Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N[C@H](CCO)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@H](CCO)C(=O)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a suspension of D-Homoserine (2.5 g, 20.99 mmol) and K2CO3 (5.8 g, 41.98 mmol) in DMSO (30 mL) was added 2-chloro-3-methyl-4-fluorobenzonitrile (3.56 g, 20.99 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 17 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (200 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a beige solid (3.39 g, 60%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.49 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.06 (br d, J=9 Hz, 1H), 4.49-4.41 (m, 1H), 3.83-3.80 (m, 2H), 2.29 (s, 3H), 2.27-2.20 (m, 1H) and 2.18-2.09 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][NH2:19])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:18][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCc2cccnc2)cc1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
2 g of 4-fluoronitrobenzene, 2.07 g of 2-(3-pyridyl)ethylamine, and 2.35 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 16 hours and, after cooling to room temperature, was then poured into a water+ice mixture. The yellow precipitate formed was filtered off, reslurried in water, and then dried over P2O5. 3.2 g of N-(4-nitrophenyl)-N-(2-pyrid-3-ylethyl)amine (3) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCCC2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2CCCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopentylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]([CH:13]([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([C:29]1[CH:41]=[CH:40][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)=[CH:31][CH:30]=1)#[N:28]>CN(C)C=O>[C:27]([C:29]1[CH:41]=[CH:40][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:20][C:18]2[CH:17]=[CH:16][C:3]([C:4]([N:6]([CH:13]([CH3:15])[CH3:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:5])=[C:2]([OH:1])[CH:19]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: CC(C)N(C(=O)c1ccc(O)cc1O)c1ccccc1
Reactant: N#Cc1ccc(OCCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)c1ccccc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A stirred solution of 2,4-dihydroxy-N-(1-methylethyl)-N-phenylbenzamide (358 mg, 1.32 mmol) in 6 mL of N,N-dimethylformamide is treated with cesium carbonate (520 mg, 1.58 mmol), and 5-(4-cyanophenoxy)pentyl bromide (U.S. Pat. No. 4,451,476, 354 mg, 1.32 mmol) and stirred at 40° C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N-(1-methylethyl)-N-phenylbenzamide as colorless foam.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1([CH2:32]Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCC2CCCCC2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 51.4 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and cyclohexylmethyl bromide (0.1 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 9 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (93 mg, yield 51%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9])=[CH:3][CH:2]=1.[ClH:15].[Cl:16]([O-])(=O)=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[ClH:16].[Cl:15][C:5]1[CH:6]=[C:1]([CH3:14])[CH:2]=[CH:3][C:4]=1[NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9]
Reactant: Cc1ccc(NC(=N)NC(=N)N)cc1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(=N)NC(=N)N)c(Cl)c1
Reaction time: 10 h

Procedure:
To 0.05 moles of 1-(p-tolyl)biguanide dissolved in 75 ml of acetic acid is added 9 ml of concentrated hydrochloric acid followed by 1.74 g. (0.0164 moles) of sodium chlorate in 4 ml of water. The temperature is held below 25°C with stirring for 10 hours and then cooled in an ice bath. To the reaction mixture is added 40% sodium hydroxide solution and extracted with ether. The ether is worked with water, dried over magnesium sulfite and evaporated to dryness. The hydrochloride salt is then prepared with ethanolic hydrochloric acid to obtain 1-(2-chloro-4-methylphenyl)biguanide hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([SH:19])[CH2:17][CH3:18]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:19][CH2:16][CH2:17][CH3:18])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CCCS
Product: CCCSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 90.8 %

Procedure:
Similarly, 61 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 15 g of 1-propylmercaptan. There is obtained 62 g (89% of theory) of (4-nitro-2-trichloromethylphenyl)-n-propyl disulfide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:12]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:12]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[CH:9]=[C:10]([C:25]3[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=3)[C:5]=2[NH:4][N:3]=1
Reactant: N#Cc1cccc(F)c1-n1cc(Br)c2[nH]nc(N)c2c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(-c2cn(-c3c(F)cccc3C#N)c(=O)c3c(N)n[nH]c23)n1
Temperature: 130 °C
Yield: 27.4 %

Procedure:
A mixture of 2-(3-amino-7-bromo-4-oxo-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-3-fluorobenzonitrile obtained in Step G (160 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (191 mg), tetrakis(triphenylphosphine)palladium(0) (53 mg), aqueous sodium carbonate solution (2 M, 0.460 mL) and N,N-dimethylformamide (10 mL) was heated with microwave irradiation at 130° C. for 90 min under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate) to give a crude product. The crude product was crystallized from ethyl acetate/diethyl ether to give the title compound (44 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH:25][C:17]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:12][NH:8]1)=[O:19])[CH3:21]
Reactant: CCN(CC)CCN
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1CN[C@H](C(=O)NCCN(CC)CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=271.0.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1C
Temperature: 90 °C
Yield: 119.1 %

Procedure:
To a solution of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74, Step C (0.200 g, 0.356 mmol), and 2-methoxyphenylboronic acid (0.081 g, 0.533 mmol) in acetonitrile (3 mL) was added a 0.4 M aqueous sodium carbonate solution (3 mL) and the mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.018 mmol) was then added and the reaction mixture heated to 90° C. for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over amnhydrous magnesium sulfate, and concentrated in vacuo to give a yellow syrup (0.23 g). Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from dichloromethane/hexane to afford the title compound (0.181 g, 94%) as a white solid, m.p. 119-124° C.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:7]([O:23][CH3:22])=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Reaction time: 1 h

Procedure:
To a solution of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitrobenzenamine (Intermediate 12. 700 mg, 1.7 mmol) in THF (20 mL) was added NaOMe solution at −78° C. (which was prepared by dissolving Na metal (39 mg, 1.7 mmol) in 4 mL of methanol). The reaction mixture was brought to rt and stirred for 1 h at same temperature. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography to yield 2,5-difluoro-N-(2-fluoro-4-iodophenyl)-3-methoxy-6-nitrobenzenamine as yellow solid (597 mg). 1H-NMR (400 MHz, CDCl3): δ 3.95 (3H, s), 6.51-6.56 (1H, m), 6.57-6.65 (1H, m), 7.34 (1H, d, J=8.8), 7.42 (1H, dd, J=1.6, 10), 7.7 (1H, s).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:28]=[C:29]=[O:30])=[C:18]([Cl:31])[CH:17]=1>O1CCCC1.O>[Cl:15][C:16]1[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([Cl:31])[CH:17]=1
Reactant: CC1(C)Oc2c(N=C=O)c(Cl)cc(Cl)c2C1=O
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Oc2c(c(Cl)cc(Cl)c2-n2c(=O)cc(C(F)(F)F)[nH]c2=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.78 g, 0.019 mole) was placed in a flask, and the mineral oil was removed from it with two heptane washes. The sodium hydride was suspended in 40 mL of dry tetrahydrofuran, and this suspension was cooled to 0°-10° C. A solution of 2.96 g (0.0162 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 5 mL of dry tetrahydrofuran was added dropwise to the suspension of sodium hydride. This mixture was then stirred at ambient temperature for 30 minutes. A solution of 4.40 g (0.0162 mole) of 4,6-dichloro-2,3-dihydro-2,2-dimethyl-benzofuran-3-on-7-yl isocyanate in 10 mL of dry tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes and then was heated at reflux for three hours. At the conclusion of this period the mixture was diluted with water, and the resulting mixture was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure, yielding 9.58 g of a gummy, pale yellow residue. This residue was triturated with methylene chloride, yielding 4.79 g of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-6-trifluoromethyluracil as an off-white solid, m.p. 308°-320° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH:10]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:9][CH:8]=[N:7]1)=[S:5])[CH3:2].I[CH3:17]>CO>[CH3:17][S:5][C:4]([N:6]1[CH:10]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:9][CH:8]=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CCNC(=S)N1N=CCC1c1ccsc1
Reactant: CI
Solvent: CO
Product: CCN=C(SC)N1N=CCC1c1ccsc1
Temperature: 50 °C
Yield: 0.2 %

Procedure:
0.70 g (1 mol equiv.) 5-Thiophen-3-yl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 14 mL methanol, 1.82 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 1 hour. Volatiles were removed in vacuo, the residue was taken up in dichloromethane and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (EtOAc:MeOH=9:1) afforded 0.48 g (64%) N-ethyl-5-thiophen-3-yl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J=7.3, 3H), 2.44 (s, 3H), 2.84 (ddd, J=18.1, 10.4, 1.5 Hz, 1H), 3.23-3.51 (m, 3H), 5.57 (t, J=10.4 Hz, 1H), 6.87 (br.s., 1H), 7.00 (d, J=4.8, 1H), 7.13 (d, J=3.0, 1H), 7.24 (dd, J=4.8, 3.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:25][C:26](=[O:28])[CH3:27])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH2:25][C:26]([CH3:27])=[O:28])[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)COS(C)(=O)=O
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)COc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (5 g, 28 mmol) in DMF (50 ml), potassium carbonate (7.7 g, 56 mmol) was added and the mixture was stirred for 30 min at 30° C. Thereafter, 2-oxopropyl methanesulfonate (4.7 g 30 mmol) was added drop wise and the reaction mixture was heated at 60° C. for 16 h. After completion, the crude was diluted with ethyl acetate (200 ml) and washed with water (3×500 ml). The organic layer was washed with brine, dried over sodium sulphate and evaporated under reduced pressure to get the crude which was then purified by column chromatography with silica gel (100-200 mesh) eluted with 10-25% ethyl acetate in hexane as eluent to get compound 1-{[3-(4-fluorophenyl)-1H-pyrazol-5-yl]oxy}acetone (2.5 g, yield 38%). MS (ESI): 231.0 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>O1CCOCC1.O>[C:3]([C:2]([NH:1][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])([CH3:7])[CH3:6])([OH:5])=[O:4]
Reactant: CC(C)(N)C(=O)O
Reactant: O=S1(=O)CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(NCCCS(=O)(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (5° C.) mixture of 2-aminoisobutyric acid (2.0 g, 19.4 mmol), NaOH (776 mg, 19.4 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added via syringe pump (over a 4-hour period), a solution 1,3-propane sultone (2.02 g, 16.2 mmol) in 1,4-dioxane (total: 4 mL). The solution was stirred at room temperature for 2 hours before it was allowed to warm up to room temperature. The reaction mixture was stirred under these conditions overnight. The solvent was evaporated under reduced pressure. The resultant solid material was recrystallized from 5% water/EtOH. The resulting solid was dissolved in water; and the aqueous solution was passed through an ion exchange column (Dowex 50WX 8, 100 g, solvent: water). The solvent was evaporated under reduced pressure. The product was lyophilized to afford Compound DI (880 mg, 28%). 1H NMR (D2O, 500 MHz) 8 ppm 3.00 (t, 2H, J=7.6 Hz), 2.91 (t, 2H, J=7.3 Hz), 2.01 (m, 2H), 1.34 (s, 6H). 13C NMR (D2O, 125 MHz) 8 ppm 176.93, 63.89, 48.13, 42.04, 22.15, 21.86. ES-MS 224 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:18])=[CH:20][CH:21]=2)(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: Nc1ccncc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3ccncc3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 4-aminopyridine (24 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-70% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(pyridin-4-yl)benzamide as an off white solid. Yield: 67 mg (65%). 1H-NMR: 10.82 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H), 7.78 (d, J=6.0 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 3.75 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([S:22](Cl)(=[O:24])=[O:23])[N:21]=[C:14]2[N:13]=1>CCCCCC.C1COCC1>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([S:22]([NH:4][C:3]3[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=3[Cl:10])(=[O:23])=[O:24])[N:21]=[C:14]2[N:13]=1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cc(Cl)cc3Cl)nc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
A solution (10.7 ml, 17.1 mmol) of 1.60M N-butyl-lithium in hexane was added to a solution of 3.20 g (16.3 mmol) of 2,4,6-trichloroaniline in 20 ml of dry THF cooled to -78° C. The resultant solution was then allowed to warm to room temperature. This solution was added to a solution of 2.00 g (8.11 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride in 30 ml of dry THF cooled to --10° C. The temperature of the reaction mixture was maintained between -13° C. and -9° C. during to course of the addition. After the addition was complete, the reaction mixture was stirred for 30 minutes and warmed to room temperature. After 1 hour at room temperature, THF was removed from the reaction mixture by evaporation. The residue was triturated with H2O and filtered. The filtrate was treated with charcoal and filtered through celite. The filtrate was washed with Et2O, and the aqueous phase was separated and acidified with 3N HCl to precipitate a solid. The solid was collected by filtration, washed with water and dried in vacuo to yield 0.70 g (21%) of the desired product as a tan solid, m.p. >200° C. (decomp.) 1H NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][I:34])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: II
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc2cc(CI)c(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (2.0 g, 10 mmol) in DCM (200 mL) were added triphenylphosphine (2.6 g, 10 mmol), iodine (2.6 g, 10 mmol) and imidazole (0.7 g, 10 mmol) and the reaction mixture was stirred for 2 h at r.t. The mixture was washed with water (50 mL) and the organic layer was separated, dried and concentrated in vacuo. Purification by column chromatography (SiO2, 50% Et2O in heptane) gave the title compound as a brown solid (2.2 g, 72%). δH (CDCl3) 8.17 (s, 1H), 7.62 (d, J 9 Hz, 1H), 7.55 (d, J 9 Hz, 1H), 7.45 (t, J 9 Hz, 1H), 4.68 (s, 2H), 2.75 (s, 3H). LCMS (ES+) 318.0, 320.0 (M+H)+, RT 4.53 minutes (Method 3).