Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[C:9]([CH3:17])[C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:13])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)nc1C
Yield: 62.4 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (251 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 109, the title compound (307 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:2].C(C1CCCC([Cl:24])C1=O)(C)(C)C>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([Cl:24])[C:7]1=[O:12])[CH3:2]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: CCOC(=O)CC1CCCCC1=O
Product: CCOC(=O)CC1CCCC(Cl)C1=O

Procedure:
The chlorination of ethyl(2-oxo-cyclohexyl)-acetate takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=1>CO>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:13][C:1](=[O:5])[CH:2]=[N:14]2
Reactant: O=CC(=O)O
Reactant: Nc1ccc(Cl)cc1N
Solvent: CO
Product: O=c1cnc2cc(Cl)ccc2[nH]1
Reaction time: 24 h

Procedure:
Following the procedure of J. Med. Chem., 24, 93 (1981), glyoxylic acid (29.4 ml) is added to a solution of 4-chloro-1,2-phenylenediamine (38.0 g) and methanol (1.87 L) at 15°. The solution is stirred for 24 hr at 20°-25° and is concentrated. The residue is washed with water (4×608 ml), isopropanol (145 ml), and dried under reduced pressure to give a solid. Two successive recrystallizations from hot (ca 90°) 2-methoxyethanol (1.49 l and 0.927 l) gives the title compound, NMR (DMSO-d6) 12.55, 8.22, 7.86, 7.62 and 7.32 δ.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[C:27]([S:31][CH2:32][CH2:33]Cl)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:33][CH2:32][S:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)SCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSC(C)(C)C)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 27.9 %

Procedure:
0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 15 cm3 of methanol was heated for 16 hours at a temperature in the region of the reflux temperature, with stirring and under an inert atmosphere, with 0.43 g of 2-chloroethyl tert-butyl sulfide in the presence of 0.33 g of potassium carbonate and 0.4 g of potassium iodide. After cooling the reaction mixture to a temperature in the region of 20° C., the insoluble material was filtered off. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 35 cm), elution being was out with a dichloromethane/methanol (97/3 by volume) mixture, and 35-cm3 fractions were collected. Fractions 54 to 70 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.265 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(tert-butylthio)ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a brown color.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 42.7 %

Procedure:
4-Chloro-3-nitropyridine (3 g, 18.9 mmol) prepared in Step 1 of Preparation 1, 4-fluorophenylboronic acid (2.9 g, 20.79 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.89 mmol), and potassium carbonate (7.8 g, 56.7 mmol) were suspended in 120 ml of 1,4-dioxane. The resulting suspension was refluxed under stirring for 24 hours, filtered with Celite, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1.76 g of the titled compound as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:6]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[N:7][CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)O
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acetic acid methyl ester (0.14 g, 0.3 mmol) in tetrahydrofuran (3.0 mL) and water (0.6 mL) was added lithium hydroxide monohydrate (0.031 g, 0.75 mmol) at ambient temperature. After stirring for 4 hours the reaction mixture was filtered through a pad of silica gel eluting with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo to provide the title compound (0.061 g).
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](OCC)(=[O:17])[CH2:14][CH2:15][CH3:16].Cl>C1(C)C=CC=CC=1.O>[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)OCC
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)CC(=O)CCc1ccccc1
Reaction time: 9 h

Procedure:
Sodium (7.3 g) was added in small portions to a solution of 4-phenyl-2-butanone (46.8 g, 0.31 mol) and ethyl butyrate (110 g, 0.95 mol) in toluene (120 ml) at 20°-60° C. under nitrogen, and stirring was continued for 9 h under reflux. After standing overnight, the reaction mixture was taken up in H2O (300 ml), neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residual reddish orange oil (84 g) was distilled under reduced pressure to afford the title compound as a pale yellow oil which was an ca 3:7 mixture of Keto/Enol as seen by the methylene singlet at δ3.52 ppm and the methine singlet as δ5.45 ppm in the 1HNMR spectrum; yield: 15.4 g; bp. 166°-168° C./2 mmHg.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH3:24])[C:4](=[O:25])[C:3]=1[NH:26][C:27]([C:29]1[CH:30]=[N:31][N:32]([CH2:34][CH:35]2[CH2:39][C:38](=[O:40])[N:37]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=3)[CH2:36]2)[CH:33]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CN(C=O)C.O>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][N:7]1[C:2]2[N:1]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([CH2:34][CH:35]4[CH2:39][C:38](=[O:40])[N:37]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=5)[CH2:36]4)[CH:33]=3)[NH:26][C:3]=2[C:4](=[O:25])[N:5]([CH2:22][CH2:23][CH3:24])[C:6]1=[O:21]
Reactant: CCCn1c(=O)c(NC(=O)c2cnn(CC3CC(=O)N(c4cccc(C(F)(F)F)c4)C3)c2)c(N)n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5cccc(C(F)(F)F)c5)C4)c3)nc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-[5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid {6-amino-1-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl}-amide (100 mg, 0.14 mmol) was taken in dry DMF (3 ml) under argon atmosphere, added P2O5 (61.4 mg, 0.43 mmol) and dipped the reaction flask in a oil bath at 100° C. and stirred the reaction mixture for 5 min. Then the reaction mixture was cooled to room temperature and diluted with water and filtered the solid (56 mg, 57%) as pure product.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[C:7]1([CH:13]([CH3:16])[C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.ClCCl>[C:7]1([CH:13]([CH3:16])[C:14](=[NH:2])[NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CC(C#N)c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C(=N)N)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Ammonium chloride (535 mg, 10.0 mmol) was suspended in toluene (3 ml), cooled to 0° C., under nitrogen then trimethylaluminium (5 ml, 2M in toluene) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. Then 2-phenylpropionitrile (1.33 ml, 10.0 mmol) in toluene (2 ml) was added and heated to 80° C. for 17 h. The reaction mixture was poured onto a slurry of silica (20 g) in dichloromethane (20 ml) and stirred for 5 min. It was filtered and the filtrate concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 95% yield, 1.75 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH2:11](Br)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]#[N:6]
Reactant: CC(C)CBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C#N)cc1F
Temperature: 110 °C

Procedure:
A reaction mixture solution prepared by suspending 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate in 1 mL of dimethylformamide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile. (2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and 24.5 mg of imidazole to the crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspending the above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([N+:35]([O-])=O)[CH:31]=3)[N:26]([CH3:38])[C:25]2=[O:39])[CH2:20][CH2:19]1>[Fe].O>[NH2:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:38])[C:25](=[O:39])[N:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:9]3[C:8]4[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH3:4])[CH:7]=4)[N:12]=[CH:11][N:10]=3)[CH2:23][CH2:22]1)[C:33]2=[O:34]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(N)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 58.3 %

Procedure:
In a solvent mixture of 15 ml of ethanol and 5 ml of water was dissolved 500 mg (1.02 mmol) of Compound 1 obtained in Example 1, and 500 mg of iron and a catalytic amount of ferric chloride were added thereto, followed by heating under reflux for 1 hour. The reaction mixture was filtered while hot by using a filter aid, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1) and recrystallized from ether to give 275.2 mg (yield: 63%) of Compound 14 as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([S@@:4]([NH:6][C@:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:8][C:9]([O:11]C)=[O:10])=[O:5])[CH3:3].[Li+].[OH-]>CO.O.CO.O>[CH3:3][C:2]([CH3:20])([S@@:4]([NH:6][C@:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:13])[CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:1]
Reactant: COC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@](C)(CC(=O)O)c1ccccc1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of (R)-methyl 3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoate (280 mg, 0.94 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added LiOH (138 mg, 3.29 mmol). The solution was stirred for 4 h and then concentrated to give the residue. The residue was dissolved in 15% MeOH/H2O and filtered to give (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoic acid (266 mg, 100%). 1H NMR (CDCl3): 1.10 (s, 9H), 1.51 (s, 3H), 2.43-2.52 (d, 1H), 2.73-2.86 (d, 1H), 7.15-7.18 (m, 1H), 7.06-7.12 (m, 3H), 7.30-7.40 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH:9]([CH3:11])[CH2:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[F:25][C:4]1[CH:3]=[C:2]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:7]2[O:8][CH:9]([CH3:11])[CH2:10][C:6]=2[C:5]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]1=[O:24]
Reactant: CC1Cc2c(c(Br)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1Cc2c(c(C#C[Si](C)(C)C)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Yield: 33.4 %

Procedure:
3-(7-Bromo-5-fluoro-2-methyl-2,3-dihydrobenzo[b]furan-4-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (1.15 g), trimethylsilylacetylene (0.53 g), a palladium chloride-ditriphenylphosphine complex (95 mg) and copper(I) iodide (27 mg) was suspended in triethylamine (11 ml) and DMF (3 ml), and the mixture was stirred at 50° C. for 12 hours. After the reaction, triethylamine was distilled off under reduced pressure. Ethyl acetate was added thereto, and the insolubles were filtered. Then, ethyl acetate was distilled off, and the resulting residue was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v) to obtain the objective 3-{5-fluoro-2-methyl-7-[2-(trimethylsilyl)-1-ethynyl]-2,3-dihydrobenzo[b]furan-4-yl}-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.40 g).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38]1([C@H:44]([N:46]=[C:47]=[O:48])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C.C(OCC)C>[C:38]1([C@H:44]([NH:46][C:47](=[O:48])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:13](=[O:14])[C@H:12]4[CH2:15][CH2:16][CH2:17][C@H:11]4[N:10]([C:18](=[O:31])[CH2:19][N:20]4[C:21](=[O:30])[C:22]5=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]5[C:24]4=[O:25])[C:9]4[CH:32]=[CH:33][CH:34]=[CH:35][C:8]3=4)=[CH:36][CH:37]=2)[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@@H](NC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)c1ccccc1
Yield: 54 %

Procedure:
Using (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one and (R)-1-phenylethyl isocyanate, the title compound was synthesized in otherwise the same manner as Example 26. Yield 54%, m.p. 158°-163° C. (ethyl acetate-diethyl ether).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][NH:4][C:3]=1/[CH:15]=[C:16]1\[C:17](=[O:35])[NH:18][C:19]2[C:24]\1=[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=O)[CH:28]=[CH:29][CH:30]=1)[CH:22]=[CH:21][CH:20]=2.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:32](=[O:34])[CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2/[C:16](=[CH:15]/[C:3]2[NH:4][CH:5]=[C:6]([C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[O:8])[C:2]=2[CH3:1])/[C:17](=[O:35])[NH:18]3)[CH:26]=1
Reactant: CN(C)CCN
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)O)c3)c21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)NCCN(C)C)c3)c21

Procedure:
(3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-acetic acid (117.6 mg, 0.25 mmol) was coupled with N,N-dimethylethylenediamine (2 eq.), EDC (1.5 eq.) and HOBt (1 eq.) in DMF (1 mL) using the general amidation procedure to give 117.3 mg of the titled compound.
Reaction SMILES: [Cl-:1].[CH3:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH3+:9])[CH2:5][CH2:4]1>C(Cl)Cl>[Cl-:1].[CH3:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH3+:9])[CH2:5][CH2:4]1
Reactant: CC1CCC([NH3+])CC1
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H]1CC[C@H]([NH3+])CC1

Procedure:
4-methylcyclohexylammonium chloride (Example 71) was suspended in 4 ml of methylene chloride cooled. The crystal obtained was filtered out, yielding 3.2 g of trans-4-methylcyclohexylammonium chloride as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Reactant: O=C(O)c1cccnc1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)c3cccnc3)cc2n1
Yield: 14 %

Procedure:
As described for Example 48, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) was converted, using nicotinic acid instead of cyclopropanecarboxylic acid, to the title compound (19.4 mg, 14%) which was obtained as an off-white solid. MS: m/e=396.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=2)=[C:4]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:3]=1.[N:23]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]3[NH:13][N:23]=[N:14][C:9]=3[CH:8]=2)=[C:4]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2Cn2cncn2)cc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Clc1ccc(Oc2ccc3[nH]nnc3c2)c(Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
4-[4-Chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]-1,2-phenylenediamine (3.2 g) from Example 39 was dissolved with 10% H2SO4 (30 ml) under ice cooling, followed by addition of an aqueous solution (3 ml) of sodium nitrite (1.4 g), and the temperature of the resulting solution was raised up to room temperature for stirring for 2 hours. The solution was neutralized, with an aqueous sodium hydrogen carbonate, and then extracted twice with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was washed with ether, to give the title compound (3 g; 91%). The purity of the compound was 99.1% by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: Clc1ccc2c(c1)NCC2
Product: COc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Yield: 77 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 77% yield from 6-chloro-indoline and 4-chloro-6-methoxy-quinazoline. (M.P. 243° C.; LC-MS: 312 (MH+)).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9]4=[C:10]([C:17](=[O:20])[C:18](=[O:19])[N:8]24)[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O>[Cl:21][C:12]1[CH:13]=[C:14]2[C:9]3=[C:10]([C:17](=[O:20])[C:18](=[O:19])[N:8]3[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:16][CH2:15]2)[CH:11]=1
Reactant: O=C1C(=O)N2c3c(cccc31)CCC2c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1C(=O)N2c3c(cc(Cl)cc31)CCC2c1ccccc1
Temperature: 80 °C
Yield: 97 %

Procedure:
A mixture of 5,6-dihydro-4-phenyl-4H-pyrrolo[3,2,1-ij]-quinoline-1,2-dione (3.1 g) and N-chlorosuccinimide (1.89 g) in dimethylformamide (DMF; 50 ml) was stirred at 80 ° C. for an hour. After cooling, the mixture was concentrated under reduced pressure and to the resulting residue was added chloroform (500 ml). The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.4 g, 96.8%). This crystals was recrystallized from acetonitrile to give dark reddish crystals, mp 173°-174 ° C.