Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cn[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
In benzene (10 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (1.54 g), and to the solution was added m-chloroperbenzoic acid (1.72 g). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (300 ml), saturated sodium hydrogen carbonate solution (300 ml) and sodium nitrite (500 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one-1-oxide (478 mg) as pale yellow crystals.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26].Cl>CS(C)=O>[CH3:14][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:16])[C:5]2[CH:4]=[C:3]([C:2]#[C:31][C:30]3[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A solution of 13.8 g (0.123 mole) of potassium tert.-butylate in 65 ml of dimethyl sulfoxide was added dropwise in the course of 30 minutes to a solution of 22.6 g (0.06 mole) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate (about 85% strength) and 7.86 g (0.06 mole) of 4-cyanobenzaldehyde in 190 ml of dry dimethyl sulfoxide at room temperature. Stirring was continued for 1 hour, after which the mixture was poured onto 1 liter of ice water and acidified with a little dilute hydrochloric acid, and the resulting crystals were filtered off under suction. Recrystallization from ethanol gave 9.2 g (49%) of the title compound of melting point 157° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
50.0 g (0.248 mol) of 2-chloro-3-nitrobenzoic acid are dissolved in 500 ml of methanol, and 20 ml of concentrated sulfuric acid are added thereto. After refluxing for 24 hours, the mixture is poured onto ice/water and the white precipitate is isolated by filtration, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Yield: 75.8 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN; 102.15 mg, 0.198 mmol), 1,3,4-thiadiazol-2-amine (40.1 mg, 0.396 mmol), cesium carbonate (194 mg, 0.594 mmol), and DMF (1 mL) (1:30 pm). The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7% MeOH/DCM) to give 1-(4-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (64.78 mg, 0.150 mmol, 76% yield) as a white solid. m/z (ESI) 433.0 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([C:38](=[O:40])[CH3:39])[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3nsc4ccccc43)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35 mg, 0.080 mmol) and triethylamine (0.022 ml, 0.16 mmol) in dichloromethane (0.8 ml) was added acetyl chloride (0.011 ml, 0.16 mmol) at room temperature. Stirring for 20 h was followed by partitioning between water (20 ml) and ethyl acetate (25 ml). The layers were separated. The organic layer was washed with two 25 ml-portions of water. The organic layer was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (26 mg, 68%) as white solid. MS m/e: 478 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6](=[O:21])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[O:21][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:7]=1
Reactant: COC(=O)CCC(=O)CNC(=O)c1cccc(C(=O)OC)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)CCc1cnc(-c2cccc(C(=O)OC)c2)o1

Procedure:
Methyl 3-{[(5-methoxy-2,5-dioxopentyl)amino]carbonyl}benzoate (520 mg, 1.7 mmol) is dissolved in anhydrous tetrahydrofuran (4 mL), and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (810 mg, 3.4 mmol). The reaction is microwaved (100 W, 2 min) in a sealed vessel, cooled, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 40% ethyl acetate/hexanes) gives the title compound. ESI MS m/z 290.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1O
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1OCC(=O)N1CCOCC1
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzonitrile, (685 mg, 5 mmol) in dimethylformamide (8 mL, Sure Seal; Aldrich) was added NaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich), and the mixture stirred for 5 min under an anhydrous nitrogen atmosphere. To this was added 4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; Avocado Organics), and stirring continued at room temperature for 21 hrs. The reaction was quenched by careful addition of water (30 mL). The resulting mixture was extracted with CH2Cl2 (25 mL×2). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of the title compound as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.63 (2H, t, J=4 Hz, NCH2), 3.67 (1H, m, OCH), 3.72 (1H, m, OCH), 4.86 (2H, s, OCH2), 6.80-6.86 (2H, m, Ar—Hs), 7.61 (1H, dd, J=8.5 Hz, 6.1 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δppm: 42.63, 46.04, 66.80, 68.33, 98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57, 161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C13H14N2O3F (M+H) 265.0988, found 265.0998.
Reaction SMILES: [Na].Cl[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([C:30]#[N:31])[CH:19]=1)=[O:16].[I-].[K+].[CH3:34][OH:35]>>[C:30]([C:20]1[CH:19]=[C:18]([NH:17][C:15]([C:4]2[CH:5]=[N:6][N:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:3]=2[O:35][CH3:34])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])#[N:31]
Reactant: CC(C)(C)COc1ccc(NC(=O)c2cnn(-c3ccc(F)cc3)c2Cl)cc1C#N
Reactant: CO
Agent: [I-]
Agent: [K+]
Agent: [Na]
Product: COc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1-c1ccc(F)cc1

Procedure:
To a methanol solution (20 ml) containing metallic sodium (0.065 g) were added 5-chloro-N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrazole-4-carboxamide (1 g) and a catalytic amount of potassium iodide, and the mixture was stirred at 65° C. for 5 h. The solvent was evaporated. Water was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.3 g), melting point: 120–123° C.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]([NH:33][C@H:34]([CH2:40][S:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][C:51]6[N:52]=[N:53][N:54]([CH:56]([CH2:59][OH:60])[CH2:57][F:58])[CH:55]=6)[CH:44]=5)[C:35]([O:37]CC)=[O:36])=[O:32])[CH:29]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=CC=1.Cl.[Li+].[OH-]>CO.O>[F:58][CH2:57][CH:56]([N:54]1[CH:55]=[C:51]([CH2:50][O:49][C:45]2[CH:44]=[C:43]([CH:48]=[CH:47][CH:46]=2)[CH2:42][S:41][CH2:40][C@@H:34]([NH:33][C:31](=[O:32])[CH2:30][N:28]2[CH:29]=[C:25]([CH2:24][O:23][C:21]3[CH:20]=[CH:19][C:17]4[N:18]=[C:14]([S:11](=[O:12])(=[O:13])[NH2:10])[S:15][C:16]=4[CH:22]=3)[N:26]=[N:27]2)[C:35]([OH:37])=[O:36])[N:52]=[N:53]1)[CH2:59][OH:60]
Reactant: CCOC(=O)[C@@H](CSCc1cccc(OCc2cn(C(CO)CF)nn2)c1)NC(=O)Cn1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1nc2ccc(OCc3cn(CC(=O)N[C@H](CSCc4cccc(OCc5cn(C(CO)CF)nn5)c4)C(=O)O)nn3)cc2s1
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask containing 136 (51 mg, 0.0486 mmol) in MeOH (2 mL) at RT, was added 1M HCl (1 mL) and stirred for 2 h. After the reaction is done, MeOH was removed and the residue was dissolved in THF:H2O (1:1, 0.5 mL). To this LiOH (3 mg, 0.0309 mmol) was added and reaction was stirred at RT for 2 h, sample dilute with water (5 mL) and purified by HPLC using CH3CN:H2O (1:2) as an eluent to afford BD-2-120 (5.9 mg, 27%) as colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)C(C)C)C.[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20]
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 124.3 %

Procedure:
A mixture of methyl 2-amino-2-methylpropanoate hydrochloride (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-2-methylpropanoate (320 mg, 125%) which was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[BrH:11]>>[Br:11][CH2:3][CH2:2]/[CH:1]=[CH:4]/[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: Br
Reactant: OC(c1cccs1)C1CC1
Product: BrCC/C=C/c1cccs1
Reaction time: 2 h

Procedure:
At 5° to 10° C., 225 g (1.46 mol) of cyclopropyl-2-thienylcarbinol was dripped over a period of 1 hour into 972ml of 48% strength hydrobromic acid. The mixture was kept for 2 hours at room temperature, after which the organic phase was separated off and the aqueous solution was extracted three times, each time with 300 ml of dichloromethane. The combined organic phases were washed neutral with dilute sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down under reduced pressure. There was obtained 322 g (94%,corrected) of crude bromide (GC: 92%). 1H-NMR (250 MHZ, CDCl3): δ=2.65-2.80 (m, 2H), 3.46 (t,2H), 5.90-6.10 (m, 1H), 6.61 (d, 1H), 6.80-7.00 (m, 2H), 7.14 (d, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O.O.C(OCC)(=O)C>[OH:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)ccc1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A mixture of ethyl 5-amino-2-methylbenzoate (14.4 g, 80.3 mmol) in aqueous 5% sulfuric acid (300 mL) was cooled with an ice-bath for 15 min. Sodium nitrite (6.09 g, 88.3 mmol) was then added dropwise as a solution in water (50 mL), and the resulting mixture stirred for at 0° C. for 30 min. After this time, the resulting mixture was heated to 60° C. for 18 h. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate (150 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 0-40%, hexanes/ethyl acetate) afforded 12.48 g (86%) of ethyl 5-hydroxy-2-methylbenzoate as red-brown solid: 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J=2.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.91 (dd, J=8.3, 2.8 Hz, 1H), 5.44 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); ESI MS m/z 181 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:17])=[O:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: O=C(O)c1ccc(NC(=O)C(F)(F)F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
step b To a solution of 120 (4.29 g, 18.40 mmol) in MeOH (50 mL) and toluene (75 mL) was added dropwise trimethylsilyldiazomethane (15.64 mL, 31.3 mmol) until the yellow color persisted. The resulting solution was stirred for 30 min then the reaction was quenched with several drops of HOAc until the yellow color disappeared. The solvents were evaporated to afford methyl 4-(2,2,2-trifluoro-acetylamino)-benzoate (122) which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH:30][C:40](=[O:41])[N:39]([CH3:43])[CH3:38])=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylamine (80 mg, 0.202 mmol), CH2Cl2 (0.5 mL), triethylamine (37 μL, 0.227 mmol), and dimethylcarbamoyl chloride (20 μL, 0.222 mmol) are combined and stirred at room temperature for 16 h. Concentrate the crude reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (64 mg, 68%).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N+](=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[N-]>CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH:1]12[C:9]([C:14]([O:16][CH3:17])=[O:15])([C:10]([O:12][CH3:13])=[O:11])[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: C1=CCCCC1
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Product: COC(=O)C1(C(=O)OC)C2CCCCC21
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To stirred, refluxing mixture of 100.0 grams (1.22 mole) of cyclohexene and 0.037 gram (0.0001 mole) of cupric acetylacetonate was fed 22.7 grams (0.14 mole) of dimethyl diazomalonate over a 25-hour period by means of a syringe pump. Refluxing was continued for an additional 8 hours after which distillation of the reaction mixture was begun, employing a small Vigreux column. After removing about 32 grams of cyclohexene overhead, to a head temperature of 80° C., the residue was allowed to cool. The solidified residue was worked up by flash column chromatography on silica gel to give 17.53 grams (0.08 mole) of dimethyl bicyclo[4.1.0]heptane-7,7-dicarboxylate having a melting point of 83° C.-86° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[CH:7]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cc(Cl)ccc2O)ccn1
Temperature: 100 °C
Yield: 8.6 %

Procedure:
(5-Chloro-2-hydroxyphenyl)boronic acid (2.0 g, 0.012 mol), 4-chloropyridine-2-carbonitrile (1.61 g, 0.012 mol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.424 g, 0.00058 mol) and sodium carbonate (3.7 g, 0.035 mol) in 1,4-dioxane (20.0 mL) and deionised water (1.0 mL) were degassed with nitrogen (×3) before heating at 100° C. for 18 hours under nitrogen. The reaction was cooled and hydrochloric acid (2.0 M aqueous solution, 30.0 mL) added. Reaction was filtered, washing with ethyl acetate (50.0 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography on the ISCO™ (40 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 7:3, by volume) to afford the title compound as a yellow solid, 0.23 g, 8.6% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(OCC)n1ccnc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A mixture of imidazole (12.81 g), triethyl orthoformate (133 ml) and 4-toluenesulphonic acid (1 g) was stirred and heated to 130° C. for 3 hours. The mixture was stored at ambient temperature for 16 hours. The triethyl orthoformate was evaporated and the residue was distilled under vacuum to give imidazole-l-carboxaldehyde diethyl acetal (3.44 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:37])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:56])C=1.C(OCC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)=[O:37])=[O:56])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3SCCCCCC(=O)N3CCN(C)CC3)cc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3S(=O)CCCCCC(=O)N3CCN(C)CC3)cc2)cc1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-ylthio]phenyl]benzamide (500 mg) and m-chloroperbenzoic acid (133 mg) in dichloromethane (20 ml) was stirred in an ice bath for 2 hours and the solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a syrup. The crude product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-ylsulfinyl]phenyl]benzamide (423 mg) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:22][OH:23])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:23][CH2:22][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[F:21])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.7 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 13) (0.37 g), benzene (20 ml) and pyridine (0.12 ml) to yield the title compound (0.43 g, 99%).