a solution of methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio) acetamido)-3-phenylpropanoate (0.4 mmol) in 3:1, THF/H2O (1.6 mL) and the mixture stirred for 18 h at room temperature. The crude reaction mixture is concentrated and acidified with aqueous HCL (1M, 1.2 mL) and then is extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried (sodium sulfate), filtered and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13](C(=O)C)[C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(NCC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2Sc3ccccc3N(C(C)=O)C(=O)C2OC(C)=O)cc1
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2Sc3ccccc3NC(=O)C2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
7-(1). 2-(4'-Methoxyphenyl)-3-acetoxy-5-acetyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one [Compound (VII)] (1.93 g) and diethylamine (0.44 g) are added to chloroform (20 ml), and the mixture is stirred at room temperature for one hour. After distilling off chloroform, water is added to the residue, and the precipitated crystals are separated by filtration, washed with water and dried to give the title compound (II) (1.63 g, 94.8%), m.p. 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C=Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c([N+](=O)[O-])c4)cc3)c2cc1OC
Yield: 143.9 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 4-chloro-3-nitrophenyl isocyanate (224 mg) was added, and the admixture was refluxed with heat for 8 minutes. The separated crystals were filtered and then washed with toluene to obtain 125 mg of the title compound (yield: 75%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](C2C=CC=CC=2)([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:17]#[N:18])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:17][NH2:18])=[CH:10][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 5 °C
Yield: 89.5 %

Procedure:
To a 5 liter flask stirring under nitrogen, fitted with a mechanical stirrer, was charged 18 g (0.45 mole) of lithium aluminum hydride in 1000 mL of dry tetrahydrofuran which was then cooled to 5° C. To the slurry was added 152 g (0.45 mole) of alpha-(2-(4-chlorophenyl)ethyl)-alpha-phenyl-1H-1,2,4-triazole-1-propanenitrile in 2000 mL of dry tetrahydrofuran over 3 hours. The reaction was kept at 5°-10° C. during the addition then allowed to warm to room temperature and stirred overnight. The reaction was cooled in an ice bath and quenched with the slow addition of sodium sulfate. The solvent was removed and the residue was extracted with ethyl acetate and washed with 1000 mL water and 1000 mL brine. After drying, and removal of the solvent, 137 g (89.5% yield) of a very viscous oil resulted.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35](O)=[O:36])[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:36])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (190 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (139 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (104 mg) and triethylamine (476 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 51) (169 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[N:8][CH:7]=1)=[O:5])[CH3:2].O.NN.C(O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][NH2:21])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc12
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(CN)c2c(OC)cc(OC)cc12
Temperature: 40 °C
Reaction time: 4 h
Yield: 123.5 %

Procedure:
To a solution of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (1.22 g, 2.90 mmol) in 80 mL of absolute ethanol hydrazine monohydrate (1.59 g, 31.8 mmol) was added and the mixture was stirred under a nitrogen atmosphere at 40° C. After 4 h, the reaction was cooled to room temperature, and the phthalhydrazide precipitate was removed by filtration, rinsing with ethanol. The filtrate was concentrated under reduced pressure to give 1.04 g of crude 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester, which was used directly the next step. H1-NMR (DMSO): δ, 8.84 (s, 1H), 7.81 (d, 1, J=2.4 Hz), 6.76 (d, 1H, J=2.3 Hz), 4.36 (q, 2H, J=7.13), 4.32 (s, 2H), 3.95 and 3.88 (s, 3H each), 1.35 (t, 3H, J=7.2 Hz); MS: APCI (M+H) calc'd for C15H18N2O4+H 291.3; found 291.1.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)#[N:4].[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1.O>O1CCCC1>[Cl:17][C:18]1[S:22][C:21]([S:23]([N:9]([C:8]2[CH:12]=[CH:13][C:5]([C:3]#[N:4])=[CH:6][C:7]=2[N+:14]([O-:16])=[O:15])[CH2:10][CH3:11])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1ccc(C#N)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in tetrahydrofuran (THF) (3.0 ml), 4-cyano-N-ethyl-2-nitroaniline (0.38 g (1.99 mmol)) was added with stirring at room temperature. To the mixture, upon stirring for 15 minutes at room temperature and after the solution had turned deep purple, 5-chloro-2-thiophenesulfonyl chloride (0.55 g (2.53 mmol)) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.22 g (30%) of the title compound as yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][N:8]=2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([Cl:18])=[O:14])[O:9][N:8]=2)[CH:2]=1
Reactant: O=C(O)c1cc(-c2cccnc2)no1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2cccnc2)no1
Temperature: 25 °C

Procedure:
600 mg (3.16 mmol) of 3-(pyridin-3-yl)-1,2-oxazole-5-carboxylic acid were initially charged in dichloromethane, and three drops of DMF were added. 1.16 g (9.15 mmol) of oxalyl chloride were added dropwise under argon (vigorous evolution of gas). The reaction solution was stirred at room temperature and then the solvent was removed on a rotary evaporator. 30 ml of toluene were added to the residue. After the toluene had been removed on a rotary evaporator, the residue was converted further directly.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O-:3])=[O:2].FC(F)(F)S(O[C:33]1[CH2:37][CH2:36][CH2:35][CH:34]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>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>[C:33]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:6]=2)[CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1[N+](=O)[O-]
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl (2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (16 g, 43.9 mmol, 1.0 equiv.) in 1,4-dioxane (320 mL) were added cyclopent-1-en-1-yl trifluoromethanesulfonate (11.4 g, 52.7 mmol, 1.2 equiv.), Pd (PPh3)4 (2.54 g, 2.2 mmol, 0.05 equiv.) and a solution of Na2CO3 (5.6 g, 52.7 mmol, 1.2 equiv.) in water (160 mL) at room temperature. The reaction was then heated to 110° C. and stirred for 4 h. The reaction mixture was filtered through celite then concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to give tert-butyl (5-(cyclopent-1-en-1-yl)-2-nitrophenyl)carbamate (4.3 g, 32% yield).
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=O)=[O:19])=[C:10]1[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]([N:32]([CH2:44][CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:34]=1)[CH3:31].C(OC(=O)C)(=O)C>>[CH2:40]([N:39]([CH2:42][CH3:43])[C:35]1[CH:34]=[C:33]([N:32]([CH2:30][CH3:31])[CH2:44][CH3:45])[CH:38]=[CH:37][C:36]=1[C:18]1([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:10]=2[CH3:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22](=[O:24])[O:19]1)[CH3:41]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in part B of Example 5 above, 2.34 g (0.006 mole) of 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]benzoic acid prepared according to Example 5, part A, and 2.40 g of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of 2.40 g of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-n-octyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; R=CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; R6 =(CH2)7CH3) as a tar-like semisolid. A toluene solution of this material developed a purple color when spotted on silica gel.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CCNCC
Product: CCN(CC)Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and N,N-diethylamine to give a yellow solid. MS m/z: 391.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(CN2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 5.3 parts of chloroacetonitrile, 14.4 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-3H-imidazo[4,5-b]pyridine, 7.4 parts of sodium carbonate and 288 parts of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was stirred into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13 parts (79.2%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineacetonitrile; mp. 80.7° C. (compound 75).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 7.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.79 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.3 ml of benzyl alcohol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 9.02 g of the title compound, melting at 149° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:19])[NH:35][C:26]3([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CN(C(=O)OC(C)(C)C)CC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 3,4-dihydro-1H-isoquinoline-2,8-dicarboxylic acid 2-tert-butyl ester (2.0 g, 7.2 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (1.5 g, 7.2 mmol), HATU (3.3 g, 8.6 mmol) in anhydrous DMF (70 mL) is added DIPEA (1.4 mL, 8.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (200 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (217) as white solid (3.3 g, 99%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][CH2:12][CH3:13])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[NH2:8].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:11][CH2:12][CH3:13])=[N:4][C:5]([S:9]([CH3:10])=[O:22])=[N:6][C:7]=1[NH2:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNc1nc(SC)nc(N)c1Br
Solvent: ClCCl
Product: CCNc1nc(S(C)=O)nc(N)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a stirring solution of 5-bromo-N4-ethyl-2-(methylthio)pyrimidine-4,6-diamine (intermediate 19) (4.2 mmol) in 10 ml of DCM, 1.04 g (4.6 mmol) of m-chloroperbenzoic acid (77%) (Aldrich) in 3 ml of DCM were added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under reduced pressure, the remaining solid was first washed with cold DCM and then several times with cold water, filtered and dried. 1.11 g (95%) of 5-bromo-N4-ethyl-2-(methylsulfinyl)pyrimidine-4,6-diamine were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[C:5](=[O:9])[N:6](C)[N:7]=1.[H-].[Na+].Br[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>CN(C=O)C.O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[N:10]1[C:4]2[C:5](=[O:9])[NH:6][N:7]=[C:2]([NH:1][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:3]=2[CH:12]=[CH:11]1
Reactant: CCC(Br)CC
Reactant: Cc1cc(C)c(-n2ccc3c(N)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Nc1n[nH]c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
To a solution of 4-amino-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (113 mg, 0.40 mmol) in DMF (1 ml) were added sodium hydride (60% in oil, 48 mg, 1.20 mmol) and 3-bromopentane (0.15 ml, 1.20 mmol). The mixture was stirred at 80° C. for 15 hours, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5:1) to give 35 mg (25%) of the title compound as crystals.