Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].Cl[CH2:14][CH2:15][CH2:16]Cl>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]1
Reactant: ClCCCCl
Reactant: N#CCc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2F)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
Slowly add NaH (922 mg, 23.0 mmol) to a solution of (2-fluorophenyl)-acetonitrile (1.27 mL, 9.95 mmol) in DMSO (40.0 mL). Stir the mixture at RT for 30 mins then add via cannula a solution of 1,3-dichloropropane (0.95 mL, 10.0 mmol) in DMSO (20 mL). After addition is complete stir at 75° C. for 5 h. Pour mixture over ice (60 g) and extract with Et2O (3×50 mL). Combine the organic solutions and wash with brine (50 mL), dry filter and concentrate. Purify the material by flash chromatography (using a linear gradient of 100% hexanes to 35% EtOAc/hexanes) to give the title compound (1.4 g, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.32 (m, 1H), 7.25 (dt, 1H, J=1.9, 8.0), 7.16 (dt, 1H, J=0.9, 7.5), 7.09 (ddd, 1H, J=1.2, 8.1, 10.7), 2.86 (m, 2H), 2.69 (m, 2H), 2.50 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH:20]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH:20]=[CH2:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile (0.113 g, 0.358 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.099 g, 0.358 mmol), and DIEA (0.125 mL, 0.715 mmol) were combined in THF (4 mL) and stirred at 25° C. overnight. Additional 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.049 g, 0.179 mmol), EDC (0.069 g, 0.358 mmol) and THF (4.00 mL) were added to the reaction mixture and stirred at 50° C. overnight. The reaction mixture was concentrated to dryness and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 70% EtOAc/hexanes to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.088 g, 0.153 mmol, 42.7% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (t, J=5.81 Hz, 1H), 8.00 (s, 1H), 7.36-7.52 (m, 3H), 7.20 (s, 1H), 7.17 (s, 1H), 5.86-6.01 (m, 1H), 5.51 (s, 2H), 5.10 (d, J=5.49 Hz, 1H), 5.07 (s, 1H), 4.50 (d, J=5.77 Hz, 2H), 3.40 (m, 4H), 0.77 (t, J=8.10 Hz, 2H), −0.07 (s, 9 H). LC-MS (ES−) m/z 573.22, 575.17 [M−1]. LC-MS (ES+) m/z 575.15, 577.16 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])[NH2:15])=[O:11].C(N(CC)[C:25](Cl)=[S:26])C.ClC1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([N:15]=[C:25]=[S:26])[CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])=[O:11]
Reactant: COc1c(Cl)cc(N)cc1C(=O)Nc1c(C)cccc1C
Reactant: CCN(CC)C(=S)Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Solvent: O
Product: COc1c(Cl)cc(N=C=S)cc1C(=O)Nc1c(C)cccc1C
Yield: 46 %

Procedure:
A mixture of 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-5-chloroaniline (650 mg), diethylthiocarbamoyl chloride (360 mg) and chlorobenzene (6 ml) is refluxed for 30 minutes. The reaction mixture is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over Glauber's salt and concentrated to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride. The eluted fractions are collected and the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-5-chlorophenyl isothiocyanate (340 mg) as crystals melting at 191°-192.5° C.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The title acid of Step 8 (5.2 g, 30 mmol) was dissolved in dimethylformamide (25 mL) and cooled to 0° C. To this potassium carbonate (5.7 g, 41.48 mmol) was added followed by benzyl bromide (5.7 g, 29.7 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 3 times of water, brine. The solution was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 90:10 heptane:ethyl acetate to give the pure title compound as yellow oil (4.5 g, 60% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C17H16O2 : C, 80.93; H, 6.39. Found: C, 80.69; H, 6.47.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CN(C)C=O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].[OH-].[Na+]>O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 110 °C
Reaction time: 44 h
Yield: 79.3 %

Procedure:
Sodium phenoxide trihydrate (7.50 g, 44.1 mmol) was dried under vacuum at 65° C. for 18 h at 0.6 mm Hg to yield 5.08 g of sodium phenoxide. Under a nitrogen atmosphere, 3,5-dibromopyridine (4.00 g, 16.9 mmol) and anhydrous N,N-dimethylformamide (40 mL) were added to the sodium phenoxide (5.08 g, 43.8 mmol). The resulting mixture was stirred at 110° C. for 44 h. After cooling to ambient temperature, water (75 mL) was added, and the pH was adjusted to 13.0 using 30% NaOH solution. The solution was extracted with diethyl ether (4×60 mL). The combined ether extracts were washed with saturated NaCl solution (50 mL), dried (NaSO4), filtered and concentrated by rotary evaporation to a brown oil (4.0 g). The oil was vacuum distilled, collecting a forerun (317 mg), bp 48°-65° C. at 0.05 mm Hg. Further distillation afforded 3.35 g (79.8%) of 3-bromo-5-phenoxypyridine as a pale-yellow oil, bp 75°-112° C. at 0.05 mm Hg (lit. bp 110°-115° C. at 1.7 mm Hg, see K. Fujikawa, et al. Agr. Biol. Chem. 34: 68 (1970).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:14](Cl)(=[O:23])[C:15]1[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1ccccc1C(=O)Cl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccccc1OC

Procedure:
Acylation of 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran with 9.9 g. (0.058 mol.) of o-anisoyl chloride according to the procedure described in Example 10 gave 2-n-butyl-3-(2'-methoxybenzoyl)benzofuran which was demethylated with pyridine hydrochloride as previously described to give 2-n-butyl-3-(2'-hydroxybenzoyl)benzofuran.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[S:9][C:10]([Br:29])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[OH:18])[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccsc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl) carbamic acid t-butyl ester (the compound of Preparation Example 96) (6 g) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (2.6 g) in small amounts on an ice bath. After stirring at room temperature for 1 hour, water was added, the solution was extracted with ethyl acetate. After the organic layer was washed with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and was dried with anhydrous magnesium sulfate. The extract was purified by passing through a column of NH silica gel, and the title compound (6.6 g) was obtained as a colorless candy-like substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:11]=2[N+:22]([O-])=O)=[CH:4][C:3]=1[NH:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:30][CH:29]=1.C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>[Fe].C(O)C>[NH2:22][C:11]1[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:26][C:27](=[O:40])[C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:32][CH:33]=2)[CH:4]=1)=[O:25]
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3[N+](=O)[O-])ccc2C)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3N)ccc2C)cc1
Temperature: 95 °C
Yield: 72.2 %

Procedure:
A mixture of N-[2-methyl-5-(3-morpholino-2-nitrobenzamido)phenyl]-4-diethylaminomethylbenzamide (1.21 g), iron powder (1.24 g), glacial acetic acid (0.44 ml), water (2.2 ml) and ethanol (22.2 ml) was stirred and heated to 95° C. for 9 hours. The resultant mixture was cooled to ambient temperature and basified to pH9 by the addition of a saturated aqueous sodium bicarbonate solution. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. There was thus obtained the title compound as a solid (0.826 g); Mass Spectrum: M+H+ 516.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10]C2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(Cl)c(Nc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 56.6 %

Procedure:
To a stirred solution of 5-acetyl-2-chloro-phenylaniline (which was obtained in Example 22) (7.40 g, 43.5 mmol) in CH2Cl2 (200 mL) and pyridine (40 mL) at 0˜5° C. was added dropwise methanesulfonyl chloride (5.0 g, 43.6 mmol) in 50 mL of CH2Cl2. After 1 hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature for another hour. The solvents were removed and the residue was dissolved in CH2Cl2 (500 mL). The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (6.1 g, 57%); 1H NMR (300 MHz, DMSO-d6) δ 2.58(s, 3 H), 3.08(s, 3 H), 7.69(d, J=8.3 Hz, 1 H), 7.83(dd, J=8.3, 2.1 Hz, 1 H), 7.94(d, J=2.1 Hz, 1 H), 9.69(s, 1 H); MS (ES) m/z: 245.9 ((M−H)−, 100%); HRMS Calcd. for C9H11ClNO3S(MH+): 248.0148. Found: 248.0135.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]1([O-])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2ncccc21
Product: Clc1ccnc2cccnc12
Temperature: 100 °C
Yield: 36 %

Procedure:
POCl3 (8.5 ml) was added to [1,5]naphthyridine 1-oxide 483 (0.85 g, 5.81 mmol) at 0° C. and the mixture was heated at 100° C. for 6 h. After cooling, the mixture was concentrated in vacuo, neutralized with NaHCO3 solution and the aqueous phase was extracted with EtOAc (40 ml). The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (88:12) as the eluent to give the title compound (0.35 g, 36%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:33]([N:35](CC)[CH2:36]C)C.CNC.O1CCCC1>C(Cl)Cl>[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:35]([CH3:36])[CH3:33])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Under ice-cooling, 1 g (9 mmol) of methanesulfonyl chloride was added dropwise to a solution of 3 g (8 mmol) of 1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 2.46 g (24 mmol) of triethylamine in methylene chloride. After the mixture was stirred at room temperature for 1 hour, 20 ml of 2N dimethylamine-tetrahydrofuran solution was added thereto, and the mixture was stirred overnight. The reaction mixture was distilled off under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 700 mg (22%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCOCC1CO1
Product: CCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.1 %

Procedure:
Using the method of Example 5, supra, 1-hexyl glycidyl ether (175 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 95 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 216 (M-121), 163 (11), 121 (22), 114 (14); 1H-NMR (CDCl3) δ 7.05 (2H, d, J=8.7), 6.79 (2H, d, J=8.7), 3.77 (1H, m), 3.75 (3H, s), 3.41 (4H, m), 2.97 (2H, broad), 2.79 (1H, dd, J=11.7 and 4.1), 2.64 (3H, m), 1.52 (2H, m), 1.26 (6H, m), 1.04 (3H, s), 1.03 (3H, s), 0.85 (3H, t, J=6.7); 13C-NMR (CDCl3) δ 158.1, 131.3, 129.9, 113.4, 73.4, 71.7, 68.9, 55.1, 53.6, 46.3, 44.6, 31.6, 29.5, 26.5, 26.4, 25.7, 22.6, 14.0; FT-IR, cm-1 3405 (broad), 1611, 1512, 1245, 1116, 824.
Reaction SMILES: BrC1[CH:3]=[C:4]([CH:29]=[CH:30]C=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C([O:48]C)C(OC)=C(OC)C=2)=NC=1)C.O1C=CC(C(O)=O)=C1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][O:48][CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccoc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc(OC)c1OC
Yield: 86 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 3-furoic acid (95 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-3-furamide (226 mg, 86%) as a yellow solid. MS m/z 399 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH2:5]1.[CH3:43]N(C)C=O.CI>O>[CH3:43][O:3][CH:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([NH2:14])[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH2:5]1
Reactant: CN(C)C=O
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1c(C)cnc(CN2N=C3CC(OC)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Sodium hydride (6.7 mg) was added to a mixture of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (40 mg) and dehydrated N,N-dimethylformamide (1 mL), and then the mixture was stirred at room temperature for one hour. Methyl iodide (6.5 μL) was added to the reaction mixture, followed by stirring for 1.5 hours. Then, water (20 mL) was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (4.8 mg, 18%) as a solid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.O[C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[C:1]1([CH:7]=[CH:8][C:9]([O:11][C:17]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: O=C(O)C=Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(C(=O)O)c1OC(=O)C=Cc1ccccc1
Yield: 81.8 %

Procedure:
Using the method of example 4, 14.815 g(0.1 moles) of 3-phenyl-2-propenoic acid and 20.82 g of SOCl2 (0.175 moles) followed by 15.24 g of 2-hydroxy-3-methylbenzoic acid (0.1 moles) give 23.1 g of 2-(3-phenyl-2-propenoyloxy)-3-methylbenzoic acid (yield 81.8%), m.p. 141°-141.5° C.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:17](Cl)Cl>OS(O)(=O)=O>[CH3:1][C:2]1([C:14]2[CH:15]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClCCl
Reactant: Oc1ccc(Br)cc1
Reactant: CC1(O)CCCCC1
Agent: O=S(=O)(O)O
Product: COc1ccc(Br)cc1C1(C)CCCCC1
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 1-methylcyclohexanol (100.00 g, 0.876 mol) and 4-bromophenol (101.01 g, 0.584 mol) in CH2Cl2 (1.0 L) and H2SO4 (44 mL) was heated to reflux for 4 days. The mixture was cooled to RT. The reaction was poured in a separatory funnel and washed with water, 0.5 N NaHCO3 (till neutralized), brine and dried (MgSO4). The mixture was filtered, evaporated and the residue was purified on silica gel (eluant: hexane: CH2Cl2, 4:1) to give a total amount of 2-(1-methylcyclohexyl)-4-bromoanisole as an oil (29.70 g, 13%). 1H NMR (300 MHz, CDCl3): δ 1.30 (s, 3H), 1.30–1.70 (m, 8 H), 2.00–2.15 (m, 2H), 4.87 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 7.15 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]2\[CH2:14][N:15]([CH:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:16][CH2:17][C@H:18]\2[SH:19])=[N:8]1)([OH:4])=[O:3].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[ClH:1].[C:39]([S:19][C@@H:18]1[CH2:17][CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[CH2:14]/[C:13]/1=[CH:12]\[C:9]1[CH:10]=[CH:11][N:7]([CH2:6][CH2:5][C:2]([OH:4])=[O:3])[N:8]=1)(=[O:41])[CH3:40]
Reactant: O=C(O)CCn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CC[C@H]2S)n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CCC(=O)O)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (4R)-(E)-3-{[1-(2-carboxyethyl)-1H-pyrazol-3-yl]methylidene}-1-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (249.4 mg) in dichloromethane (12 ml) were added pyridine (0.24 ml) and acetic anhydride (0.24 ml) at 0° C. After the mixture was stirred at room temperature for 2.5 hours, solvents were removed under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane and methanol (99:1 to 93:7) as eluents to afford the free base of the title compound (75.5 mg), which was treated in acetonitrile (2 ml) with a 4N hydrogen chloride dioxane solution (120 μl). The solvent and excess hydrogen chloride were removed under reduced pressure to afford the title compound (79.4 mg, yield: 29%) as a pale yellow amorphous solid.