Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.S(=O)(O)[O-].[Na+].[C-:14]#[N:15].[K+]>O>[CH:1]1([CH:7]([OH:8])[C:14]#[N:15])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=CC1CC=CCC1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CC(O)C1CC=CCC1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
3-Cyclohexene-1-carbaldehyde (11.7 ml. 0.1 mole) and sodium bisulfite (15.5 g., 0.15 mole) were combined with 150 ml. of H2O and heated at 50°-60° C. for 2 hours. The mixture was cooled to 5° C. and added dropwise over 10 minutes to a cold solution of KCN (19.5 g., 0.3 mole) in 50 ml. H2O. The mixture was warmed to 20° C., KCN (6.5 g., 0.1 mole) added as a solid, stirred for 10 minutes, and product extracted into 100 ml. ethyl acetate. The ethyl acetate extract was washed with brine and evaporated to yield title product as an oil, 8.5 g., Rf (5:1 hexane:ethyl acetate/5% CH3CO2H) 0.5.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Sn]([N:31]=[N+:32]=[N-:33])(C)C>C1(C)C(C)=CC=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[NH:33][N:32]=[N:31][N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(C#N)ccc32)n1)c1ccccc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4nnn[nH]4)ccc32)n1)c1ccccc1
Yield: 26.6 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-cyanobenzimidazol-1-yl ]pyrimidine (20 mg) and trimethylstannylazide (18 mg) were heated (110° C.) in xylene for 15 hours. Upon cooling, the solution was evaporated to dryness and the residue was purified with preparatory thin-layer chromatography (SiO2, 5% MeOH/1% triethylamine in CH2Cl2) to yield 6 mg of the title compound Mass spectrum (ESI) 384.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].CC1(C)[O:19][C:18](=O)[CH:17]=[C:16]([CH3:21])[O:15]1>CCOC(C)=O>[O:15]=[C:16]([CH3:21])[CH2:17][C:18]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)=[O:19]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NCc1cccc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
3-(Trifluoromethyl)benzylamine (2.0 ml, 13.95 mmol) was mixed with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.0 ml, 15.12 mmol), The mixture was stirred at 150° C. for 2 hours followed by 60 hours at 50° C. The reaction was cooled, diluted with EtOAc (50 ml), washed with 1M HCl (40 ml), NaHCO3 (2*40 ml, sat aq), dried over MgSO4 and evaporated. The crude product was purified by precipitation from toluene/pet.ether to give 2.57 g (71%) of 3-oxo-N-(3-(trifluoromethyl)benzyl)butanamide as pale solids.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=O)[NH:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:14]I.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH3:14])[C:16](=[O:19])[N:10]([CH3:9])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: CI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)n(C)c(=O)n2C
Yield: 82 %

Procedure:
5-Acetyl-1H-benzo[d]imidazol-2(3H)-one (1 g, 5.67 mmol), methyl iodide (3.22 g, 22.71 mmol), and cesium carbonate (4.62 g, 14.19 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 5-acetyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (0.95 g, 82%). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, 1H), 7.61 (s, 1H), 7.00 (d, 1H), 3.50 (s, 6H), 2.62 (s, 3H); MS (ESI) m/z: Calculated for C11H12N2O2: 204.1. found: 205.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].O>C(Cl)Cl>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)ccc1=O
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2ccc(=O)n(C)c2)c1
Temperature: 30 °C
Reaction time: 12 h
Yield: 26.4 %

Procedure:
To a solution of 5-[5-amino-2-(2,4-difluorophenoxyl)phenyl]-1-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtSO2Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30° C. for 12 h. Water (4 mL) was added and the mixture was extracted with DCM (4 mL×3). The organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (10 mg, 26%) as light yellow gum. 1H NMR (CDCl3, 400 MHz) δ7.68-7.66 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.13-7.10 (m, 1H), 7.09 (s, 1H), 7.00-6.92 (m, 2H), 6.84-6.86 (m, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.14 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)+ 421.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=C[C:9]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1.FC1C=CC(C(=O)C(=[O:45])C2C=CC(F)=CC=2)=CC=1.CCOC(CC(CC(OCC)=O)=O)=O.[OH-].[Na+]>CO>[C:26]([C:9]1[C:11](=[O:45])[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: CCOC(=O)CC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1=C(c2ccc(F)cc2)C(c2ccc(F)cc2)=C(C(=O)OCC)C1=O
Reaction time: 8 h
Yield: 81 %

Procedure:
Diethyl 2,3-di(4-fluorophenyl)-1,4-benzenedicarboxylate In a 500 mL round bottom flask was loaded difluorobenzil (12.3 g, 50.0 mmol), diethyl acetonedicarboxylate (12.1 g, 60.0 mmol) and methanol (100 mL) with stirring. This was cooled in an ice/water bath and methanolic NaOH (2 g in 50 mL of methanol) added to the mixture. This was stirred overnight. The resultant yellow precipitate was filtered and washed with methanol (2×20 mL) and air-dried. The yellow precipitate was then added to acetic anhydride (300 mL). The mixture was cooled in an ice/water bath and then sulfuric acid was added dropwise until an orange solution resulted. Several more drops of sulfuric was then added and the solution stirred for 30 min. The excess acetic anhydride was destroyed by addition of water. Excess water (1 L) was added to precipitate out the orange product. The orange precipitate was filtered and washed repeatedly water and air-dried to give 2,5-dicarboethoxy-3,4-di-(4-fluorophenyl)-cyclopentadienone (16.7 g, 81% yield). In a 100 mL round-bottom flask was loaded 2,5-dicarboethoxy-3,4-di-(4-fluorophenyl)-cyclopentadienone (2.6 g, 6.3 mmol), norbornadiene (2.9 g, 31.5 mmol) and toluene (45 mL) with stirring. The mixture was refluxed for 5 hour and then the solvent was removed. Methanol was then added to precipitate out the white product. The white precipitate was filtered and washed with methanol (2×5 mL) and air-dried (1.22 g, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][S:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:41][CH:40]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CSc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (112 mg, 0.3 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (45.5 mg, 0.45 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-methylsulfanyl-benzene (59.4 mg, 0.36 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide as a white solid (Yield 0.13 g, 80%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:9](=[O:11])[C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Cc1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)C#Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 14.61 g (0.10 mole) phenylpropiolic acid, 14.28 g (0.12 mole) thionyl chloride and 50 mL benzene was stirred and heated between 60°-70° C. for 3 hrs. The reaction was allowed to cool to room temperature and solvent was evaporated. The reaction vessel was charged with 50 mL of fresh benzene and the mixture cooled in an ice bath. Added next, dropwise in 50 mL benzene, was 21.43 g (0.20 mole) of 4-toluidine. After addition was complete, the ice bath was removed and the mixture stirred at room temperature for one hour. The mixture was poured into 200 mL cold water and the layers were separated. The aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were then washed sequentially with 100 mL portions of 5% aqueous hydrochloric acid, water, 5% aqueous sodium carbonate and water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was recrystallized twice from ethanol/water to provide 11.58 g (49.20 mmol, 49%) N-(4-methylphenyl) phenylpropiolamide as a white powder, mp=139°-141°. NMR (CDCl3 /TMS): 2.35 (S, 3H), 7.1-7.6 (m, 10H). IR (Nujol):2214, 1636. High resolution mass spectrum: Calculated; 236. 107539. Measured; 236. 107101. Anal. calcd. for C16H13NO: C 81.70, H 5.53, N 5.96; Found C 3581.55, H 5.40, N 6.05.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])=[C:35]=O.[F:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:52][C:51]=1[CH3:62]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:59]1[CH2:58][CH2:57][N:56]([C:53]3[CH:54]=[CH:55][C:50]([F:49])=[C:51]([CH3:62])[CH:52]=3)[CH2:61][CH2:60]1)[N:34]([C:37]1[C:38]([O:47][CH3:48])=[CH:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Cc1cc(N2CCNCC2)ccc1F
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)c(C)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting with 1.0 g (2.2 mmol) of the iminophosphorane from Example 10A, 500 mg (2.31 mmol) of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene (Example 17A) and 427 mg (2.2 mmol) of the phenylpiperazine from Example 13A, 1.03 g (79% of theory) of crude product are obtained following filtration through silica gel (cyclohexane/ethyl acetate 2:1 (v/v)). This product is reacted further without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:26](#[N:29])[CH:27]=[CH2:28].CCOC(C)=O>C1COCC1>[C:26]([CH2:27][CH2:28][N:23]1[CH2:22][CH2:21][CH:20]([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:25][CH2:24]1)#[N:29]
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Reactant: C=CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(CCC#N)CC2)cc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.) in THF (0.70 mL) was treated with acrylonitrile (55 μL, 0.84 mmol, 4.2 equiv.). After being stirred for 24 h at 50° C., the reaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2, gradient elution) gave the title compound as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 4.16-4.09 (m, 1H), 3.02-2.98 (m, 2H), 2.75-2.70 (m, 3H), 2.57-2.54 (m, 3H), 2.26-2.20 (m, 2H), 2.15-2.08 (m, 2H), 1.92-1.87 (m, 2H), 1.78 (s, 3H), 0.58-0.53 (m, 2H), 0.46-0.42 (m, 2H); MS(ESI) 410 [M+H]+.
Reaction SMILES: C(NCC)C.O.[CH2:7]([O:9][C:10](=[O:31])[CH:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([Cl:22])[CH:21]=1)[C:12](O)=O)[CH3:8].C=O>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:31])[C:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([Cl:22])[CH:21]=1)=[CH2:12])[CH3:8]
Reactant: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)O
Agent: C=O
Solvent: CCNCC
Solvent: O
Solvent: ClCCl
Product: C=C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.3 %

Procedure:
Diethylamine (3.67 ml, 3.67 mmol) was added dropwise followed by water (2.5 ml) and CH2Cl2 (2.5 ml) to a mixture of 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.40 g, 3.64 mmol) and 37% aq. solution of formaldehyde (0.29 ml, 3.75 mmol) in CH2Cl2 (2 ml) at 0° C. The mixture was stirred for 20 h at room temperature and then poured onto ice-water and extracted with methylene chloride. The organic layer was washed with 5% NaHCO3, dried and concentrated under reduced pressure. Flash chromatography (1-2.5% methanol in CH2Cl2) yielded 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-acrylic acid ethyl ester 0.81 g (65%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:37][C:38]1[N:43]=[CH:42][C:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:40][CH:39]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:37][C:38]3[N:43]=[CH:42][C:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:40][CH:39]=3)=[O:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (Preparation 1; 2.0 g, 5.42 mmol) was dissolved in DCM (20 mL). To this solution was added DMF (0.41 mL, 5.42 mmol) and cooled to 0° C., followed by the addition of oxalyl chloride (0.77 mL, 8.14 mmol) and further stirred for 1 hr at room temp. To this mixture, a solution of tert-butyl 6-aminopyridine-3-carboxylate (preparation 54, 1.26 g, 6.51 mmol) and pyridine (2.19 mL, 2.71 mmol) in DCM 20 (mL) was added drop wise at 0° C. and was stirred further for 1 hr at room temperature. The reaction mixture was diluted with DCM (50 mL), organic layer was washed with water, followed by brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by silica gel column chromatography to get the title product (1.6 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[O:10][C@@H:9]1[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.O.Cl>[CH2:1]([C@H:8]1[O:10][C@H:9]1[C:11]([OH:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCCCC[C@@H]1O[C@@H]1CO
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC[C@H]1O[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 300 mg (1.16 mmole) (2R-cis)-3-heptyloxiranemethanol in 50 ml of DMF was added 2.62 g (6.97 mmole) of pyridinium dichromate. The reaction was allowed to stir overnight under argon. The mixture was then diluted with 150 ml H2O and 20 ml 0.1M HCl and washed three times with 50 ml of Et2O. The combined Et2O layers are dried over MgSO4, filtered and evaporated to afford a white powder. This residue was crystallized from petroleum ether to afford 155 mg of white power, mp 53°-5° C. 1H NMR (CDCl3) δ3.60 (d, 1, J=5 Hz), 3.24 (dd, 1, J=5 12 Hz), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M-45(--CO2H)(3.7)141.1, M(100)41.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:40]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:36]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:37])[NH2:40]
Reactant: On1nnc2ccccc21
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 50.1 %

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (540 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (345 mg) and WSC.HCl (383 mg) in DMF (10 ml) was stirred at room temperature for 24 hr, and the mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object product (270 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([CH3:31])[CH:33]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: Cc1cccc(CN)c1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2cccc(C)c2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 3-methylbenzylamine
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:38]=[CH:37][C:27]([C:28]([N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1.[BH4-].[Na+].O>CO>[OH:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]([C:27]2[CH:26]=[CH:25][C:24]([C:3]3[N:4]=[C:5]4[N:11]([CH2:10][CH2:9][C:8]5[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=5[CH:6]4[O:16][CH:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]4)[C:2]=3[CH3:1])=[CH:38][CH:37]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: Cc1c(-c2ccc(C(=O)N3CCC(=O)CC3)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)CC3)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reaction time: 2 h

Procedure:
To a solution of 1-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-benzoyl}-piperidin-4-one (example 218) (93.7 mg, 0.183 mmole) in MeOH (2 mL) is added portionwise NaBH4 (10.5 mg, 0.275 mmole). After 2 hours at room temperature, water is added and the aqueous phase is extracted with AcOEt. AcOEt phase is dried over MgSO4, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (90:1) then (CH2Cl2:MeOH:NH4OH) (9:1:0.1). The residual solid is triturated three times with Et2O to give (4-hydroxypiperidin-1-yl)-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH2:18])[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:20]=[S:21].CO.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH:18][C:20]([NH:19][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[S:21])[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CN=C=S
Reactant: CC(=NN)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=S)NN=C(C)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 0.72 %

Procedure:
A solution of 2-(3,4-dichlorophenyl)-4-(1-hydrazonoethyl)thiophen-3-ol (30 mg, 0.10 mmol) prepared in Reference Synthetic Example 1 and methyl 2-isothiocyanatoacetate (20 mg, 0.15 mmol) in dimethyl formamide (300 μL) was stirred at room temperature, 40° C. and 50° C. for 2 hours, respectively. After addition of methanol-water, the solution was stirred at room temperature for 0.5 hour, and the resulting crystals were collected by filtration as the desired product (yield 0.72%).
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=1)#[N:2].[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1.C(C1C=C(O)C(=CC=1)O)(C)(C)C>CN(C)C=O>[C:1]([C:3]12[CH2:8][CH2:7][CH:6]([CH:5]=[CH:4]1)[CH:11]1[CH:10]2[C:9](=[O:15])[NH:13][C:12]1=[O:14])#[N:2]
Reactant: N#CC1=CC=CCC1
Reactant: O=C1C=CC(=O)N1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: CN(C)C=O
Product: N#CC12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
59 g (0.56 mol) of 1-cyano-cyclohexa-1,3-diene are heated at 150° C. with 54 g (0.56 mol) of maleimide and 5 g of 4-(tert-butyl)-pyrocatechol in 1000 ml of dimethylformamide for 8 hours. The mixture is concentrated, the residue is stirred with water and toluene and the product which has crystallized is filtered off with suction, washed with isopropanol and dried in air.