Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[N+]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)([O-])=O.O.C(OCC)(=O)C.[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1>>[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([O:40][CH2:13][C:12]1[CH:15]=[CH:16][CH:9]=[CH:10][CH:11]=1)=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 47.7 %

Procedure:
In 5 mg of DMP was dissolved 0.33 g of t-Boc-Trp(CHO)-OH, 0.17 g of sodium hydrogen carbonate was added. The solution was then stirred. To the mixture was added 1.08 g (5 mmol) of p-nitrobenzyl bromide, and stirring was effected at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution. The mixture was shaken, and the organic layer was recovered and the solvent was evaporated. The residue was purified with a silica gel column (manufactured by Merck Co., Kieselgel 60, 50 g, elution with hexane:ethyl acetate=6:4), to obtain 0.2 g of t-Boc-Trp(CHO)-OBzl (NO2). The peptide was dissolved in 5 ml of DMF, 0.5 ml of piperidine was added thereto, and the mixture was stirred at 0° C. for 1.5 hours. The solvent was evaporated under reduced pressure, 0.5 ml of 98% formic acid was added thereto, and the mixture was stirred at room temperature for 4 hours. About 30 ml of ether was added to obtain a precipitate. The precipitate was filtered and dried to obtain 0.16 g of H-Trp-OBzl (NO2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:17]([CH3:33])=[C:18]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:12][N+:13]([O-])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O1CCCC1.C(OCC)(=O)C.[Zn]>[NH2:13][CH2:12][CH:11]([C:16]1[C:17]([CH3:33])=[C:18]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=[CH:20][CH:21]=1)[C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(Br)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.8 %

Procedure:
To a mixture of benzyl 3-(1-(6-bromo-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate (3.00 g, 5.90 mmol) and ammonium chloride (4.42 g, 83 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) at 0° C. was added zinc dust (5.40 g, 83 mmol) in one portion. The mixture was stirred at room temperature for 7 hr, then diluted with ethyl acetate (100 mL) and filtered through CELITE®. The filtrate was concentrated under vacuum. To the residue was added water (60 mL), and the mixture was extracted with ethyl acetate (4×80 mL). The combined extract was washed with brine (60 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (2.82 g, 5.89 mmol, 100% yield) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)OC1>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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1ccc(I)c(Br)c1
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
Solvent: O
Product: COC(=O)c1ccc(-c2ccnn2C)c(Br)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 3-bromo-4-iodobenzoate (409 mg, 1.2 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (497 mg, 3.6 mmol), tetrakistriphenylphosphine Pd(0) (69 mg, 0.06 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (349 mg, 3.6 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (307 mg, 87%): LC-MS (ES) m/z=296 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[CH2:31]([OH:33])[CH3:32].C(OCC)(=[O:36])C>[Pd].O>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:9]3[C:10](=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[NH:16][C:31](=[O:33])[C:32]2=[O:36])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCO
Reactant: CCOC(C)=O
Reactant: Nc1cc(F)ccc1NC(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(F)ccc2n(C(c2ccccc2)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of 1.6 g (5.0 mmol) N-diphenylmethyl-2-amino-4-fluoroaniline in 100 ml ethyl acetate was hydrogenated at atm. pressure by using 5% Pd/C (100 mg) as a catalyst. The reaction mixture was filtered and 4.2 ml (30 mmol) dry triethylamine was added 3.4 ml (30 mmol) ethyl oxalylchloride was added dropwise, and the reaction mixture was stirred for 1 h. The reaction mixture was filtered and evaporated in vacuo to give an oil. A mixture of the oil, 40 ml 1N hydrochloric acid and 60 ml ethanol was stirred at 80° C. for 4 h. After cooling to 25° C. 50 ml H2O was added, and the precipitate was filtered off. The crude product was dissolved in 20 ml ethanol, filtered and evaporated in vacuo to give an oil. The oil was stirred with 30 ml water for 1 h. The product was filtered off and dried to give 0.4 g (23%) 1-diphenylmethyl-6-fluoroquinoxaline-2,3(1H,4H)-dione. M.p. 143.8° C., 1H-NMR (CDCl3): 8.5-6.5 (3H, m), 7.2 (10H, s) 3.8 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2OC(C#N)[CH2:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[OH2:15].[C:16]([O:19]CC)(=[O:18])[CH3:17]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH:17]([C:16]([OH:19])=[O:18])[CH2:8][C:7](=[O:13])[C:6]=2[CH:14]=1
Reactant: N#CC1CC(=O)c2cc(F)ccc2O1
Reactant: CCOC(C)=O
Reactant: O
Agent: Cl
Product: O=C1CC(C(=O)O)Oc2ccc(F)cc21
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of 6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carbonitrile (78.3 g, 0.41 mol)(obtained through the process as described in said Item (c) in 760 ml of concentrated hydrochloric acid was heated at reflux temperature for 50 minutes. After cooling the reaction solution, 700 ml of water and 1 liter of ethyl acetate were added to carry out an extraction. Resulting organic layer was evaporated in vacuo to dryness. To the residue, 700 ml of saturated sodium biscarbonate was added and stirred for 30 minutes. The aqueous basic solution was washed with 500 ml of ethyl acetate, acidified with 6N-hydrochloric acid and extracted with 1 liter of ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 76.9 g (89.3%) of the desired compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]1[C:24]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:33])[N:22]=[C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:20]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:19]1[C:24]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:33])[N:22]=[C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:20]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCc2ccccc2C1
Temperature: 100 °C
Yield: 93.4 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (0.190 mL, 1.5 mmol) and triethylamine (0.277 mL; 2 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL) and heated in a sealed tube to 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.194 g (93%) of the title compound.
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH2:19][C@H:18]([NH3+:22])[C@H:17]1[NH3+:23].C(N(CC)CC)C.[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O>ClCCl>[C:36]([O:35][C:33](=[O:32])[NH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C:16]([F:24])([F:15])[C@@H:17]1[NH2:23])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: [NH3+][C@@H]1[C@@H]([NH3+])CCCC1(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC(F)(F)[C@@H]1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of (1S,2R)-3,3-difluorocyclohexane-1,2-diaminium bis(trifluoroacetate) (7.5 g, 19.8 mmol) in dichloromethane (100 mL) was added triethylamine (11.1 mL, 79.0 mmol) followed by BOC2O (5.52 mL, 23.8 mmol). The reaction was stirred for 10 hr at ambient temperature. Concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (CDCl3, 500 MHz) 4.76 (br s, 1H); 3.39 (m, 1H); 2.71-2.64 (m, 1H); 2.2-2.1 (m, 2H); 1.7-1.59 (m, 2H); 1.56-1.51 (m, 2H); 1.45 (s, 9H); 1.29-1.21 (m, 2H). 19F NMR (CDCl3, 564 MHz) −100.4-−100.9 (d, 1F); −114.35-−114.87 (d, 1F).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[OH:13][CH2:14][C:15]([CH3:19])([CH2:17]O)[CH3:16].C(OCC)(OCC)OCC>CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:7]([CH:8]2[O:13][CH2:14][C:15]([CH3:19])([CH3:17])[CH2:16][O:9]2)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(C=O)c1O
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Br)c(C2OCC(C)(C)CO2)c1O
Temperature: 110 °C
Yield: 99.9 %

Procedure:
A mixture of 6-bromo-2-hydroxy-3-methoxy-benzaldehyde (2.31 g, 10.0 mmol), neopentyl glycol (1.14 g, 11.0 mmol), TsOH (9.5 mg) and triethyl orthoformate (1.93 g, 13.0 mmol) were heated at 110° C. for 30 min and then partitioned between NaHCO3 (300 mL) solution and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3×30 mL) and the combined extracts were washed with brine and dried through Na2SO4. Evaporation of solvent afforded the title compound (3.17 g, 100%). 1H NMR (CDCl3) δ 0.85 (s, 3H), 1.27 (s, 3H), 3.70 (s, 2H), 3.82 (s, 2H), 3.85 (s, 3H), 5.90 (s, 1H), 6.72 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.C(C1C=CC(C2N=CC(C(Cl)=O)=C[N:35]=2)=CC=1)CCC.N>O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([NH2:35])=[O:19])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1
Reactant: CCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1

Procedure:
8.3 G. of 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid are reacted with 50 ml. of thionyl chloride with the exclusion of moisture and worked up on a manner analogous to that given in Example 7. The remaining 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid chloride is dissolved in 100 ml. of absolute dioxane and added to a solution of 200 ml. of absolute dioxane saturated with ammonia at room temperature with stirring and further treated in a manner analogous to that described in Example 7. The obtained crude 2-(p-n-butylphenyl)-5-pyrimidinecarboxamide can be sublimed in a high vacuum at 185° C. for purification; melting point 264.0°-266.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].[C:28](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
DMF (5 drops) was added to a suspension of 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (42.6 g, 97 mmol) in dichloromethane (500 mL) at 0° C. Oxalyl chloride (12.71 mL, 145 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h. MeOH (30 mL) was added, and the resulting mixture was stirred at 0° C. for 2 h and allowed to warm to room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted with water, treated with saturated aqueous NaHCO3, and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified via column chromatography (ISCO, 330 g silica, 40-100% methylene chloride/hexanes) to afford methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (29.8 g, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.96-8.01 (m, 2H), 7.89 (d, J=7.78 Hz, 1H), 7.77 (t, J=7.65 Hz, 1H), 7.65 (s, 1H), 4.08 (s, 3H), 4.03 (s, 3H), 2.34 (s, 3H); MS (m/z) 455.0 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]([N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)([CH3:7])[C:4]([OH:6])=O.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:4](=[O:6])[C:3]([CH3:2])([N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH3:7])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C(=O)O)n1cncn1
Agent: Cl
Product: CC(C)(C(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)n1cncn1
Yield: 36 %

Procedure:
Proceeding as in Example 1, but substituting 2-methyl-2-(1H-1,2,4-triazol-1-yl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 255, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-methyl-2-(1H-1,2,4-triazol-1-yl)propanamido)propanamide (93.3 mg, 36%). 1H-NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.42 (d, 2H), 7.39-7.24 (m, 7H), 7.11 (d, 1H), 7.05-6.91 (m, 5H), 4.65-4.59 (m, 2H), 4.50 (d, 1H), 4.00 (dd, 1H), 3.58-3.52 (m, 1H), 1.92 (s, 3H), 1.90 (s, 3H). MS (EI) for C28H28FN5O4 found 518 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([NH:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9](=[S:10])[N:14]([CH2:12][CH3:13])[C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])[CH:7]=1
Reactant: CCNc1c(C)nn(C)c1C
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: CCN(C(=S)Nc1cc(Cl)ccc1C)c1c(C)nn(C)c1C
Yield: 34.1 %

Procedure:
Prepared using Method A from 9.33 g (51 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4-ethylamino-1,3,5-trimethylpyrazole (7.2 g, 47 mmol) of step B to give 5.4 g of title compound as a white solid (70% yield, m.p. 144-145° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:25])[S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[Cl:48]CCCl>>[ClH:48].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:29])[C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:25])[S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1
Reactant: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Reactant: ClCCCl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1C
Product: Cl
Temperature: 17.5 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Stir (S)-6-fluoro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (5.00 g, 13.4 mmol) under nitrogen to dissolve in 1,2-dichloroethane (DCE, 55 mL). Cool to 15-20° C. and add formaldehyde (37% wt. in water, 1.03 g solution, 0.38 g, 12.7 mmol) in one portion. Add sodium triacetoxyborohydride (3.41 g, 16.1 mmol) in portions over 5-10 minutes, keeping the pot temperature below 20° C. Stir at 15-20° C. for 15 minutes, and then allow warming to ambient temperature. Stir for 2 hours, and then add aqueous saturated sodium bicarbonate (50 mL). Stir for 15 minutes, and then separate layers. Extract the product with methylene chloride. Extract the combined organic layers with brine, dry over magnesium sulfate, and then concentrate under reduced pressure to a residue. Add methylene chloride to the residue and concentrate under reduced pressure to give 4.94 g (100%) of the free base of the title compound. 1H NMR (400 MHz, DMSO-d6) 87.78 (bs, 1H), 6.79 (m, 1H), 6.68 (m, 1H), 6.53 (m, 1H), 6.34 (s, 1H), 3.74 (m, 2H), 3.36 (m, 3H), 3.22 (s, 3H), 2.95 (m, 1H), 2.77 (m, 1H), 2.69 (m, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 2.17 (bs, 1H), 1.84 (m, 1H), 1.52 (m, 1H). HRMS (ES) exact mass M+H calcd for C20H25FN4OS 389.1811; found 389.1802.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.51 mmol) in DCM (12 mL) was added TFA (8 mL) and the reaction mixture stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, the residue triturated in diethyl ether to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt as a grey solid (1.34 g, 100%). LCMS: RT=2.88 min, M+H+ =379
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4](=[O:6])[CH3:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1.O>C(Cl)Cl>[C:15]([O:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4](=[O:6])[CH3:5])(=[O:17])[CH3:16]
Reactant: CC(=O)CC(O)CCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(CCc1ccccc1)OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 850 mg of 4-hydroxy-6-phenylhexan-2-one (T. Mukaiyama et al., Chemistry Letters, 1976, 95) in 10 ml of methylene chloride were added 1 ml of acetic anhydride and 0.8 ml of pyridine under ice-cooling at 0° C, and then stirring was continued for further 1 hr at room temperature. The reaction mixture was poured into water, the methylene chloride layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to afford 1.10 g of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14].CN(C)CCN(C)C.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([F:46])([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CCC(F)(C(=O)OC)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl 2-(1,3-dioxoisoindolin-2-yl)-pentane-1,5-dioate (1.0 g, 3.3 mmol) and tetramethylethylene diamine (0.5 g, 4.3 mmol) in tetrahydrofuran (10 mL) is added 2.5M n-butyl lithium (1.6 mL, 4 mmol,) at -79° C. After 30 minutes, N-fluorobenzenesulfonimide (1 g, 3.2 mmol) is added to the mixture which then is allowed to reach room temperature. The solvent is removed in vacuo and the residue is stirred with methylene chloride (100 mL) for 10 minutes. The organic layer is washed with water and brine (30 mL each), and dried over sodium sulfate. The solvent is removed in vacuo to yield dimethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,5-dioate which is further purified by chromatography and converted to 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline as described above in Part D of Example 9.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:14]C1C=C(C(CC=O)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.[Cl:37][C:38]1[CH:39]=[C:40]([C@H:45]([CH2:57][CH:58]=O)[CH2:46][N:47]([CH3:56])[C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:41]=[CH:42][C:43]=1[Cl:44]>>[ClH:14].[Cl:37][C:38]1[CH:39]=[C:40]([C@H:45]([CH2:57][CH2:58][N:11]2[CH2:12][CH2:13][CH:8]([N:3]3[CH2:4][CH2:5][CH:6]=[CH:7][C:2]3=[O:1])[CH2:9][CH2:10]2)[CH2:46][N:47]([CH3:56])[C:48](=[O:55])[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: O=C1C=CCCN1C1CCNCC1
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: CN(C[C@@H](CCN1CCC(N2CCC=CC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 7, except replacing 4-(2-oxopyrrolidin-1-yl)piperidine with 4-(2-oxo-1,2,5,6-tetrahydropyrid-1-yl)piperidine and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was obtained as a white solid; MS: m/z=514(M+1). Analysis for C28H33Cl2N3O2 ·2.50 HCl·0.30 Et2O: Calculated: C, 55.86; H, 6.18; N, 6.69; Found: C, 55.83; H, 6.43; N, 6.66.