Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:12]1[C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Cl)c2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2c(C(=O)O)ccc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (200 mg, 0.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (180 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[NH:26][C:25]1=[O:32]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[NH:26][C:25]3=[O:32])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH:3]=1
Reactant: FC(F)(F)COc1cc(Cl)ccc1N1CCNCC1
Reactant: Cc1cn(CCCCl)c(=O)[nH]c1=O
Product: Cc1cn(CCCN2CCN(c3ccc(Cl)cc3OCC(F)(F)F)CC2)c(=O)[nH]c1=O
Product: Cl

Procedure:
substituting 1-[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-(3-{4-[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 205°-206° C.; Anal.: Calcd. for C20H24ClF3N4O3.(HCl)2 : C, 43.53; H, 5.10; N, 10.15%; Found: C, 43.77; H, 5.10; N, 10.13%;
Reaction SMILES: [Na].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([OH:11])=[CH:5][C:4]=2[O:3]1.[Br:12][CH2:13][CH:14]=[CH:15][CH2:16]Br>COCCOC>[Br:12][CH2:13][CH:14]=[CH:15][CH2:16][O:11][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:2][O:3][C:4]=2[CH:5]=1
Reactant: BrCC=CCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: COCCOC
Product: BrCC=CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 g (0.04 mol) of sodium salt of 3,4-methylendioxyphenol are added at -20° to a solution of 8.6 g (0.04 mol) of 1,4-dibromo-2-butene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 0° for 3 hours and subsequently at room temperature for 1 hour. The solvent is distilled off at reduced pressure and the residue is taken up in ether. The ether solution is extracted with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate 9 : 1. The 5-(4-bromo-2-butenyloxy)-1,3-benzodioxol is obtained as colourless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]([CH2:8][CH3:9])[CH2:4][C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:12][O:6][C:5](=[O:7])[CH2:4][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH3:9]
Reactant: CCC(CC(=O)O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CCC(CC(=O)OC)C(F)(F)F

Procedure:
To a stirred solution of Example 1D (250 mg, 1.47 mmol) in dichloromethane (10 mL) and methanol (0.25 mL), under nitrogen atmosphere, trimethylsilyldiazomethane (2.0 M solution in diethyl ether) (2.1 mL, 4.19 mmol) was added drop wise at 0° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH2:11][N:10]=2)[CH:4]=1.[CH3:23]OS(OC)(=O)=O>CC(C)=O>[CH3:23][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:8]=[CH:7][CH:6]=2)=[N:10][CH2:11][C:12]1=[O:20]
Reactant: COS(=O)(=O)OC
Reactant: O=C1CN=C(c2cccc(C(F)(F)F)c2)c2ccccc2N1
Solvent: CC(C)=O
Product: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 15.2 g. of 1,3-dihydro-5-(α,α,α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one in 360ml. of acetone is treated with 7.5 ml. of dimethylsulfate and 45 g. of finely triturated, dry potassium carbonate and stirred intensively at room temperature for 15 hours. The mixture is then poured into 400 ml. of ice-water, the acetone is evaporated under reduced pressure and the separated oil extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to dryness. The resulting oil crystallizes on trituration with hexane, and there is obtained 1,3-dihydro-1-methyl-5-(α,α,α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one having a melting point of 117°-119° C., which can be employed in the next stage without further purification. A sample for analysis is obtained by crystallization from ethanol; melting point 121°-122° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:10]([CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 60 °C

Procedure:
To a solution of tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-(methanesulfonyloxy)propyl)carbamate XL (2.31 g, 6.6 mmol) in DMF was added NaN3. The mixture was heated overnight at 60° C., diluted with DCM and washed with 10% Na2S2O3 (5×), 5% NaHCO3, brine and dried over MgSO4. The solvent was evaporated under vacuum to give crude product (1.75 g). The product was purified on a silica gel column (1:10 EtOAc:hexane) to give the pure tert-butyl N-(2-azido-3-{[(tert-butoxy)carbonyl]amino}propyl)carbamate XLI as white crystals (1.33 g, 4.2 mmol, 67% yield). 1H NMR (CDCl3) 1.47 (s, 18H), 3.07-3.26 (m, 2H), 3.27-3.53 (m, 2H), 3.59-3.75 (m, 1H), 5.06 (brs, 2H); ESIMS found for C13H25N5O4 m/z 316 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(#N)C>C(OCC)(=O)C.ClCCl>[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:29][CH:28]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Temperature: 75 °C
Yield: 79.7 %

Procedure:
Mix 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole (0.400 g, 1.18 mmol), potassium carbonate (0.326 g, 2.36 mmol), 4-methylbenzylamine (0.606, 5.00 mmol) and acetonitrile (5.0 mL) and heat (75° C.), overnight. Cool the reaction mixture and filter through a Waters Sep-Pak 1 g silica cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Dissolved residue in 50% ethyl acetate in dichloromethane and chromatograph on silica (10 g) using ethyl acetate to give the title compound (356 mg, 80% yield). Purity by LC/MS (APCI)=98, [M+H]+=379.
Reaction SMILES: C(O)(=O)C.C([O:12][C:13]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])C1C=CC=CC=1.CO>[C].[Pd].C(Cl)(Cl)Cl>[OH:12][C:13]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]2)=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1O
Temperature: 75 °C
Reaction time: 7 h
Yield: 55.1 %

Procedure:
To an acetic acid (20 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-phenylbenzoate (0.77 g), 10% palladium-carbon (0.35 g) was added, followed by stirring under hydrogen pressure (5 kg/cm2) at 70 to 80° C. for 7 hours. The reaction mixture was cooled to room temperature, and acetic acid, methanol, and chloroform were added thereto. The insoluble substance was removed by filtration. The solvent was removed under reduced pressure, and then chloroform and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.36 g of tert-butyl 2-(2-hydroxy-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([OH:14])=[O:13].[C:21]([O-])(=O)[CH3:22].[Na+].C(Br)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([O:14][CH2:21][CH3:22])=[O:13]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCBr
Product: CCOC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 78.4 %

Procedure:
To a solution of 6.2 g of 2-(2,6-dichloroanilino)-phenylglyoxylic acid in 30 ml of dimethylformamide were added 3.3 g of anhydrous sodium acetate and then dropwise added 3 ml of ethyl bromide under ice-cooling. The mixture was stirred at room temperature for 10 hours. Thereafter, the reaction mixture was poured into 300 ml of water and the whole mixture was extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to column chromatography with silica gel (Wacogel C 200), using etherhexane (1:2) as a developing solvent, to give 5.3 g of ethyl 2-(2,6-dichloroanilino)phenylglyoxylate as yellow crystals. m.p. 84°-85° C. Yield: 78% of theoretical amount
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([C:18](O)=[O:19])[C:12](=[CH:16][CH:17]=1)[C:13](O)=[O:14]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:18](=[O:19])[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccccc1
Temperature: 5 °C

Procedure:
To a suspension of 750 g of monosodium-4-chlorophthalate and 1200 ml water was added 120 ml conc. sulfuric acid. The resulting brown solution was extracted with three 400 ml portions of ether. The combined extracts were treated with carbon black, filtered and the ether distilled. The 4-chlorophthalic acid obtained was dehydrated by heating to 170°C for two hours to give 548 g of anhydride. To a solution of the anhydride in 2250 ml of xylene was added 279 g of aniline diluted with an equal weight of xylene. The solution was refluxed for 16 hours and the water formed was collected in a Dean-Stark trap. After treatment with carbon black the hot xylene solution was cooled to 5°C to give 475 g of crude 4-chloro-N-phenyl phthalimide. Recrystallization from 2000 ml toluene, twice, provided 364 g of 92% pure imide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OC(C)(C)C)=O.CC#N.O>C(Cl)Cl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC=O
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step I, from (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9 g, 9.95 mmol) and Dess-Martin periodinane (4.22 g, 9.95 mmol) in CH2Cl2 (30 mL), slowly wet CH2Cl2 (0.20 mL of water in 30 mL of CH2Cl2) as colorless oil. MS: 437.2 [M+H-BOC]+. tR (HPLC, Nucleosil C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 4.99 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[C:3]2[C:10]([OH:12])=[O:11])([O-:15])=[O:14]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a suspension of indazole-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].N1C=CC=CC=1.[CH2:10]([O:12][N:13]=[C:14]([CH2:18][C:19]([CH3:21])=[CH2:20])[C:15](=O)[CH3:16])[CH3:11]>O.CO>[CH2:10]([O:12][N:13]=[C:14]([CH2:18][C:19]([CH3:21])=[CH2:20])[C:15](=[N:3][OH:2])[CH3:16])[CH3:11]
Reactant: [NH3+]O
Reactant: C=C(C)CC(=NOCC)C(C)=O
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: C=C(C)CC(=NOCC)C(C)=NO
Yield: 81.8 %

Procedure:
By the method of Example 4, 211.3 g of hydroxylammonium chloride in 400 ml of water and 240 g of pyridine were reacted with 342.4 g of 5-methylhex-5-ene-2,3-dione 3-(O-ethyloxime) in 800 ml of methanol. This gave 305 g of the title compound as a yellowish solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:28]=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:39][N:38]=2)[C:30]2[N:31]([CH:33]=[CH:34][N:35]=2)[CH:32]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[N:28]=[C:29]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)=[CH:39][N:38]=3)[C:30]3[N:31]([CH:33]=[CH:34][N:35]=3)[CH:32]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(N4CCN(C)CC4)cn3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3nc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn4ccnc34)nc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
A mixture of 106d (200 mg, 0.92 mmol) and LiOH (300 mg, 10 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (1 mL) was stirred at 50° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with Ethyl acetate (10 mL×2). The combined Ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 106 (45 mg, 20%). LCMS: [M+H]+ 622. 1H NMR (500 MHz, DMSO) δ 9.04 (s, 1H), 8.41 (s, 1H), 8.13-8.10 (m, 2H), 7.98 (s, 1H), 7.71 (s, 1H), 7.47-7.44 (m, 2H), 7.39-7.37 (m, 1H), 6.53 (s, 1H), 5.38-5.36 (m, 1H), 4.37-4.44 (m, 2H), 4.19-3.98 (m, 4H), 3.12 (s, 4H), 2.60-2.58 (m, 2H), 2.50-2.45 (m, 6H), 2.21 (s, 3H), 1.79-1.68 (m, 2H), 1.69-1.67 (m, 2H)
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[NH:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1C=C(C[F:38])C=CC=1CBr)#N>>[CH:1]1([CH2:7][CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([F:38])=[CH:22][CH:23]=3)[C:18]2=[NH:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C1c2ccccc2CN1C(CC1CCCCC1)C(=O)Nc1nccs1
Reactant: N#Cc1cc(CF)ccc1CBr
Product: N=C1c2cc(F)ccc2CN1C(CC1CCCCC1)C(=O)Nc1nccs1

Procedure:
The title compound was synthesized according to the method described in connection with Compound 11, except that 2-cyano-4-fluoromethylbenzyl bromide was used. 1H NMR (400 MHz, MeOH-d4) δ: 7.99 (dd, J=2.4, 8.0 Hz, 1H), 7.76-7.82 (m, 1H), 7.58-7.66 (m, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.13 (d, J=0.6 Hz, 1H), 5.11-5.21 (m, 2H), 4.96 (d, J=20.0 Hz, 1H), 2.03-2.24 (m, 2H), 1.70-1.90 (m, 5H), 1.0-138 (m, 6H). [M+H] calc'd for C20H23FN4OS, 387; found, 387.
Reaction SMILES: C[NH+]1CCOCC1.[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:12]([C:33]#[N:34])=[C:11]([SH:35])[N:10]=1.Br[CH2:37][C:38]([NH2:40])=[O:39].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:8][C:9]1[N:10]=[C:11]([S:35][CH2:37][C:38]([NH2:40])=[O:39])[C:12]([C:33]#[N:34])=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)[C:14]=1[C:15]#[N:16]
Reactant: NC(=O)CBr
Reactant: CN1CCN(S(=O)(=O)c2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)CC1
Agent: C[NH+]1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(C#N)c(N)nc(SCC(N)=O)c3C#N)cc2)CC1

Procedure:
84 mg (0.163 mmol) of 2-amino-4-{4-[(4-methylpiperazino)sulfonyl]phenyl}-6-sulfanyl-3,5-pyridinedicarbonitrile N-methylmorpholinium salt together with 53.3 mg (0.244 mmol) of bromoacetamide and 54.7 mg (0.65 mmol) of NaHCO3 are stirred in 0.5 ml of DMF overnight. After filtration, the reaction solution is initially purified by preparative HPLC. The isolated fraction is reconcentrated under reduced pressure and the residue is purified by preparative thin-layer chromatography.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCCN(C)C)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and N1,N1-dimethylethane-1,2-diamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O)[CH3:2].[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([O-:18])=[O:17].Cl.[N+]([C:30]1C=CC(N)=C[CH:31]=1)([O-])=O>C(O)CCC>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH2:2][CH2:30][CH3:31]
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 118 °C
Yield: 434.3 %

Procedure:
Into a dry 2 L round-bottom flask was placed 106.3 grams (0.506 moles) of 3-(3-fluorophenyl)-3-oxo-propionic acid ethyl ester, 63.0 grams (0.456 moles) of 4-nitro-aniline and 4.0 grams (0.023 moles) of 4-nitro-aniline hydrochloride. To the mixture was added 1.3 L of n-butanol, the flask was fitted with a Soxhlet extractor (cup volume of 0.3 L), condenser and nitrogen inlet. Dry, activated 4 Å sieves (200 grams) were placed in the extractor cup and the reaction mixture heated to reflux temperature of 118° C. under nitrogen and maintained at that temperature for 90 hours. The reaction mixture was decanted while hot from a small amount of solids and chilled to −15° C. for 48 hours Crystalline solids were collected by vacuum filtration. The crystals were washed with 0.2 L of cold ethanol and two 0.2 L portions of hexanes and vacuum dried at 50° C. overnight to yield 35.8 grams (20.8% yield) of the title compound.
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[CH:5]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Methyl iodide (1.49 mL, 24 mmol) was added to a suspension of 4-bromo-2-fluorobenzoic acid (4.38 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) in dimethylformamide (50 mL), and the mixture was stirred overnight at room temperature. After completion of the reaction, ethyl acetate was added, and the mixture was washed with water and a saturated ammonium chloride aqueous solution. After drying over magnesium sulfate, concentration was carried out to obtain 4.50 g of the desired product as a colorless solid (yield 97%).