Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9].C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[C:8]([O:11][C@@H:12]1[NH:5][C:6](=[O:7])[C@H:13]1[CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9]
Reactant: CCCC=COC(C)=O
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC[C@@H]1C(=O)N[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 120 h
Yield: 3.4 %

Procedure:
Eight hundred microliters of chlorosulfonyl isocyanate was added to a solution of 1.28 g (10 mM) pent-1-enyl acetate in 5 ml methylene chloride at 0° under nitrogen. After stirring at 0° 5 days, the reaction mixture was added dropwise to a mixture of 5 g ice, 1.15 ml water, 2.82 g NaHCO3 and 1.0 g Na2SO3 and stirred at 0° for 30 minutes. The mixture was extracted with 2×25 ml methylene choride and the combined organic phases washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel in hexane/ethyl acetate to yield 60 mg trans 4-acetoxy-3-n-propylazetidin-2-one (3.4%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:18]=1[C:19](OC)=[O:20].[H-].[Na+]>O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:19](=[O:20])[C:18]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:17]=1[O:16][CH3:15])=[O:3]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: COC(=O)c1cc(C)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2cc(C)ccc2OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A solution of methyl 3-acetyl-4-hydroxy-benzoate (6 g) and methyl 2-methoxy-5-methyl-benzoate (12 g) in dioxane (40 ml) was slowly added under stirring at room temperature to a suspension of sodium hydride 50% (4.5 g) in dioxane (40 ml). The mixture was kept under stirring for 3 hours at 80° C., cooled, then diluted with petroleum ether (100 ml), and filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl-acetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-(2-methoxy-5-methyl-benzoyl)-methane (7.9 g; m.p.=145°-147° C.), which was then refluxed for 15 minutes with 99% formic acid (28 ml). After cooling and dilution in water and filtration, the collected precipitate was crystallized from acetone to obtain 6-carbomethoxy-2'-methoxy-5'-methyl-flavone (6 g), m.p.=154°-156° C., which was hydrolyzed with a 1% solution of potassium hydroxide (100 ml) in 95% ethanol at reflux temperature for 30 minutes. The mixture was cooled, acidified with 23% HCl to pH=3, and the precipitate was filtered, washed with ethanol 95% and water so obtaining, after crystallization from ethanol, 6-carboxy-2'-methoxy-5'-methyl-flavone (5.3 g), m.p.=246°-247° C.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:33][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:27]=3[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:34][C:35](OC(C)=O)=[O:36]>CN(C=O)C.C(OCC)(=O)C>[C:35]([N:30]1[CH2:31][CH2:32][C:27]2[N:26]=[C:25]([C:21]3[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=3)[C:4]([N:6]3[CH2:7][CH2:8][CH:9]([C:12]4[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=4)[CH2:10][CH2:11]3)=[O:5])[NH:33][C:28]=2[CH2:29]1)(=[O:36])[CH3:34]
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2nc(-c3cc(C(=O)N4CCC(c5ccc(C#N)cc5)CC4)c(C)cc3C)[nH]c2C1
Temperature: 1.5 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a stirred mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 20 mg, 0.02 mmol, 1.00 equiv, 50%) in DMF (2 mL) under nitrogen was added a solution of Ac2O (2.4 mg, 0.02 mmol, 1.00 equiv) in DMF (0.2 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at 0-3° C. in a water/ice bath. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2×20 mL of brine. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude residue (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, abridge C18; mobile phase, WATER WITH 0.05% NH3.H2O and CH3CN (hold 5% CH3CN in 2 min, up to 20%-46% in 10 min, up to 100% in 12 min, down to 20% in 14 min); Detector, UV 254/220 nm. The fractions containing pure compound were combined and lyophilized to yield 5.5 mg of the title compound as a white solid. m/z (ES+) 482 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.39-7.28 (m, 2H), 4.90 (m, 1H, partially obscured by the solvent peak), 4.67 and 4.62 (2 singlets, acetamide rotamers, MeCONCH2-imidazole, 2H), 3.92 (m, 2H), 3.66 (m, 1H), 3.23 (m, 1H), 3.00 (m, 2H), 2.85-2.76 (m, 2H), 2.48 (s, 3H), 2.41 and 2.31 (2 singlets, aryl amide rotamers, ArCH3, 3H), 2.25 and 2.22 (2 singlets, acetamide rotamers, CH3CON, 3H), 2.04 (m, 1H), 1.92-1.20 (m, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=2)[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=O)=O.Cl.[CH3:31][NH:32][CH3:33].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:31][N:32]([CH3:33])[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=2)[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of 2-[1-(4-cyanopyridin-2-yl)-5-[(4-fluorophenyl)methoxy]pyrazol-4-yl]ethyl methanesulfonate (42 mg, 0.1 mmol) and dimethylamine hydrochloride (41 mg, 0.5 mmol) in ACN (3 mL) was added K2CO3 (276 mg, 2 mmol) and KI (62 mg, 0.4 mmol) at rt. The reaction mixture was heated to 80° C. and stirred overnight. Filtered, solvent removed and purified by prep-HPLC to give the title compound (16 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 2.45 (6H, s), 2.56-2.61 (2H, m), 2.69-2.73 (2H, m), 5.16 (2H, s), 7.03-7.07 (2H, m), 7.35-7.41 (3H, m), 7.53 (1H, s), 8.03 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H20FN5O, 366; Found, 366.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.CN1CCOCC1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:2][CH:3]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(N)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 1,4-phenylenediamine (0.5 g, 4.62 mmol) in anhydrous CH2Cl2 (15 mL) was added NMM (0.51 mL, 4.62 mmol). To the resulting mixture was added dropwise butyryl chloride (0.45 mL, 4.62 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C., and stirred for 0.5 h. The reaction mixture was extracted with CH2Cl2 (20 mL) and washed with H2O (20 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc:hexane=1:3) to give N-(4-aminophenyl)butyramide (KYJ3-006-2, 0.31 g, 36%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:13])([CH3:12])[C@@H:5]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[NH2:6].C(N(CC)CC)C.S=[C:22]1[CH2:26][S:25][C:24](=[O:27])[NH:23]1>C(O)C>[CH3:2][O:3][C:4]([CH3:13])([CH3:12])[C@@H:5]([C:7]([N:9]([CH3:10])[CH3:11])=[O:8])[NH:6][C:22]1[CH2:26][S:25][C:24](=[O:27])[N:23]=1
Reactant: COC(C)(C)[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(C)(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-methoxy-N,N-dimethyl-L-valinamide hydrochloride obtained in B) (697 mg) and triethylamine (810 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (533 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (60 mg, 0.17 mmol) and phenethyl amine (78 mg, 0.68 mmol). The title compound was obtained as a yellow solid (70 mg, 91% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (3H, m), 8.39 (1H, s), 7.27 (2H, m), 7.19 (3H, m), 3.42 (2H, m), 2.80 (2H, m). MS m/z: 452.24, 454.26 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][C:21](=[O:22])[NH:9][N:8]=2)=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1-c1n[nH]c(=O)o1

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (800 mg, 3.5 mmol) was taken in DMF (4 mL). Added CDI (3.8 mmol, 1.1 equiv.) and stirred at room temperature for overnight. The reaction mass was concentrated under reduced pressure to remove excess of DMF. The residue was diluted using EtOAc, washed the EtOAc layer with water followed by brine solution. Collected the EtOAc layer, dried over Na2SO4, filtered and concentrated. The crude material obtained was taken to next step as such, without purification. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.76 min; LCMS (ES-API), m/z 255.6 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1cc(C)ccc1O
Product: COC(=O)CCC(=O)c1cc(C)ccc1OCC1CO1

Procedure:
Methyl 3-(5-methyl-2-hydroxybenzoyl)propionate was reacted with epibromohydrin in a similar manner to the procedure described in Example 1(ii) to give methyl 3-[5-methyl-2-(2,3-epoxypropoxy)benzoyl]propionate as an oil.
Reaction SMILES: [C:1]([C:4]1[C:13]([CH2:14]Br)=[N+:12]([O-:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:17])(=[O:3])[CH3:2].[C:18]([O-:21])(=[O:20])[CH3:19].[K+].[I-].[K+]>CN(C)C=O>[C:1]([C:4]1[C:13]([CH2:14][O:21][C:18](=[O:20])[CH3:19])=[N+:12]([O-:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:17])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(C(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a stirred slurry of 50.0 g. (0.168 mol.) of 2-acetyl-3-bromomethylquinoxaline 1,4 dioxide in 200 ml. of N,N-dimethylformamide, was added 18.2 g. (0.185 mol.) of potassium acetate, followed by 4.15 g. (0.025 mol.) of finely ground potassium iodide. Stirring was continued for 20 minutes at ambient temperature, and then the reaction mixture was filtered. The dark filtrate was added dropwise to 4,000 ml. of ether, and the solid which precipitated was removed by filtration and discarded. Evaporation of the ether in vacuo afforded a yellow solid which was recrystallized from methanol. This gave 31.6 g. (76% yield) of 2-acetyl-3-acetoxymethylquinoxaline 1,4-dioxide having m.p. 124°-125° C.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](Cl)=[O:11])(=[O:4])=[O:3].[CH3:13][OH:14].Cl>C(Cl)(Cl)Cl>[CH3:13][O:14][C:10]([C:6]1[S:7][CH:8]=[CH:9][C:5]=1[S:2]([Cl:1])(=[O:4])=[O:3])=[O:11]
Reactant: CO
Reactant: O=C(Cl)c1sccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
48 G. (0.196 mol) of the obtained 3-chlorosulfonylthiophene-2-carboxylic acid chloride are dissolved in 500 ml. of absolute chloroform, 9.6 g. (0.3 mol) of absolute methanol are added and the mixture is heated to reflux for 3 hours [until no more hydrogen chloride evolution]. The mixture is evaporated to dryness in vacuo and the residue allowed to crystallize. There is obtained pure 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]12[NH:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=1[F:31])[CH2:9]2.C(N(CC)CC)C>ClCCl>[C:1]([N:13]1[CH:12]2[CH:8]1[CH2:9][N:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=1[F:31])[CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4NC4C3)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4C(C3)N4C(C)=O)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Acetic anhydride (3.5 μL, 0.05 mmol) was added to a cooled (0° C.) solution of N-({(5S)-3-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (12 mg, 0.036 mmol) in triethylamine (10 μL, 0.072 mmol) and dichloromethane (0.7 mL). After 1 hour, the solution was diluted with dichloromethane, and washed with dilute NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by pTLC (4% MeOH—CH2Cl2) provided the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2].C([Li])CCC.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([S:28]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=3)[C:6]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1ccc2[nH]cc(CCC(=O)O)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
The indole propionic acid 14 (100 mg, 0.46 mmol) was dissolved in THF (5.0 mL) and cooled to −78° C. To this solution was added n-butyllithium (n-BuLi; 0.4 mL, 1.0 mmol, 2.4 M in hexanes) dropwise and the mixture was stirred at −78° C. for 1 hour. To this mixture was added benzenesulfonyl chloride (0.13 mL, 1 mmol) and the reaction was allowed to stir overnight and warm to room temperature. The mixture was poured into ice cold H3PO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (5% MeOH/CHCl3) to give compound 6 as a white solid (10 mg; M−1=356.4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2([O:24][CH3:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.Cl.[NH2:27][OH:28]>>[NH2:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12](/[C:15](=[N:27]/[OH:28])/[CH3:16])=[CH:13][CH:14]=2)[CH:5]=[C:4]([C:18]2([O:24][CH3:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: COC1(c2cc(Sc3ccc(C(C)=O)cc3)nc(N)n2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(Sc3ccc(/C(C)=N/O)cc3)nc(N)n2)CCOCC1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 43, 4'-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yl-thio]acetophenone oxime in 75% yield, m.p. 237°-240° C.;
Reaction SMILES: CO[C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:14][C:13]=3[OH:26])[NH:11][C:7]=2[CH:6]=1)=[O:4].[CH3:29][NH2:30]>>[CH3:29][NH:30][C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:14][C:13]=3[OH:26])[NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Product: CNC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A suspension of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid methyl ester (37.5 mg, 0.1 mmol) in aqueous methylamine solution (40%, 2 mL) was heated at 140° C. in a Biotage Initiator Sixty microwave reactor for 15 min, cooled to the room temperature, and concentrated under reduced pressure. The residue was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (19 mg, 50%). 1H NMR (DMSO-d6) δ 2.84 (s, 3H), 3.92 (s, 3H), 7.11-7.17 (2H), 7.62-7.83 (4H), 8.10-8.29 (3H), 8.50 (br, 1H, NH). ESI-MS m/z 375.3 (MH+).
Reaction SMILES: [C:1]1([NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][CH:21]([Cl:29])[C:22]([Cl:28])([S:24](Cl)(=O)=O)[CH3:23]>C(Cl)(Cl)Cl>[Cl:20][CH:21]([Cl:29])[C:22]([Cl:28])([S:24][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH3:23]
Reactant: CC(Cl)(C(Cl)Cl)S(=O)(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(SC(C)(Cl)C(Cl)Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred, cooled solution of 18.5 g. of N-phenyl ethane sulfonamide in 10.1 g. of triethylamine and 200 ml. of chloroform was added at a temperature below 10° C. a solution of 1,1,2-trichloropropane-2-sulfonyl chloride (21.4 g.) in 50 ml. of chloroform. During the addition, an exothermic reaction took place. When the addition was complete, the mixture was allowed to cool to room temperature. The product was washed twice with water, dried over sodium sulfate and filtered and stripped. A viscous red oil was formed which on evaporation with benzene yielded a solid product of 29.6 g. (92% of theory), m.p. 85°-86° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[F:19].C([Li])CCC.[I:25]I>O1CCCC1.O>[F:19][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:5][C:6]2[C:11]([C:2]=1[I:25])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: II
Reactant: Fc1ccccc1-c1nc2ccccc2c(Cl)c1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1nc2ccccc2c(I)c1F
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of 4-chloro-3-fluoro-2-(2-fluoro-phenyl)-quinoline (from step E, 0.160 g, 0.47 mmol) in tetrahydrofuran (3 mL) at −78° C. was added butyl lithium (0.6 mL, 2.5 M in hexane, 1.3 mmol). The mixture was stirred for 3 h. and iodine (0.148 g, 0.58 mmol) in 0.8 mL of THF was added. The reaction mixture was stirred for an additional 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, concentrated and purified by silica gel column chromatography to yield the title compound (0.148 g, 84%). MS (ES) 368.1 (M+H)+.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[C:5](/[C:14](/I)=[CH:15]/[C:16](=O)[C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2>C1COCC1.[Cu]I>[F:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[C:16]([C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[CH:15][C:14]=2[CH3:1]
Reactant: [Li]C
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of copper(I) iodide (Aldrich, 190 mg, 1.0 mmol) in dry THF (2 mL) was added methyllithium (Aldrich, 1.4 M solution in ether, 1.42 mL, 2.0 mmol), under argon, at 0° C. and the reaction mixture was stirred for 15 minutes. To the colorless solution obtained was added dropwise a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (39.6 mg, 0.1 mmol) in THF (2 mL). After stirring at 0° C. for another 45 minutes, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product (28.5 mg) which was further purified by preparative TLC (silica gel, 20% ethyl acetate in hexanes) to afford 6-fluoro-5-methyl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 12.6 mg, 47.4%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](OC3C=CC([N+]([O-])=O)=CC=3)=[O:53])[CH2:47][CH2:46]2)=[O:44])=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[O:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](=[O:53])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:47][CH2:46]2)=[O:44])=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCCCc1ccccc1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)NCCCCc2ccccc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of 4-phenylbutylamine (610 μl, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature overnight. An additional 204 μl (1.29 mmol) of 4-phenylbutylamine and 180 μl (1.29 mmol) of triethylamine were added and the reaction stirred at room temperature for approximately 7 hours. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 2.02 g of a crystalline solid. Purification of the solid on silica gel (230-400 mesh) using 5%-20% ethyl acetate-methylene chloride as the eluent gave 1.43 g (70%) of the title compounds as a white crystalline solid, mp 84°-86° C.