Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[CH:4]=[N:3]1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC>CC(N(C)C)=O>[C:34]([O:33][C:32]([NH:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1c(C)nc(S(C)(=O)=O)nc1-c1cnn(C)c1C
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1C

Procedure:
A solution of ethyl 4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.07 g, 0.207 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.089 g, 0.414 mmol) and Et3N (0.115 mL, 0.827 mmol) in DMA (3 mL) was heated in a sealed tube at 90° C. for 8 h. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate, which was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound. [M+H] calc'd for C24H36N6O4, 473. found, 473.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:32]([CH3:43])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCCl>[CH3:43][C:32]1[CH:31]=[C:30]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][CH:11]=[C:12]([C:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=2)[CH:13]=4)[CH:35]=[CH:34][C:33]=1[CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)ccc1CN1CCOCC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCNCC5)ccc4c3c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(8-carbamoyl-6-(3-methyl-4-(morpholinomethyl)phenyl)-9H-carbazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate 484 (3 mg, 5.17 μmol) was mixed with TFA (0.2 mL, 2.60 mmol) in 1,2-Dichloroethane (0.4 mL). The mixture was stirred at r.t. for 1 hr. The mixture was concentrated to give the titled product as TFA salt. MS (ESI) m/z 481.07 (M+H)+. 1H NMR (MeOD-d4) δ ppm 8.60 (d, 1H, J=1.8), 8.27 (d, 1H, J=1.8), 8.21 (d, 1H, J=8.2), 7.87 (s, 1H), 7.82 (dd, 1H, J=7.9, 1.5), 7.75 (d, 1H, J=1.3), 7.63 (d, 1H, J=7.9), 7.43 (dd, 1H, J=8.2, 1.5), 6.31 (bs, 1H), 4.51 (s, 2H), 4.1-3.85 (m, 6H), 3.56 (t, 2H, J=6.1), 3.47-3.2 (m, 4H), 2.98 (bs, 2H), 2.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[CH2:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31]Cl)[CH3:21].C(N(CC)CC)C.[I-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:31][C:23]3[N:22]([CH2:20][CH3:21])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:7]=1
Reactant: CCn1c(CCl)nc2ccccc21
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCn1c(CNc2ccc(S(=O)(=O)Nc3nc(C)cc(C)n3)cc2)nc2ccccc21

Procedure:
32.4 mg (0,12 mmol) sulfamethazine and 36 mg (0.18 mmol) 1-ethyl-2-chloromethylbenzimidazole were dissolved in 4 ml methanol. 64 μl (0.44 mmol) triethylamine and catalytic amount of sodium iodide were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to provide white crystals of the title compound, 10 mg (20%). 1H NMR (DMSO-d6, 500 MHz): 7.68 (2H, m), 7.60 (1H, m), 7.52 (1H, m), 7.22 (1H, m), 7.17 (1H, m), 7.00 (1H, br, s), 6.78 (3H, m), 6.60 (1H, br, s), 4.60 (2H, m), 4.30 (2H, q, 7.2 Hz), 2.18 (6H, s), 1.28 (3H, t, 7.2 Hz); MS (ESI+): m/z 437 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH:15](=O)[CH:16]([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:15][CH:16]([CH3:18])[CH2:17][NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CN[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl (3S)-3-aminopiperidine-1-carboxylate (5.0 g), isobutyraldehyde (2.66 ml) and acetic acid (1.72 ml) were dissolved in methanol (100 ml), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added sodium triacetoxyborohydride (13.2 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was basified with aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A part of the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object compound (3.04 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])O[C:3]=1[C:17]([OH:19])=[O:18].[CH2:20]([NH2:23])[CH2:21][CH3:22].Cl>CCO.O.S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:23]([CH2:20][CH2:21][CH3:22])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: CCCN
Reactant: Cc1c(C(=O)O)oc(=O)c2cc(C(F)(F)F)ccc12
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCCn1c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of 350 mg (1.3 mmol) 4-methyl-1-oxo-7-(trifluoromethyl)-1H-isochromene-3-carboxylic acid in EtOH (15 ml) was cooled to 0° C. and treated dropwise with a solution of 1.1 ml (12.9 mmol) n-propylamine in EtOH (2 ml) at this temperature. The RS was then stirred at RT for 2 h followed by concentration in vacuo. The residue obtained was diluted with water and acidified with 2M hydrochloric acid to pH˜2 while cooling (ice-water-bath). Afterwards the RS was extracted with a MeOH/EtOAc mixture (1:9 v/v, 100 ml). The organic layer was washed with water (30 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo. This residue obtained was diluted with EtOH (15 ml) and 1 ml conc. sulfuric acid was added slowly at 0° C. The RS was the heated at 80° C. for 2 h. After cooling to RT, the RS was concentrated in vacuo. The residue obtained was diluted with water and extracted with a MeOH/EtOAc mixture (1:9 v/v, 100 ml). The organic layer was washed with water (30 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo to give 360 mg (1.1 mmo, 89%) 4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[NH:28][CH:27]=[CH:26]2>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:26]2[C:25]3[C:29](=[C:30]([CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=[C:23]([F:22])[CH:24]=3)[NH:28][CH:27]=2)=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
96 mg (0.44 mmol) of the compound from Example 156A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 3 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 162 mg (86% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH:14][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(N)ccc21
Solvent: c1ccncc1
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
The material from step 3 of Example 24 (1 g, 0.0027 mol) was combined with methane sulfonyl chloride (345 mg, 0.003 mol) in 10 mL pyridine. The mixture was stirred at room temperature, under argon, for 3 hours. The reaction was then concentrated in vacuo. The resulting solid was washed with water and diethyl ether, and was then air dried to give the desired as a tan solid. 950 mg. (MW=443.46, 79% yield). LC/MS m/z=444 (m+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:28]=1)[C:23](Cl)=[O:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:28]=1)[C:23]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:24]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cc(F)cc(N2CCOCC2)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(F)cc(N2CCOCC2)c1
Yield: 65 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-fluoro-5-morpholinobenzoyl chloride to afford the title compound as a light brown solid (38 mg, 65%). 1H-NMR (δ, ppm, DMSO-d6): 3.22 (m, 4H, CH2N), 3.74 (m, 4H, CH2O), 6.48 (d, 1H, HPy,5, J=6.0 Hz), 6.91 (d, 1H, Harom, J=8.0 Hz), 6.98 (d, 1H, Harom, J=10.5 Hz), 7.11 (d, 1H, Harom, J=9.0 Hz), 7.26 (s, 1H, Harom,Ph′), 7.42 (ps t, 1H, Harom, J=8.5 Hz), 7.61-7.64 (m, 2H, Harom), 7.81 (d, 2H, HPy,6, J=6.0 Hz), 10.28 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 47.76, 65.85, 104.17, 104.41, 106.58, 109.73, 110.86, 113.75, 114.57, 116.35, 130.16, 137.05, 140.61, 141.35, 144.60, 147.15, 152.65, 154.21, 154.73, 162.98, 164.81. HRMS (EI): m/z [M+H] calcd for C23H21FN5O4: 450.1578; found: 450.1571.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)c(F)c1
Yield: 86.2 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylamine (0.25 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropyl-3-fluorobenzenesulfonamide (0.37 g, 86%) was provided after purification. HRMS: calcd for C9H9BrFNO2S−H+, 291.94486; found (ESI, [M−H]−), 291.9462. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[CH:10][N:9]=1>O>[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:11]=[CH:10][N:9]=1
Reactant: COc1c(Cl)ncnc1Cl
Reactant: C1CNCCN1
Solvent: O
Product: COc1c(Cl)ncnc1N1CCNCC1
Yield: 103.9 %

Procedure:
Piperazine (6.00 g, 70 mmol, 6.25 eq) is dissolved in water (30 ml), and to this solution is added 4,6-dichloro-5-methoxypyrimidine (2.00 g, 11.2 mmol, 1.0 eq). The mixture is stirred vigorously at room temperature for 2.0 h, during which 4,6-dichloro-5-methoxypyrimidine is gradually dissolved. The aqueous phase is extracted with CH2Cl2 (25 ml*2). The extracted liquids are combined, dried over anhydrous sodium sulfate and filtered by vacuum filtration, and concentrated to give a light yellow oily crude product (2.66 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H-].[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:4])[C:2]([F:14])([F:15])[F:1]
Reactant: O=C(NCCc1ccccc1)C(F)(F)F
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Yield: 63.1 %

Procedure:
2,2,2-Trifluoro-N-(2-phenylethyl)acetamide (21.7 g., 0.1 mole) in dry dimethyformamide (100 ml) was added dropwise with stirring and under nitrogen to sodium hydride (2.4 g ., 0.1 mole, ether washed) in dry dimethylformamide (150 ml). Stirring was continued until a clear solution was obtained and 1,6-dibromohexane (73.2 g., 0.3 moles) was added. The solution was heated at 60°. for 3 hr then poured into water and extracted with ether. The extracts were washed well with water dried and evaporated. Excess dibromohexane was recovered by distillation (b.p. 60°-70°/0.1 mmHg) and the residue was separated on a silica gel column using ether-light petroleum (1:2) as eluant. The major fraction was evaporated to give the title compound as a pale yellow oil (24 g). A sample was distilled to give a colourless viscous liquid, b.p. 146°-152°/0.05 mmHg, (with slight decomposition)
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([SH:25])[CH2:23][CH3:24]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[C:2]([S:25][CH2:22][CH2:23][CH3:24])=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: CCCS
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Yield: 95.2 %

Procedure:
To a mixture of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (1.50 g, 6.26 mmol), potassium carbonate (1.72 g, 12.5 mmol), and DMF (31 mL) was added 1-propanethiol (0.620 mL, 6.86 mmol). The reaction mixture was heated at 90° C. for 16 h, then allowed to cool to 23° C. and poured into ice/brine (300 mL). The resulting yellow precipitate was collected to yield the titled compound (1.67 g, 95%). MS (ESI/CI): mass calcd. for C10H11F3N2O2S, 280.1; m/z found, 281.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.41 (s, 1H), 6.58 (s, 1H), 6.36 (br s, 2H), 2.97 (t, J=7.3 Hz, 2H), 1.87-1.72 (m, 2H), 1.10 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cu][C:28]#[N:29]>CN(C)C=O>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[C:5]2[C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:2]([C:28]#[N:29])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: COc1ccc(Cn2c(=O)[nH]c3cc(Br)cc(C(F)(F)F)c32)c(OC)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)[nH]c3cc(C#N)cc(C(F)(F)F)c32)c(OC)c1
Yield: 112.8 %

Procedure:
To a solution of 5-bromo-1-(2,4-dimethoxybenzyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (1090.7 mg) and copper(I) cyanide (793.8 mg) in N,N-dimethylformamide (100 ml) was heated at reflux for 34 hours. The reaction mixture was concentrated in vacuo. To the resultant residue were added saturated aqueous sodium bicarbonate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1076.5 mg, quantitative yield). HPLC retention time: 30.54 min (condition 2).
Reaction SMILES: Cl[CH2:2][C:3](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>C1(C)C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[CH2:2][P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23]
Reactant: COP(OC)OC
Reactant: NC(=O)NN=C(CCl)COc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: COP(=O)(CC(COc1cccc(C(F)(F)F)c1)=NNC(N)=O)OC
Temperature: 0 °C
Yield: 58.3 %

Procedure:
A mixture of 1-chloro-3-[3-(trifluoromethyl)phenoxy]-2-propanone semicarbazone (36.5 g, 0.12 mol), P(OMe)3 (18.6 g, 0.15 mol) and toluene (100 mL) was refluxed for 3 h and cooled to 0° C. The precipitate was filtered off, washed on the filter with cold toluene and recrystallized from toluene to afford 26.8 g (59%) of dimethyl 3-[3-(trifluoromethyl)phenoxy]-2-semicarbazonopropylphosphonate as about 10:1 mixture of two isomers: mp 132–133° C. 1H NMR (CDCl3) (major isomer) δ: 9.40 (s, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 5.80 (br.s, 2H), 4.68 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.11 (d, J=12 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8](Cl)=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:8](=[N:9][OH:10])[C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: ON=C(Cl)c1ncccc1F
Reactant: Nc1cccc(Cl)c1
Solvent: C1COCCO1
Product: ON=C(Nc1cccc(Cl)c1)c1ncccc1F
Reaction time: 12 h

Procedure:
A solution of 3-fluoro-N-hydroxypicolinimidoyl chloride 2 (1.35 g, 7.73 mmol) in 1,4-dioxane (15 mL) was added via cannula to a solution of 3-chloroaniline (4.5 mL, 43 mmol) in 1,4-dioxane (10 mL). After 12 h at rt, the r×n was added to EtOAc: H2CO (1:1). The organic layer was separated and washed with brine (30 mL), dried (MgSO4), filtered and concentrated to afford N-(3-chlorophenyl)-3-fluoro-N′-hydroxypicolinimidamide was taken through to the next step.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14](C(O)=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)CCC>[CH2:7]([O:8][C:9]([NH:11][CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:16][CH2:15]1)=[O:10])[CH2:1][CH2:2][CH3:3]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCCCO
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In a manner similar to that described in Preparation 6, 1-[(phenylmethoxy)carbonyl]piperidine-4-carboxylic acid and 1-butanol are reacted to give the title compound.
Reaction SMILES: [CH:1]1([N:8]=[C:9]=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:20]=[C:19](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:1]1([NH:8][C:9](=[O:10])[NH:8][CH2:1][CH2:2][CH2:3][C:19]2[CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:21]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[N:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Reactant: O=C=NC1CCCCCC1
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)NC3CCCCCC3)cc2-c2ccccc2)cc1
Yield: 91 %

Procedure:
The titled compound was prepared in 91% yield from cycloheptyl isocyanate using the procedure detailed for compound 7. mp 164.2-169.8° C. 1H NMR (300 MHz, DMSO-d6): δ 7.79 (d, J=9 Hz, 2H), 7.47-7.36 (m, 7H), 7.29-7.22 (m, 2H), 6.55 (s, 1H), 5.82-5.70 (m, 2H), 3.63-3.49 (m, 1H), 3.13-3.02 (m, 2H), 2.63 (t, J=8 Hz, 2H), 1.84-1.66 (m, 4H), 1.60-1.27 (m, 10H). MS (ESI) m/z: 496.24 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([NH:11][C:12](=[NH:21])OC1C=CC=C(C)C=1)#[N:10].[Cl-].[Na+]>C(O)(C)C>[C:9]([NH:11][C:12]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[NH:21])#[N:10]
Reactant: NCc1ccncc1
Reactant: Cc1cccc(OC(=N)NC#N)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#CNC(=N)NCc1ccncc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
4-Amino methyl pyridine (16.22 g) is added to a stirred suspension of N-cyano-O-(m-cresyl)pseudourea (27.51 g) in 200 ml of isopropanol. The mixture is heated to boiling and refluxed for five hours. The reaction mixture is filtered and the filtrate evaporated under reduced pressure. The residue is stirred in 250 ml of chloroform overnight, the solvent removed under reduced pressure, treated with 250 ml of diethyl ether, the ether decanted and the residual gum treated with 200 ml of 5% HCl and stirred at room temperature for one hour. The mixture is filtered, extracted twice with 200 ml portions of diethyl ether and cooled to about 5° C. The solution is treated carefully with a 50% aqueous sodium hydroxide solution to a pH of 9 and extracted twice with 250 ml portions of methylene chloride. The organic extracts are combined, dried, filtered and evaporated to dryness under reduced pressure leaving a small amount of colored liquid. The aqueous layer is saturated with sodium chloride and re-extracted. After drying, the extracts are evaporated under reduced pressure. The aqueous phase is concentrated under reduced pressure and diluted with ethanol. The precipitated salts are removed by filtration and the filtrate concentrated under reduced pressure. The residue is azeotroped with 150 ml of toluene. The residue is stirred with 250 ml of isopropanol, filtered and evaporated under reduced pressure. The residue is triturated with 250 ml of isopropanol and filtered. The filtrate is dried, filtered, and evaporated under reduced pressure. The residue is taken up in a methanol/ethyl acetate mixture and allowed to stand. After trituration, the mixture is stirred in water overnight, the precipitate then collected and dried in air. The off-white solid is recrystallized from water yielding 12.10 g of pale yellow crystals which are dried in vacuo (55° C.), MP 92°- 93° C. IR and elemental analysis indicate the desired guanidine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[OH:19].O>C(O)(C)(C)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([OH:19])[CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: CCc1ccc(C(O)CBr)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1

Procedure:
Into a solution of 22.6 g (0.181 mol) of 4-hydroxy benzaldehyde dissolved in 75 mL tertiary butanol, was added 38.5 g (0.278 mol) of potassium carbonate in 10 min. Reaction mixture was refluxed for 1 hr. and 15 g (0.06 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanol dissolved in 75 mL tertiary butanol was added slowly in one hr. Reaction mixture was refluxed further for 10 hr. and at 25° C. poured into excess of water. Product was extracted with toluene. Subsequent concentration under reduced pressure and purification gave the desired product. Yield of the product was 12.37 g (70%). m.p. 80° C.