Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1cc(O)ccc1NS(C)(=O)=O
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a mixture of 24.00 g (0.089 mol) of N-(2-methyl-4-hydroxyphenyl)methanesulfonamide, 9.00 g (0.089 mol) of triethylamine, and 150 ml of methylene chloride cooled to approximately 0° C. was added a solution of 9.32 g (0.089 mol) of methacryloyl chloride in 150 ml of methylene chloride and 50 ml of methylene chloride wash over approximately 20 minutes. The reaction mixture was then stirred for another 4 hours at reduced temperature, after which it was washed with 2 percent hydrochloric acid and twice with water. The organic phase was dried over magnesium sulfate, treated with decolorizing carbon, filtered and concentrated to an oil, which crystallized on cooling. The solid was recrystallized from 1:1 dichloroethane:hexane to give 14.7 g (61.3 percent of theory) of N-(2-methyl-4-methacryloyloxyphenyl)methanesulfonamide, m.p.=95° to 97° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13](C(F)(F)F)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:42])C(=O)C1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([Cl:42])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C1CN(Cc2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2ccc3c(Cl)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate (140 mg, 0.34 mmol) and NCS (90 mg, 0.68 mmol, 2.0 eq.) were dissolved in MeCN (5 mL). Then CF3COOH (12 mg, 0.1 mmol, 0.3 eq.) was added to the mixture at 0° C. The mixture was warmed to r.t. and stirred for 1 h. Then the pH of the solution was adjusted to 7 with saturated Na2CO3, concentrated and the mixture was extracted by EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE/EA (6/1) to give product methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)methyl)azetidine-3-carboxylate (65 mg, 43%) as a slight yellow oil. EDI-MS (M+1)+: 444.0. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.69-7.66 (m, 2H), 7.50-7.47 (m, 1H), 7.28-7.27 (m, 1H), 4.25-4.19 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.59-3.58 (m, 2H), 3.38-3.37 (m, 3H), 2.23-2.20 (m, 2H), 1.88-1.85 (m, 2H), 1.61-1.52 (m, 2H), 1.12-1.07 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[Na].[OH2:27]>>[N+:1]([CH:4]=[C:5]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH:6][CH2:7][CH2:8][S:9]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:27])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCSCc1nccs1
Reactant: O
Agent: [Na]
Product: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCS(=O)Cc1nccs1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Nitro-2,2-bis-[2-(2-thiazolylmethylthio)ethylamino]ethylene (4.5 g) was added to a stirred solution of an equivalent amount of sodium methaperiodate (2.3 g) in water (1600 ml), and the resulting solution was stirred at room temperature for 20 hours. Evaporation of the solvent and chromatographic purification of the residue on silica gel gave the title product as an oil. The structure of the product was confirmed by the 100 mHz n.m.r. spectrum in 2H6 -dimethylsulphoxide which showed the following resonances:
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Li]CCCC.[CH3:31][O:32][C:33](=[O:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O.O>C1COCC1>[CH3:31][O:32][C:33](=[O:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: COC(=O)CCCCC=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC=C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a stirred suspension of cyclopentyltriphenylphosphonium bromide (10.0 g, 23.8 mmol) in TMF (60 mL) was added dropwise n-BuLi (10.2 mL, 2.5 M solution in hexanes, 23.8 mmol) at 0° C. under N2. The resulting solution was stirred at this temperature for 30 min and cooled to −78 ° C. A solution of 6-oxo-hexanoic acid methyl ester (3.33 g, 23.1 mmol) in THF (6 mL) was added quickly. The resulting mixture was then allowed to warm to room temperature and stirred overnight. Water (30 mL) was added. The aqueous phase was extracted with hexane. The combined organic phases were washed with saturated aqueous NH4Cl and brine and dried. Concentration and purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate, 10:1) afforded 6-cyclopentylidene-hexanoic acid methyl ester (3.15 g, 70%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.20 (1H, m), 3.64 (3H, s), 2.29 (2H, m), 2.16 (4H, m), 1.96 (2H, m), 1.62 (6H, m), 1.35 (2H, m); 13C NMR (75 MHz, CDCl3) δ 174.26, 143.54, 119.65, 51.66, 34.29, 33.79, 29.44, 28.86, 26.69, 26.61, 24.91.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-bromothiophene-2-carboxylate (1.5 g, 6.38 mmol) in aqueous conc. H2SO4 (6 ml) cooled to 0° C., aqueous 65% HNO3 (2 ml) was added, and the reaction was left to warm to RT and stirred for 1 hour. The mixture was poured into ice-water and extracted with EtOAc (×3); the combined organic layers were dried over sodium sulfate and the solvent was removed affording ethyl 5-bromo-4-nitrothiophene-2-carboxylate (Int. 40) which was used without any additional purification (550 mg, 1.964 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Cl:30]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([Cl:30])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccc(F)cc2)c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c1O)c(Cl)c(-c1ccc(F)cc1)n2-c1ccc(F)cc1
Yield: 74.7 %

Procedure:
The mixture of 1,2-bis-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (80 mg, 0.203 mmol), N-chlorosuccinimide (NCS)(28 mg, 0.203 mmol) and BzOOBz (2.5 mg) in tetrachloromethane (6 mL) was refluxed overnight, then the solvents were removed, the residue was purified on column to give the desired title compound (65 mg); ESI MS (m/z): 429 (M+H+).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15]/[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17]\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.ClCCl>[ClH:32].[C:24]1(/[C:16](=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC/C(=C\c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOC/C(=C\c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The above ester (3.15 g, 8 mmol) was dissolved in absolute ethanol (25 ml) and 4N sodium hydroxide (4.0 ml) was added. After stirring at ambient temperature for 4.5 h the mixture was diluted with dichloromethane (400 ml), cooled to 0° C. and 4N hydrochloric acid (7.5 ml) was added. The mixture was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone, suspended in diethylether and stirred for 21 days to give an amorphous solid which was triturated 16 h with anhydrous diethylether. This afforded 2.1 g of the title compound as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[NH:20]([C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1)[NH2:21]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)C(F)(F)F
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1C(F)(F)C(F)(F)F
Yield: 95 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-pentafluoroethylpyrimidine-5-carboxylate (0.30 g, 0.99 mmol) and hydrazine (0.16 g, 5.0 mmol) in THF (20 mL) resulting in a 95% yield (0.28 g); 1H NMR (CDCl3) δ 8.86 (bs, 1H), 7.12 (bs, 1H), 4.37 (q, 2H), 1.72 (bs, 2H), 1.38 (t, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([O:21]CC3C=CC=CC=3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4].O>CO>[CH3:30][C:2](=[CH2:1])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)OCc1ccccc1)C2=O
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 15 (65 mg, 0.16 mmol) in methanol (2.5 ml) were added aq. NAOH (1.6 ml, 1N) and H2O (1.6 ml) and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated at reduced pressure, and the residue was partitioned between H2O (20 ml) and DCM (20 ml). The aqueous phase was acidified to pH=2 with aq HCl (10 ml, 0.1 N) and extracted with DCM (3×20 ml). The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated at reduced pressure to afford 18 (44 mg, 85%) as a white solid. HPLC [Column Novapack C18 (Waters), 3.9×150 mm, Φ=1 ml/min, λ=214 nm, eluent: ACN/0.05% TFA, (25/75)] Rt=6.38 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([CH2:27][NH:28][C:29]2[CH2:33][S:32][C:31](=[O:34])[N:30]=2)[CH2:26][CH2:25]1.CC(C)([O-])C.[K+]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][CH:24]3[CH2:25][CH2:26]3)=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCC2CC2)CS1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1N=C(NCC2CC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
1-[2,4-Bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (200 mg) and 4-[(cyclopropylmethyl)amino]-1,3-thiazol-2(5H)-one (100 mg) were suspended in ethanol (3 mL), potassium tert-butoxide (66.1 mg) was added, and the reaction mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (180 mg).
Reaction SMILES: [Li]CCCC.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH:21]1([CH2:26]I)[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)[CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: ICC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 1 L round bottom flask containing 250 mL of 9:1 THF/DMPU at −78 C are added under nitrogen 11 mL (78.6 mmol) anhydrous DIEA followed by rapid addition of 32 mL of 2.5 M n-BuLi in hexanes. After 10 min at −78° C. a solution of 15.4 g (74 mmol) of p-nitrophenylacetic acid, ethyl ester in 100 mL of 9:1 THF/DMPU is added dropwise over 30 min. A deep purple solution results, and the reaction mixture is stirred at −78° C. for 30 min and then cyclopentyl methyl iodide (17.6 g, 78 mmol) in 50 mL of 9:1 THF/DMPU is added. The reaction is stirred while warming slowly to RT overnight. The mixture is poured into 1 L of 1 N HCl and extracted twice with MTBE. The combined MTBE extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and reduced to an orange oil. Flash chromatography over silica eluting with 4:1 hexane/MTBE affords 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester as an orange oil: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.2 (t, 3H, J=7.2), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.74 (t, 1H, J=7.8), 4.1 (m, 2H), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8); LC/MS 290 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(O)C>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Clc1ncnc2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(CNc2ncnc3ccccc23)c1

Procedure:
A mixture of 1.65 g of 4-chloroquinazoline, 1.5 g of [3-(trifluoromethyl)phenyl]methyl amine, and 1.0 g of triethylamine in 50 ml of ethanol was refluxed for 6 hours. The mixture was then cooled, and washed with water. After removing solvents in vacuo the product was crystallized from a mixture of ethyl acetate and hexane. Yield: 1.0 g. M.P. 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([Br:21])C(=O)C1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH2:9][Br:21]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Yield: 23.6 %

Procedure:
A stirring solution of 3-chloro-4-acetyl-nitrobenzene (1.685 g, 8.44 mmol) (prepared as described in J. Med. Chem. 2005, 48, 6066) and paratoluenesulfonic acid (2.41 g, 12.66 mmol) in acetonitrile (100 mL) was treated with NBS (1.503 g, 8.44 mmol) and heated to 80° C. for 23 h. Another gram of NBS was added after 21 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in EtOAc and the organic layer was washed with water (2×), brine, and dried over MgSO4, filtered, and adsorbed on silica. Purification on silica by flash chromatography using a gradient of 0-40% EtOAc/hexane yielded 554 mg of the titled compound as a waxy solid (23% yield): 1H NMR (400 MHz, DMSO-d6) δ 4.95 (s, 2H), 8.09 (d, 1H), 8.35 (dd, 1H), 8.44 (d, 1H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO>[NH2:17][C:16]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[N:11]=[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])[CH:15]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 94.9 %

Procedure:
A cream suspension of 4-cyanophenylhydrazine hydrochloride (1.70 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.31 g, 10.5 mmol) in EtOH (25 mL) was stirred at reflux for 4 h, then at RT for 64 h, and again at reflux for 24 h. The solution was cooled to RT, concentrated in vacuo, and partitioned between water (50 mL) and EtOAc (75 mL). The organics were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange solid (2.28 g, 95%). LCMS (Method 3): Rt 3.45 min, m/z 241 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+].Cl>CCOC(C)=O>[ClH:1].[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([C:22]2[N:21]=[CH:20][NH:19][N:18]=2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nc[nH]n2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 195 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (350 mg, 1.44 mmol) followed by 1,2,4-triazole (Aldrich Chemical Company) (200 mg, 2.88 mmol) and solid Na2CO3 (610 mg, 5.76 mmol). The flask was purged with N2 and heated to 190-200° C. for 4 h. The reaction was allowed to cool to room temperature and the residue was dissolved in MeOH (25 mL). The remaining salts were filter off and the organic layer evaporated under reduced pressure. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes as eluant to give 180 mg (45% yield) of an off white solid. The free base (168 mg, 0.608 mmol) was dissolved in hot EtOAc (15 mL) and anhydrous ethereal HCl (0.61 mL, 1.0 M soln, 0.61 mmol) was added dropwise. A precipitate formed and the reaction was allowed to cool to room temperature and stirred for 1 h. The solid was filtered off and dried under vacuum at 60° C. overnight to give 182 mg (96% yield) of an off white solid. Mp: 264-265° C. 1H NMR (DMSO-d6; 400 MHz): d 2.77 (s, 3), 7.22 (s, 1), 7.57 (m, 3), 8.10 (d, 2, J=5.5), 8.6 (d, 1, J=3.4), 9.64 (d, 1, J=4.2), 11.87 (br m, 1). MS m/z: 277.0 (M+1); 275 (M−1).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC=CC=1.[S:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:7][C:6]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:24][CH:25]=2)=[C:3]([C:8]([O:10][CH3:11])=[O:9])[S:4][CH:5]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1scc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1scc(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
To a stirred suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (compound 7a, 9.0 g, 38.0 mmol) in ethanol: toluene (100:30 ml) in sealed tube, (4-sulfamoylphenyl)boronic acid (8.46 g, 42.0 mmol) and potassium carbonate (10.57 g, 76.0 mmol) were added under a nitrogen atmosphere at room temperature (about 25° C.). Nitrogen gas was purged to this suspension for further 15 minute at room temperature (about 25° C.) and tetrakis(triphenyl phosphine)palladium(0) (2.21 g, 1.9 mmol) was added at 25° C. and sealed tube was closed. The reaction mixture was stirred at 105° C. for 15 hr and the progress of the reaction was monitored by TLC. Reaction mixture was filtered and washed with ethyl acetate (2×100 ml). Organic layer was concentrated under reduced pressure to obtain crude product as semi-solid (11.2 g); which was purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (8.8 g, 70.70%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.C[OH:15]>N1C=CC=CC=1>[N:4]1[CH:3]=[CH:2][CH:1]=[C:13]2[C:12](=[O:15])[C:11]3[C:6]([C:5]=12)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CO
Reactant: c1ccc2c(c1)Cc1cccnc1-2
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ncccc21

Procedure:
See general oxidation method of Sprinzak, J. Am. Chem. Soc., 80 (1958) 5449. 4-Azafluorene (5.0 g, 30 mmol) was dissolved in 50 mL anhydrous pyridine containing in solution 2 mL Triton B solution (prepared by evaporating 5 mL of 40% Triton B in methanol (Aldrich Chemical, Inc.) and 5 mL pyridine with heat and reduced pressure followed by q.s. to 10 mL with pyridine). Then air was continuously bubbled through the solution with stirring. An addition of 2 mL Triton B solution was made twice more at two-hour intervals. After six hours the reaction mixture was evaporated to dryness. The residue was triturated in 30 mL water and extracted four times with ethyl acetate (total volume 200 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was chromatographed (silica gel and chloroform) to yield after evaporation of the solvent 4.5 g (83%) of (28). m.p. 132°-136° C. (reported 142° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][CH:18]=[O:20])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC=O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in a mixture of acetic anhydride (6 parts) and formic acid (6 parts) is stirred at 0° C. for 1 hour. The reaction mixture is concentrated in vacuum, diluted with ethyl acetate, washed with diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried, and concentrated in vacuum to give 2-(2-formamido-4-thiazolyl)malonic acid diethyl ester. Yield: 70%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[F:18][C:19](I)([F:24])[C:20]([F:23])([F:22])[F:21]>>[F:18][C:19]([F:24])([C:13]1[CH:14]=[C:8]([C:3]([F:15])([C:4]([F:7])([F:6])[F:5])[C:2]([F:16])([F:17])[F:1])[CH:9]=[CH:10][C:11]=1[NH2:12])[C:20]([F:23])([F:22])[F:21]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Reactant: FC(F)(F)C(F)(F)I
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)C(F)(F)F

Procedure:
According to the method of 1-1 of Example 1, a target compound was prepared from 4-(perfluoropropan-2-yl)aniline obtained in Example 2-1 and 1,1,2,2,2-pentafluoroethyliodide.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1cccnc1Cl
Solvent: Cc1ccccc1C
Product: O=C(O)c1cccnc1Nc1ccccc1F

Procedure:
50 g of 2-chloronicotinic acid and 31 ml of 2-fluoroaniline in 180 ml of xylene are refluxed for 5 hours. The precipitate is filtered off and washed with xylene and then with water to yield the desired compound.