Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:22])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[SH:7][C:4]1[S:3][C:2]([NH:1][C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[N:6][N:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nnc(S)s1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1nnc(S)s1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
61 g of 2-amino-5-mercapto-1,3,4-thiadiazole were dissolved in 230 ml of dimethylacetamide, and 40.8 ml of pyridine were added thereto. The resulting solution was cooled to a temperature not higher than 0° C., and 79 g of phenyl chlorocarbonate were added dropwise thereto. After completion of the dropwise addition, the solution was stirred for 1.5 hours at a temperature not higher than 0° C., and the reaction mixture was then poured into 1 liter of ice-water. Precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Cc2cccc(Cl)n2)=NO)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 142.9 mmol) in methanol (500 mL) was added hydroxylamine hydrochloride (49.7 g, 714.5 mmol) followed by the addition of a sodium hydroxide solution (28.6 g, 714.5 mmol in 50 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (38.7 g, 97%) as a white solid. 1H NMR (CDCl3): δ 8.23 (b, 1H), 7.63 (d, 2H), 7.48 (d, 1H), 7.12 (m, 2H), 6.83 (dd, 2H), 4.33 (s, 2H), 3.76 (s, 3H); MS m/z 277 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]=1[C:8](Cl)=[O:9])[CH3:2].[Br:15][C:16]1[C:25]([O:26][CH:27]([C:35]([O:37][CH3:38])=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH2:39][NH3+:40])=[CH:21]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[CH:27]([O:26][C:25]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:39][NH:40][C:8]([C:7]3[C:6]4[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=4[O:4][C:3]=3[CH2:1][CH3:2])=[O:9])[CH:21]=2)[C:16]=1[Br:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Reactant: CCc1oc2ccccc2c1C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Ethyl-benzofuran-3-carbonyl chloride (0.444 mmol), prepared in step 2 of Example 21, was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.200 g, 0.444 mmol), prepared in step 3 of Example 53, in 20 mL of methylene chloride. Triethylamine (0.124 mL, 0.888 mmol) was then added to the mixture. The reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% sodium bicarbonate. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-(1-bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (0.27 g, 100%) as a tan solid, mp 139-143° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[C:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH2:25]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]3[CH3:14])[C:17]=2[CH:24]=1)[CH3:26]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1cc2c(Cl)ncnc2s1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)C[C@H]3C)ncnc2s1
Yield: 92 %

Procedure:
1-BOC-3-(R)-methylpiperazine was coupled with 4-chloro-6-ethylthiopheno[2,3-d]pyrimidine according to Example 87. Yield=92%, ES-MS: (M+H)+ 363.
Reaction SMILES: C[Mg+].[Br-].[CH2:4](OCC)C.CON(C)[C:12]([C:14]1[N:15]=[C:16]([CH3:23])[O:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:13]>>[CH3:23][C:16]1[O:17][C:18]([C:19]([F:20])([F:21])[F:22])=[C:14]([C:12](=[O:13])[CH3:4])[N:15]=1
Reactant: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1nc(C)oc1C(F)(F)F
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of MeMgBr in diethyl ether (3 M, 0.63 ml, 1.89 mmole) was added at 0° C. a solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid methoxy-methyl-amide (300 mg, 1.26 mmole) and stirring was continued at 22° C. for 1 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (4:1) to give the title compound (155 mg) as a colorless oil. MS: m/z=193 [M]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[N:4][C:3]=1[O:14][CH:15]([CH3:17])[CH3:16].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([O:14][CH:15]([CH3:17])[CH3:16])[N:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: Cc1c(OC(C)C)ncc2c1C(=O)NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CN2CCOc3cnc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94608.2 %

Procedure:
To a solution of 6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131f, 70 mg, 0.30 mmol) in dry DMF (6 mL) was added NaH (36 mg, 0.90 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 10 minutes. To the mixture was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 155 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (20 mL). The solution was washed with brine (5×15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131 g, 0.14 g, 100%) as a colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1.F[S:24]([C:27]1[N:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25]>C1COCC1>[CH3:34][O:33][C:30]1[N:29]=[N:28][C:27]([S:24]([C:14]2[O:13][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[OH:22])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: O=C1COc2ccccc21
Reactant: COc1ccc(S(=O)(=O)F)nn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2oc3ccccc3c2O)nn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
n-Butyl lithium (12 mmol, 4.7 mL) was added dropwise to a solution of diisopropyl amine (12 mmol, 1.7 mL) in THF (5 mL) at −78° C. After 10 minutes, a solution of 3-coumaranone (10 mmol, 1.92 g) in THF (10 mL) was added. The temperature was maintained at −78° C. and stirred for 10 minutes. To this was added a solution of 3-fluorosulfonyl-6-methoxy-pyridazine. The reaction mixture was brought to room temperature over one hour and quenched with ammonium chloride (1 g) and extracted with EtOAc (2×25 mL). The EtOAc extract was washed with H20, the organic layer was collected, dried, filtered and the filtrate was evaporated to a residue. This residue was purified by silica gel chromatography (eluent: hexanes:EtOAc::9:1) to yield 3-methoxy-6-(3-hydroxy-benzofuran-2-sulfonyl)-pyridazine (17%, 622 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40].O>C1C=CC=CC=1>[CH3:23][C:22]1([C:19]2[CH:20]=[CH:21][C:16](/[CH:15]=[C:14](/[C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)\[CH3:25])=[CH:17][CH:18]=2)[O:40][CH2:39][CH2:38][O:24]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C/C(=C\c1ccc(C2(C)OCCO2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
3.0 g of 4'-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-acetophenone (prepared as described in Example 22) dissolved in 40 ml of benzene are treated with a catalytic amount of p-toluenesulphonic acid and 0.6 g of ethyleneglycol and warmed in a Dean-Stark apparatus, the water formed being concurrently separated off. After heating under reflux for 2 days, the mixture is cooled down, introduced into ice/saturated sodium bicarbonate solution and exhaustively extracted with ether. The ether extract is washed twice with a saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure to remove the solvent. The oily residue is purified by adsorption on silica gel using hexane/ether (9:1) for the elution. The 2-methyl-2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-phenyl]-1,3-dioxolane obtained from the eluate melts at 122°-123° C. after recrystallisation from ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].[H-].[Na+].[CH3:38]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]([CH3:38])[S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N(C)S(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes, and then 0.17 ml of methyl iodide was added thereto, followed by stirring under ice-cooling for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 545 mg of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH3:17][CH:18](O)[CH3:19]>>[CH:18]([O:15][C:5]1[CH:6]=[CH:7][C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]=1[C:3]([OH:2])=[O:16])([CH3:19])[CH3:17]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: CC(C)O
Product: CNS(=O)(=O)c1ccc(OC(C)C)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B13(d-e) from 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 2-Propanol. MS (m/e): 272.2 ([M−H]−, 100%)
Reaction SMILES: [C:1]([C:12]1[CH:20]=[C:16]([C:17]([OH:19])=O)[C:15]([OH:21])=[CH:14][CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].P(Cl)(Cl)Cl.[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClC1C=CC=CC=1>[C:1]([C:12]1[CH:20]=[C:16]([C:17]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[O:19])[C:15]([OH:21])=[CH:14][CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCCCCCCCC(=O)c1ccc(O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 60 °C
Yield: 23.2 %

Procedure:
In a 100 ml round-bottom flask fitted with a condenser and drying tube is placed 5-n-decanoylsalicylic acid (1.85 g., 6.7 mmoles), dry chlorobenzene (50 ml), and phosphorous trichloride (0.47 g., 3.4 mmoles). The mixture is then stirred by means of a magnetic stirring bar while the mixture is heated to 60° C. for three hours. The resulting solution is cooled to room temperature and 0.93 g. (6.7 mmoles) of p-nitroaniline is added. The mixture is then heated to 60° C. for three hours, with stirring, and then refluxed for 24 hours. The solvent is removed by vacuum vaporization and the residue is recrystallized from ethanol-water. The crystalline product is triturated with concentrated hydrochloric acid, collected and washed with water. Recrystallization from ethanol-water gives 0.64 grams of 5-n-decanoyl-4'-nitrosalicylanilide, mp 142°-143° C.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]4[N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=[CH:36][C:29]=34)[CH:25]=[N:24]2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+]>O.C(O)C>[OH:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]4[N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[CH:35]=[CH:36][C:29]=34)[CH:25]=[N:24]2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ccnc21
Reaction time: 8 h

Procedure:
To {3-{[tert-butyl(diphenyl)silyl]oxy}-1-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (2.0 g, 3.0 mmol, a mixture of diastereomers from Step A) ethanol (82 mL) was added 5.0 M sodium hydroxide in water (9 mL, 50 mmol). The reaction was stirred overnight. The reaction mixture was diluted with water and ethanol was removed in vacuo. The aqueous mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water, then brine, dried over sodium sulfate, decanted and concentrated. The product, as a mixture of diastereomers, was used without further purification in Step C. LCMS (M+H)+: 424.2.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:17][C:16]3=[CH:18][NH:19][C:14]4[C:15]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:9]2=[O:20])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28]([CH2:30][C:31](ON1C(=O)CCC1=O)=[O:32])#[N:29]>CCO>[CH3:1][C:2]1([N:8]2[CH2:17][C:16]3=[CH:18][NH:19][C:14]4[C:15]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:9]2=[O:20])[CH2:7][CH2:6][N:5]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:4][CH2:3]1
Reactant: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)CC#N)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
4-(4-Methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (21 mg, 0.078 mmol) and triethylamine (0.032 mL, 0.233 mmol) were dissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (17 mg, 0.093 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 13 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.61 (m, 1H), 7.43 (m, 1H), 5.08 (s, 2H), 3.90 (m, 2H), 3.72 (m, 1H), 3.61-3.62 (m, 1H), 3.51-3.52 (m, 2H), 2.65-2.69 (m, 1H), 2.51-2.57 (m, 1H), 2.22-2.26 (m, 1H), 2.10-2.12 (m, 1H), 1.66 (s, 3H). [M+H] found 338.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:56]1[CH2:60][CH2:59][CH2:58][C@@H:57]1[CH2:61][OH:62]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:56]2[CH2:60][CH2:59][CH2:58][C@H:57]2[CH2:61][OH:62])=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: OC[C@H]1CCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (R)-(−)-2-pyrrolidine methanol (2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give 54 mg of the titled compound as an orange solid.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:14]([O:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6])(=[O:16])[CH3:15]
Reactant: CCCCC(O)c1cccc(C)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(OC(C)=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65.4 g of 3-(1-hydroxypentyl)toluene are dissolved in 500 ml of absolute methylene chloride at 0° C., and 104 ml of acetic anhydride, 89 ml of pyridine and 1 g of dimethylaminopyridine are added in succession. The reaction solution is stirred at 0° C. for 1 hour and at 25° C. for 2 hours and then poured onto 1 l of ice-water. After the organic phase has been separated off, it is extracted 3 times with 200 ml of methylene chloride each time. The organic phases are washed 3 times with 200 ml of 2N HCl each time, 3 times with 200 ml of saturated NaHCO3 each time and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated in vacuo. The residue is distilled at 95° C./0.1 mm (bulb tube).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:30]/[CH:31]=[CH:32]/[CH2:33][C:2]([CH3:7])([CH3:3])[CH3:1])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (3.15 g, 13.1 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with a lithium hexamethyldisilazide solution (14.4 mL, 1M in tetrahydrofuran, 14.4 mmol) and stirred for 30 minutes at −78° C. Example 35B (3.26 g, 17.0 mmol) was added to the solution and the reaction was allowed to warm to 25° C. and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, washed with a saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 5% ethyl acetate in hexane, and 10% ethyl acetate in hexane to give the title compound (3.32 g, 72%). 1H NMR (300 MHz, CDCl3): δ ppm 0.80 (m, 9 H) 1.53 (m, 3 H) 1.79 (m, 2H) 2.63 (m, 1 H) 2.82 (m, 1 H) 5.10 (m, 2 H) 5.18 (m, 1 H) 5.47 (m, 1 H) 7.27 (m, 10 H). MS (ESI+) m/z 368 (M+NH4)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])/[CH:37]=[C:38](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:39])=[CH:32][CH:31]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: COc1ccc(C(=O)CC(C)=O)cc1
Product: COc1ccc(C(=O)/C=C(/C)N[C@@H](Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 52 mg (0.27 mmol) of Intermediate 22 to yield 126 mg of Example 41. TLC (EtOAc/MeOH (7:3): Rf=0.44: 1H NMR (DMSO-d6, 400 MHz) δ11.30 (d, 1H, J=7.00), 7.87 (m. 2H), 7.73 (d, 2H, J=8.72), 7.45 (m, 3H), 7.10 (d, 2H, J=8.37), 6.88 (d, 2H, J=8.89), 6.77 (d, 2H, J=8.37), 5.74 (s, 1H), 4.11 (m, 2H), 4.01(m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.31 (s, 3H), 1.65 (s, 3H); low resolution MS (ES−) m/e 539 (M-H); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 10-50% CH3CN in H2O) with 0.1% HCO2H buffer: 30 minutes
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]cnc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A mixture of 78 (4.5 g, 23 mmol), 3,4-dihydro-2H-pyran (9 mL, 0.1 mol), p-TsOH.H2O (1.0 g, 3.4 mmol) in THF (200 mL) was stirred under nitrogen at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (100:1) to afford 6.0 g (100%) of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (80) as yellow oil: MS (ESI) m/z=281.0 (M+1).