Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19].C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][CH2:32][NH:2][C@H:3]1[C@H:4]([O:18][CH3:19])[CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:15](=[O:16])[NH2:17])=[CH:8][CH:7]=2)[C:12]1([CH3:14])[CH3:13])[CH3:28]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN[C@H]1[C@H](OC)Cc2ccc(C(N)=O)cc2C1(C)C
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of trans-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (0.25 g, 0.88 mmol) anhydrous ethanol (0.90 mL), triethylamine (0.14 mL, 1.32 mmol) and acrylic acid ethyl ester (0.14 mL, 1.0 mmol) were heated at 70° C. After 23 h, additional acrylic acid ethyl ester (0.04 mL, 0.3 mmol) was added and heating was continued. Five hours after the addition, the reaction was cooled to room temperature, combined with another run (0.36 mmol scale) and concentrated under vacuum. The title compound (0.61 g) was used without further purification. (m/z): [M+H]+ calcd for C19H28N2O4 349.21; found 349.0.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:22])[C:14]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:15].[N+:23]([O-])([OH:25])=[O:24]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:23]([O-:25])=[O:24])=[CH:9][C:8]=1[C:13](=[O:22])[C:14]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:15]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)C(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
To concentrated sulfuric acid (15.0 ml) at 5° C. is added 2′-chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol) followed by dropwise addition of concentrated nitric acid (90%, 0.740 ml, 0.0204 mol). After stirring 5 minutes, the mixture is poured onto ice and extracted with ethyl acetate. The organic layers are washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:23]([O:22][C:20]([C:18]1[O:19][C:15]([CH2:14][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[Cl:1])=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 24 h

Procedure:
Alternately, combine 2-chlorobenzimidazole (20 mmol) and sodium hydride (20 mmol) in dimethylformamide (30 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (20 mmol) and stir. After 1 day, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=2)[O:2]1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([O:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc2c1OCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3c2OCO3)cc1
Temperature: 60 °C

Procedure:
A solution of 2,3-methylenedioxyphenol (17.45g) and benzyl bromide (27.5 mL) in dimethylformamide (200 ml) was treated with potassium carbonate (35 g), and the mixture was heated at 60° C. overnight. After cooling and filtering, the mixture was evaporated. The residue was dissolved in ethyl acetate and washed with 1 M hydrochloric acid. The organic extract was dried, filtered and evaporated to afford 1-benzyloxy-2,3-methylenedioxybenzene, mp 62°-63° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:31])[C:13]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].O>CS(C)=O>[CH3:30][C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:13]3([C:12]([O:11][CH2:9][CH3:10])=[O:31])[CH2:4][CH:14]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:21]=2)[N:26]=1
Reactant: CCOC(=O)C=C(C(=O)OCC)c1ccc2nc(C)ccc2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1(C(=O)OCC)c1ccc2nc(C)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Sodium hydride (0.52 g) was added in small portions to a stirred suspension of trimethylsulfoxonium iodide (2.81 g) in DMSO (28 mL) at room temperature. After 0.5 h, the clear reaction mixture was cooled to 0° C. and a solution of diethyl-2-(2-methyl-6-quinolinyl)-2-butenedioate (2.0 g) in DMSO (14 mL) was quickly added and the stirring continued for 0.5 h after which time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulphate and evaporated under reduced pressure to give 2 g of the title product which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Nc2ccccc2Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A −78° C. solution of Example 1C (236 mg, 1.0 mmol) and 2-phenoxyaniline (370 mg, 2.0 mmol) in THF (10 mL) was treated with 1M lithium hexamethyldisilazide in THF (4 mL, 4.0 mmol), warmed to room temperature over 4 hours, diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 384 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:12][NH:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4]
Reactant: CCN1CCC[C@H]1CN
Reactant: OC[C@@H]1CCCN1
Agent: CC=O
Product: CNCCN1CCC[C@H]1CO

Procedure:
By using L-prolinol (500 mg) as a starting material, the title compound (0.22 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Si](C)(C)Cl)(C)(C)C.BrC1C=C(C=CC=1)CO.C([Li])CCC.[OH:39][CH2:40][C@@H:41]1[C@:49]2([CH3:50])[C@@:44]([OH:52])([CH2:45][C:46](=[O:51])[CH2:47][CH2:48]2)[CH2:43][CH2:42]1>C1COCC1.CCCCCC>[OH:39][CH2:40][C@@H:41]1[C@:49]2([CH3:50])[C@@:44]([OH:52])([CH2:45][C@:46]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:11]=3)([OH:51])[CH2:47][CH2:48]2)[CH2:43][CH2:42]1
Reactant: C[C@]12CCC(=O)C[C@@]1(O)CC[C@@H]2CO
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: OCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc([C@@]2(O)CC[C@]3(C)[C@@H](CO)CC[C@]3(O)C2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a suspension of 60.0 g of 3-(tert-butyldimethylsilyloxymethyl)bromobenzene (prepared from tert-butyldimethylchlorosilane and 3-bromobenzyl alcohol according to the procedure described by Kendall P. M. et al., J. Org. Chem., 1979, 44, 1421) in 500 ml of anhydrous THF cooled to -78° C., 131 ml of 1.6M n-butyllithium in n-hexane were added under a nitrogen atmosphere and the resulting mixture was stirred for 2.5 hrs. A solution of 6.30 g of (1S,3aS,7aR)-1-hydroxymethyl-3a-hydroxy-7a-methyl-5-perhydroindenone in 60 ml of anhydrous THF was added. After 1 hr the reaction mixture was allowed to warm to 0° C., and cautiously quenched with 300 ml of 5% aqueous NaH2PO4.H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with n-hexane/acetone/chloroform 6:2:2 as the eluant to give 9.62 g of (1S,3aS,5R,7aR)-1-hydroxymethyl-5-(3-tert-butyldimethylsilyloxymethylphenyl)-7a-methylperhydroinden-3a,5-diol as a white foam.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][OH:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Si:1]([O:8][C:9]1[C:10]([CH2:20][CH2:21][CH3:22])=[CH:11][C:12]([CH:18]=[O:19])=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1cc(C=O)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5.03 g (15.4 mmol)of t-butyl-dimethylsilyloxy-2,6-dipropyl-4-hydroxymethyl benzene in 30 mL of methylene chloride was added 8.7 g of pyridinium dichromate (PDC). The reaction mixture was stirred for 3 hours and then diluted with 300 mL of ethyl ether. The solution was then filtered through a pad of a 1:1 mixture of florisil and celite. Concentration of the tiltrate gave 4.85 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:7][C:2]=1[Br:1]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D3 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: O[C@@H:2]([CH3:20])[C@@H:3]([NH:7][C:8]([O:10][C@@H:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:19][C@H:11]([O:10][C:8](=[O:9])[NH:7][C@H:3]1[C:4](=[O:6])[O:5][C@H:2]1[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC[C@H](C)OC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC[C@H](C)OC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 53.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-[[(1S)-1-methyloctoxy]-carbonylamino]-butanoic acid (0.2 g, 0.69 mmol) in dry CH2Cl2 (20 mL), Et3N (0.29 mL, 2.07 mmol) and subsequently TBTU (0.27 g, 0.83 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 40:60) to give the title compound (0.1 g, 53%) as a white solid. MS (ESI) m/z: 272 [M−H]+; (ESI) m/z: 270 [M−H]−. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.8 Hz, 3H), 1.15 (d, J=6.3 Hz, 3H), 1.20-1.31 (m, 10H), 1.34 (d, J=6.4 Hz, 3H), 1.41-1.56 (m, 2H), 4.63-4.74 (m, 1H), 4.83 (dq, J=6.3 Hz, 1H), 5.39 (dd, J=6.3, 9.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][S:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[C:21]2([C:24]#[N:25])[CH2:22][CH2:23][CH:18]([S:17][CH2:16][CH:13]3[CH2:14][CH2:15]3)[CH2:19][CH2:20]2)[CH2:28][CH2:27]1
Reactant: O=CC1CC1
Reactant: N#CC1CCC(SCC2CC2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(C(O)C2CC2)CCC(SCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirred solution of diisopropylamine (1.59 ml; 11.3 mmol) in THF (10 ml) at 0° C. was added dropwise butyl lithium (2.5 M in hexanes; 4.51 ml; 11.3 mmol). The mixture was stirred at 0° C. for 15 minutes then cooled to −78° C. A solution of 4-cyclopropylmethylsulfanyl-cyclohexanecarbonitrile (2 g; 10.2 mmol) in THF (10 ml) was added dropwise. On complete addition, the mixture was stirred at −78° C. for 30 minutes. Cyclopropanecarboxaldehyde (0.91 ml; 12.2 mmol) was added dropwise and the mixture was allowed to warm slowly to room temperature and stir for 64 hours. The mixture was quenched with brine (50 ml) and extracted with EtOAc (2×75 ml). The combined organics were washed with saturated sodium hydrogen carbonate solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give an orange oil. The crude product was chromatographed on silica eluted with 25-30% EtOAc in hexane to give the product as an orange oil (1.9339 g). 1H NMR (400 MHz, DMSO): δ 5.29 (1H, d, J 4.9), 2.76 (1H, dd, J 4.9, 7.8), 2.68-2.58 (1H, m), 2.15-2.11 (1H, m), 2.04-1.98 (4H, m), 1.56-1.38 (4H, m), 0.98-0.88 (2H, m), 0.52-0.48 (3H, m), 0.45-0.37 (1H, m), 0.34-0.28 (2H, m), 0.19-0.17 (2H, m). m/z=266 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:14]([N:16]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)[CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:15].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:14]([N:16]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCN(CCCCO)C1CCc2cc(OC)ccc2C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CCCCOC(=O)c1ccc(OC)c(OC)c1)C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.9 g of 3,4-dimethoxybenzoic acid and 4 ml of thionyl chloride were heated for 4 hours at reflux and concentrated under reduced pressure to obtain 3,4-dimethoxybenzoyl chloride. The 3,4-dimethoxybenzoyl chloride was dissolved in 10 ml of anhydrous benzene, and the resulting solution was added dropwise to a solution of 4.0 g of N-ethyl-N-(4-hydroxybutyl)-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 2.2 g of triethylamine in 50 ml of anhydrous benzene. After the addition, the resulting solution was stirred for 30 minutes at room temperature (about 25° C.) and heated for 3.5 hours at reflux. The reaction solution was washed with water, a 2 N-NaOH aqueous solution and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified through silica gel chromatography to obtain N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a colorless oily product. To this oily product was added an ethanolic solution of hydrogen chloride having a concentration of about 18% and the resulting solution was concentrated under reduced pressure to obtain a residue. The residue was dissolved in a mixed solvent of acetone and diethyl ether, and the solution was left at a temperature of about 2° to 3° C. to form crystals. By collecting the crystals through filtration and recrystallization from a mixed solvent of acetone and diethyl ether, 3.0 g of N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride was obtained as colorless crystals having a melting point of 139°-140° C. The melting point, the infrared spectra and other physical data of this product corresponded to the date of the compound obtained in Example 2 (ii).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[O:32][CH3:33].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1.ClCCl>[CH3:33][O:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CN
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 21.5 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)-3-methoxyphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (151 mg, 0.33 mmol) in pyridine, cooled to 0° C., were added methanesulfonyl chloride (151 mg). The resulting reaction mixture was stirred for 15 h at room temperature. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Methoxy-4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 78) (38 mg) was obtained as 22% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: O=C(O)c1cnc(-c2ccccc2F)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (105 mg, 0.48 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (74 mg, 0.54 mmol) and PS-DCC (501 mg, 1.28 mmol/g, 0.64 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (29.9 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (385 mg, 3.75 mmol/g, 1.44 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (60 mg, 63%) as a solid. MS: 294 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5]2[C:4](=[CH:10][CH:9]=[CH:8][C:7]=2[O:11][C:15]([NH:14][CH3:13])=[O:16])[CH2:3]1
Reactant: CN=C=O
Reactant: CC1(C)Cc2cccc(O)c2O1
Product: CNC(=O)Oc1cccc2c1OC(C)(C)C2

Procedure:
The carbofuran phenol from Examples 3 and 4 is then reacted with methyl isocyanate in the presence of a tertiary amine catalyst to give carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methyl carbamate).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.[Fe](Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH2:10][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CN1CCNCC1
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CN1CCN(C)CC1)NC(C)=O
Temperature: 20 °C
Reaction time: 66 h

Procedure:
To a solution of 8.57 g of methyl 2-acetamidoacrylate in 500 mL of dichloromethane stirred under inert atmosphere, about 6.65 mL of N-methylpiperazine are added, then 0.97 g of iron trichloride are added, and the mixture is stirred at a temperature of about 20° C. for 66 hours. Then, 300 mL of an aqueous solution of sodium sulfate are dropped to the reaction medium while stirring the reaction mixture and the mixture filtered through Celite. After separation of the phase by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated in a vacuum oven under reduced pressure (2 kPa) at a temperature of about 40° C. in order to obtain an orange-colored liquid. The aqueous phase is extracted with 3 times 150 mL of dichloromethane and all of the organic extracts are collected, dried over sodium sulfate, then concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. in order to obtain an yellow oil. Both of the organic extracts as described above are combined and purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 40–63 μm; diameter 5 cm; height 25 cm), eluting with successive mixtures of 20% dichloromethane/methanol/aqueous ammonia (99/1/0, 97/3/0, 90/10/0.25, 80/20/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 30° C. About 3.3 g of methyl 2-(acetylamino)-3-(4-methyl-piperazinyl)propanoate are obtained in the form of a yellow liquid. [Infrared spectrum CCl4 3437; 3318; 2941; 2798; 1749; 1685; 1499; 1458; 1374; 1286; 1204; 1168 and 1014 cm−1].
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:13][CH:12]=[C:4]([C:3]([CH:2]([F:11])[F:1])=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:15]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)F
Temperature: 92.5 °C
Yield: 86.4 %

Procedure:
To the concentrated product of crude ethyl difluoroacetoacetate (˜0.93 mole) are added triethyl orthoformate (266.8 g, 1.8 moles) and acetic anhydride (367.6 g, 3.6 moles). The mixture is heated to 90-95° C., and kept gently refluxing for 6 hours. (GC shows ethyl difluoroacetoacetate content <0.1%). The reaction mixture is cooled to 60-70° C. and then concentrated under vacuum to remove excess acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid (178.6 g) is obtained. The yield of two steps is 80%.