Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[O:6][N:5]=1)([CH3:3])[CH3:2].O.NN>C(O)C>[CH:1]([C:4]1[N:8]=[C:7]([CH2:9][NH2:10])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)c1noc(CN)n1

Procedure:
To a vigorously stirred suspension of compound 2-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]-1H-isoindole-1,3(2H)-dione (79 g, 0.29 mol) in ethanol (500 mL), hydrazine hydrate (16 g, 0.32 mol) was added. After the precipitate was completely dissolved, the reaction mixture was heated to reflux for 4 h. The precipitate was removed by filtration. The mother liquor was evaporated. The residue was dissolved in ether (200 mL). The precipitate was removed by filtration. The filtrate was evaporated. The residue was redistilled under high vacuum collecting the fraction boiling at 62-65° C./0.02 mmHg to yield the title compound.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1CC[CH2:49][CH2:48][CH2:47]1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:39][CH2:49][CH2:48][CH2:47][CH2:6]3)=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: C1CCNCC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (137 mg) described in Example 769 and piperidine (26 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (54 mg) was obtained.
Reaction SMILES: OS(O)(=O)=O.N[C:7]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:8]=1[C:9]#[N:10].CC(O)C.N([O-])=O.[Na+]>O>[Cl:15][C:14]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: N#Cc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Concentrated H2SO4 (440 mL) was added slowly to crushed ice (1200 g) and 2-amino-3-chloro-5-nitrobenzonitrile (43.8 g) was suspended in the resulting H2SO4 solution. After addition of 2-propanol (1600 mL), the mixture was heated to 40° C. internal temperature with vigorous stirring. A solution of NaNO2 (66.0 g) in water (100 mL) was added dropwise. After completion of addition, the mixture was kept at 40° C. for an additional 3 h, then cooled to ambient temperature and extracted with CH2Cl2. The organic extract was washed sequentially with water, 0.1 N NaOH, water, and brine, and then dried over MgSO4, filtered through a pad of silica gel, and evaporated to yield the crude product as a yellow solid. Chromatography on silica gel (20% EtOAc/hexanes) followed by crystallization from 2-propanol yielded the product as yellow crystals. 1H-NMR (CDCl3): δ 8.47 (1H, t, J=2.0 Hz), 8.43 (1H, dd, J=1.4, 2.0 Hz), 7.98 (1H, dd, J=1.4, 2.0 Hz). 13C-NMR (CDCl3): δ 148.8, 137.4, 137.0, 128.1, 125.3, 115.4, 115.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: Nc1cccc(-c2ccccn2)c1
Product: O=[N+]([O-])c1cc(I)ccc1Nc1cccc(-c2ccccn2)c1
Yield: 40 %

Procedure:
N-(3-(2-Pyridyl)phenyl)-4-iodo-2-nitroaniline (6f) was prepared analogously from 1c (Example 1) and 2f (Example 4). Yield: 40%. Mp 195-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[N:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11](C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O.[C:54]([OH:63])(=[O:62])[C@@H:55]([C@H:57]([C:59]([OH:61])=[O:60])[OH:58])[OH:56]>ClCCCl.C(Cl)Cl.C(#N)C.O>[C:59]([C@@H:57]([C@H:55]([C:54]([OH:63])=[O:62])[OH:56])[OH:58])([OH:61])=[O:60].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[N:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(-c3ccc(C(F)(F)F)nn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC#N
Solvent: O
Solvent: ClCCCl
Product: Fc1cc2c(cc1-c1ccc(C(F)(F)F)nn1)CNCC2c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.2 %

Procedure:
To (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (320 mg, 0.70 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (299 mg, 0.70 mmol) in 1,2-dichloroethane (5 mL) was added 1-chlorethyl chloroformate (0.15 mL, 1.4 mmol) drop wise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with methylene chloride (30 mL) and washed with 1N HCl (10 mL), water (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue was added methanol (15 mL) and the mixture was heated to reflux. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material in acetonitrile (1.5 mL) was added L-tartaric acid (9.2 mg, 0.06 mmol) in water (5 mL). The resultant solution was lyophilized to give (+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline, L-tartrate salt (47 mg, 11%) as a white powder: 1H NMR (CD3OD, 500 MHz) δ 8.32 (d, J=8.5 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.24 (dd, J=8.5, 2.0 Hz, 1H), 6.85 (d, J=11.5 Hz, 1H), 4.59-4.48 (m, 3H), 4.41 (s, 1.8H), 3.77-3.71 (m, 1H), 3.40-3.38 (m, 1H); ESI MS m/z 442 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)c1cn(-c2ccc(OC)cc2)nc1C
Yield: 64.9 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (5.7 g) synthesized in Example 1(3) and 4-methoxyphenylboronic acid (12.4 g) and in the same manner as in Example 17(1), the title object compound (6.5 g, 65%) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:36][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:27]=[CH:26][C:25]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CN5CCOCC5)cc34)cc2C)cn1
Yield: 81 %

Procedure:
The procedure of Example 62 was repeated except for using 0.09 g of the compound obtained in Example 67 and 0.05 ml of morpholine instead of the compound obtained in Example 61 to obtain the title compound (0.08 g, 81%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>C(#N)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCC2CCNCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
N-Cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.172 g), potassium carbonate (0.114 g) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.114 g) were stirred together in acetonitrile (10 mL) at reflux overnight. The cooled reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate (20 mL) and water (20 mL). The separated aqueous layer was further extracted into ethyl acetate (2×20 mL), the combined organics were dried (MgSO4) and evaporated. The residue was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (1 ml), after stirring at room temperature for 1 h, the solvent was evaporated to leave the crude product. Purification by preparative HPLC (Gemini column—acetonitrile/0.2% ammonia mobile phase) afforded the title compound as a solid (50 mg).
Reaction SMILES: [CH:1]1([C:7]2[N:16]=[C:15](O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[CH:1]1([C:7]2[N:16]=[C:15]([Cl:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C2CCCCC2)nc2ccccc12
Solvent: CN(C)c1ccccc1
Product: Clc1nc(C2CCCCC2)nc2ccccc12

Procedure:
2-Cyclohexyl-4-hydroxyquinazoline was treated with phosphorus oxychloride and N,N-dimethylaniline according to the procedure described in S. Lee et al., J. Med. Chem. 1995, 38(18), 3457, to give a nearly quantitative yield of 2-cyclohexyl-4-chloroquinazoline as a yellow solid, which was used immediately in the next step.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14]C(C)C)=[O:13])#[N:10].N1CCCCC1>C(O)(=O)C>[C:9]([C:11](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: O=Cc1ccccc1
Reactant: CC(C)OC(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccccc1)C(=O)O

Procedure:
A mixture of 95 g of benzaldehyde, 114.3 g of 7A, 1 g of piperidine and 200 ml of acetic acid was heated on a steam bath for 1 hour. The acetic acid and unreacted benzaldehyde were distilled off, to 100° C./0.2 Torr. The residue was extracted with hot hexane; no residue was left. The solution was chilled, and the solid that formed was recrystallized from methanol to give the 1-methylethyl ester of 2-cyano-3-phenyl-2-propenoic acid (7B), mp: 72°-73° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[C:22](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:20](Br)[C:15]2=[N:14]1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[C:22](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:15]2=[N:14]1
Reactant: O=c1n(CCc2ccc3ncccc3n2)nc2c(Br)cccn12
Reactant: OB(O)c1ccncc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1n(CCc2ccc3ncccc3n2)nc2c(-c3ccncc3)cccn12
Temperature: 100 °C
Yield: 23 %

Procedure:
Triazolopyridinone 10-3 (22 mg, 0.059 mmol) and pyridin-4-ylboronic acid (11 mg, 0.089 mmol) were placed in a microwave vial and dissolved in dioxane (1 mL). To the mixture was added 1 M aq. Cs2CO3 solution (0.12 mL, 0.12 mmol). The mixture was then sparged with N2 gas for 3 min, and bis(tri-tert-butylphosphine)palladium (3.0 mg, 0.006 mmol) was added. The vial was capped and heated at 100° C. under microwave irradiation for 20 min. After cooling, the reaction mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (12 g cartridge), eluting with 0-15% MeOH/CH2Cl2. The fractions containing the desired product (10-4) were pooled, and after solvent removal in vacuo, 5.0 mg (23%) of a semisolid were obtained. 1H NMR (300 MHz, CHCl3-d): δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 2H), 8.37-8.31 (m, 2H), 7.84 (dd, J=6.9, 1.2 Hz, 1H), 7.71 (dd, J=4.8, 1.8 Hz, 2H), 7.63 (dd, J=8.7, 4.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.39 (dd, J=6.9, 1.2 Hz, 1H), 6.64 (t, J=6.9 Hz, 1H), 4.65 (t, J=6.9 Hz, 2H), 3.60 (t, J=6.9 Hz, 2H). HRMS (ES) 369.1443 found (M+H), 369.1461 required.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[O:24][C:25]([CH3:30])=[C:26]([CH2:28]Cl)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:24][C:25]=2[CH3:30])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1C)OCC
Yield: 63 %

Procedure:
A mixture of [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (50 mg, 0.2 mmol), 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (41 mg, 0.22 mmol, example 1, step b]), cesium carbonate (71 mg, 0.22 mmol) and a trace of potassium iodide were suspended in acetone (5 ml). The suspension was heated under reflux for 14 h, the solvent evaporated under reduced pressure and the residue dissolved in 2 N HCl/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 50 mg (0.12 mmol, 63%) of the title compound as colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH2:21]1[C:31]2=[C:32]3[C:27](=[CH:28][CH:29]=[CH:30]2)[CH2:26][CH2:25][C:24](=O)[N:23]3[CH2:22]1.B(F)(F)F.CCOCC.N1CCCC1>CCCCCC.O1CCCC1>[CH2:21]1[C:31]2=[C:32]3[C:27](=[CH:28][CH:29]=[CH:30]2)[CH2:26][CH2:25]/[C:24](=[CH:14]\[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[N:23]3[CH2:22]1
Reactant: O=C1CCc2cccc3c2N1CC3
Reactant: CC(=O)OC(C)(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)/C=C1\CCc2cccc3c2N1CC3
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
25 ml of a 1.6M solution of n-butyllithium in n-hexane were added to a solution of 4.04 g of diisopropylamine in 20 ml of tetrahydrofuran at 0° C. under nitrogen. After 10 minutes, the stirred solution was cooled to -78° C. and a solution of 9.28 g of t-butyl acetate in 20 ml of tetrahydrofuran was added. After 10 minutes, 3.46 g of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one in 20 ml of tetrahydrofuran was added followed by 8 ml of boron trifluoride diethyl etherate. The mixture was stirred at -78° C. and then 20 ml of pyrrolidine were added. The mixture was partitioned between ethyl acetate and water and the organic extracts were washed with water and sodium chloride solution, dried and evaporated. The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:3). There were obtained 4.1 g of t-butyl (E)-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ylidene)acetate of melting point 105°-107° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:8]([NH2:10])=[O:9].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:13]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[O:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Yield: 91.3 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzamide (1 g), iron powder (1 g), and ammonium chloride (0.1 g) in ethanol (20 ml) and water (10 ml) was refluxed with stirring for an hour. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to give pale yellow crystals of 4-amino-3-(2,4-difluorophenoxy)benzamide (0.82 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]([NH2:27])[CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH:25]([NH:27][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:26])[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1
Reactant: COc1cc(OC)cc(C(C)N)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2C(=O)C(F)(F)F)c1
Yield: 33.7 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.0 g, 4.8 mmol), 1-(3,5-dimethoxyphenyl)ethanamine (0.95 g, 5.2 mmol) and N,N-diisopropylethylamine (1.2 g, 9.6 mmol) were stirred at 60° C. in dry acetonitrile (50 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (600 mg, 34% yield). 1H NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 7.79 (t, 1H), 6.44 (s, 2H), 6.35 (m, 2H), 6.23 (d, 1H), 4.48 (m, 1H), 3.77 (s, 6H), 1.61 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1
Reactant: Nc1nc(Br)cs1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(Br)cs1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 4-bromothiazol-2-amine (0.500 g, 2.81 mmol), acetic anhydride (0.43 mL, 4.50 mmol) and acetic acid (5 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford N-(4-bromothiazol-2-yl)acetamide (0.300 g, 49%) as a white solid. MS (ESI, pos. ion) m/z 221, 223 [M+H]+.
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.[CH3:11][C:12](O)([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]=[CH2:14].[CH2:27]=[C:28]1[O:32]C(=O)[CH2:29]1>>[CH3:11][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:13][CH2:14][CH2:27][C:28](=[O:32])[CH3:29]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)C
Reactant: C=C1CC(=O)O1
Solvent: c1ccc2c(c1)CCCC2
Product: CC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Yield: 84.7 %

Procedure:
The procedure was the same as in Example 2 except that the diluent solvent was 10 g of tetraline and the starting reactants were 226 g (1.0 mole) of 3,7,11-trimethyl-1-dodecen-3-ol and 101 g (1.2 moles) of diketene. 6,10,14-Trimethyl-5-pentadecen-2-one with the boiling point of 123° to 125°C/1 mmHg and the refractive index of 1.4560 at 20°C was obtained in an amount of 212 g corresponding to 84.7% yield based on 3,7,11-trimethyl-1-dodecen-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=S)[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1.[NH3:42]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=[NH:42])[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1
Reactant: N
Reactant: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(NC(=N)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
As illustrated in the scheme above, to a solution of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[4-(4-morpholinyl)-1-naphthalenyl]-thiourea (EXAMPLE 11) (0.029 g, 0.05 mmol) and silver triflate (0.038 g, 0.15 mmol) in dichloromethane (2 ml) was added a solution of ammonia (0.25 ml, 2M in methanol). The reaction mixture was stirred at room temperature for 3 h, diluted with dichloromethane (10 ml) and washed with brine (2×5 ml). The organic layer was dried with MgSO4 filtered, concentrated in vacuo. The residue was triturated with ether to give the title compound (0.008 g, 28%) as a pale yellow solid. 1H-NMR (CDCl3): δ 8.22 (d, J=9.2 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.75 (br.s, 1H), 7.50-7.41 (m, 7H), 7.31 (d, J=8.8 Hz, 1H), 7.04 (m, 2H), 5.8 (br.s, 1H), 3.96 (t, J=9.2 Hz, 4H) 3.51 (s, 3H) and 3.05 (br.s, 4H).). (ESI) (M+H)+=587.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2C(=O)C(F)(F)F>C[O-].[Na+].CO>[Cl:1][C:2]1[C:10]([S:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)(=[O:12])=[O:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: CC1(N2CCN(S(=O)(=O)c3ccc4c(c3Cl)CCN4C(=O)C(F)(F)F)CC2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(N2CCN(S(=O)(=O)c3ccc4c(c3Cl)CCN4)CC2)CC1
Temperature: 60 °C

Procedure:
1-(4-chloro-5-(4-(1-methylcyclopropyl)piperazin-1-ylsulfonyl)indolin-1-yl)-2,2,2-trifluoroethanone was dissolved in 1 N sodium methoxide solution in methanol. The mixture was heated to 60° C. The reaction mixture was then concentrated in vacuo and the solid residue was purified by chromatography to give the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.32-0.33 (m, 2 H) 0.49 (br s, 2 H) 1.02 (s, 3 H) 2.67 (br s, 4 H) 3.09 (t, J=8.73 Hz, 2 H) 3.14 (br s, 4 H) 3.71 (t, J=8.71 Hz, 2 H) 6.38 (d, J=8.40 Hz, 1 H) 7.63 (d, J=8.35 Hz, 1 H).