Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:12]1.Cl>O1CCOCC1>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)[CH:19]=2)[N:7]=[CH:6][N:5]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cc(Nc2cccc(CN3CCN(C)CC3)c2)ncn1
Temperature: 150 °C

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (385 mg, 2.68 mmol, 1.1 equiv), 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.44 mmol) and 4N HCl in dioxane (7 mL) is heated in a sealed tube to 150° C. for 17.5 h. The solvent is removed and the residue diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM and DCM/MeOH (95:5). The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a beige solid: ESI-MS: 313.2 [MH]+; tR=1.00 min (purity: 100%, system 1); TLC: Rf=0.05 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:31]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.10 mmol) in THF:H2O:MeOH (3:1:2) (3 mL), was added LiOH in water (1N) (0.3 mL, 0.3 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (30.0 mg, 61%) as a foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:4]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:2]([C:3]1[N:8]=[C:7]([O:9][C:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[N:4]=1)=[O:1]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(CO)n3)cccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C=O)n3)cccc2s1
Temperature: -78 °C

Procedure:
To a solution of N-(4-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (80 mg, 0.174 mmol, Example 98) in DCM (2 mL) was added oxalyl chloride (0.35 mL, 2M solution in DCM, 0.7 mmol, Aldrich). The mixture was cooled to −78° C., and a solution of DMSO (0.1 mL, 1.4 mmol) in DCM (0.5 mL) was added dropwise with stirring. The reaction mixture was stirred at −78° C. for 2 h, TFA (141 mg, 1.4 mmol) was added dropwise, and the mixture was allowed to reach room temperature. The reaction mixture was partitioned between water (10 mL) and DCM (10 mL). The organic phase was separated, washed with sat. aqueous solution of sodium bicarbonate, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give the crude title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 459 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1)=[O:4].[C:14]1([CH2:20][CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH2:20][CH2:21][NH:22][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
N,N'-Carbonyldiimidazole (16.2 g, 0.1 mole) was added portionwise under nitrogen to 1,4-benzenedicarboxylic acid monomethyl ester (18 g, 0.1 mole) in dry dichloromethane (250 ml) and stirred for 1 hour. Benzeneethanamine (12.1 g, 0.1 mole) was added and the reaction stirred for 3 hours. The solution was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and water, dried and evaporated. The residue, on trituration with ether, afforded the sub-title compound (23.8 g) as a white solid mp 148°.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH2:25])[CH2:23][NH2:24])=[CH:17][CH:16]=1>C(Cl)Cl>[NH2:25][C@@H:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1)[CH2:23][NH:24][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11]
Reactant: NC[C@@H](N)Cc1ccc(Cl)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](CNC(=S)NC(=O)c1ccccc1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of benzoyl isothiocyanate (2.94 mL, 21.9 mmol) in DCM (50 mL) was added dropwise via an addition funnel to the mixture of (S)-3-(4-chlorophenyl)propane-1,2-diamine dihydrochloride (5.63 g, 21.9 mmol) and TEA (7.60 mL, 54.6 mmol) in DCM (200 mL) at −10° C. under nitrogen. The addition took 30 minutes. The mixture was then gradually warmed to ambient temperature and stirred overnight. The solvent was removed in vacuo. The residue was partitioned between EtOAc and water. The combined organic portions were washed with brine. The crude product was purified by flash column chromatography (20 to 100% of EtOAc in hexanes, Biotage Si 40M). The product was obtained as an off-white foamy solid, 5.53 g, 73%. 1H NMR (300 MHz, CDCl3) δ 1.84 (broad, NH2), 2.57-2.71 (m, 1H), 2.82-2.94 (m, 1H), 3.34-3.48 (m, 1H), 3.51-3.65 (m, 1H), 3.82-3.99 (m, 1H), 7.13-7.21 (m, 2H), 7.28-7.34 (m, 2H), 7.49-7.58 (m, 2H), 7.59-7.68 (m, 1H), 7.80-7.91 (m, 2H), 9.00 (broad, NH), 11.07 (broad, NH). LCMS (API-ES): 348.1/350.1 (M++H), chloro pattern.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:16]([CH2:15][CH:14]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:37])[CH3:36]
Reactant: COCOc1ccc(CC(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(CC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A portion of 144 mg of 60% sodium hydride were suspended in 15 ml of dimethylformamide and cooled to 0° C., followed by dropwise addition of 1.34 g of N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzene sulfonamide, and then followed by addition of 391 mg of ethyl chlorocarbonate. After stirring at room temperature for four hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methylene chloride was obtained 1.49 g of N-ethoxycarbonyl-N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2o1
Yield: 84.3 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzofuran-2-carboxylic acid ethyl ester (7.10 g, 19.4 mmol) and 1-bromopinacolone (4.17 g, 23.3 mmol) and K2CO3 (5.35 g, 38.8 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (7.60 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:13][C:11]([C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:9]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (4.00 g, 17.7 mmol) and SEMCl (4.71 mL, 26.6 mmol) in DMF (90 mL) was added sodium hydride (0.851 g, 21.3 mmol) portion-wise at 0° C. The resulting yellow suspension was stirred at 0° C. for one hour and then allowed to warm to room temperature over one hour. The reaction was quenched with water slowly then extracted with ethyl acetate (×3). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-50% ethyl acetatehexane to afford ethyl-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C15H23ClN3O3Si [M+H]+: 356; found 356.
Reaction SMILES: [CH2:1]([C:5]1([CH2:35][CH2:36][CH2:37][CH3:38])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:5]1([CH2:35][CH2:36][CH2:37][CH3:38])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][C:20]=3[S:19](=[O:32])(=[O:33])[N:18]=2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(/C=C/C(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(CCC(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Yield: 75.5 %

Procedure:
A solution of the product of Example 20C (33 mg) in ethyl acetate (15 mL) was treated with 10% palladium on carbon (20 mg) and hydrogenated at one atmosphere for 18 h. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to afford the title compound (25 mg, 76%) as a light beige solid. 1H NMR (300 MHz, DMSO-d6): δ 0.53 (m, 2 H) 0.68 (t, J=7.35 Hz, 6 H) 0.90 (m, 2 H) 1.10 (m, 4 H) 2.00 (m, 2 H) 2.19 (m, 2H) 2.42 (t, J=7.35 Hz, 2 H) 2.92 (t, J=7.54 Hz, 2 H) 6.79 (s, 1 H) 7.31 (s, 1 H) 7.60 (m, 3 H) 7.79 (m, 3 H) 13.70 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:7]=1[CH2:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:5])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH3:31])[C:7]=1[CH2:17][C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)n(C)c1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 2-adamantan-1-ylmethyl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (Example 1, step b) (726 mg, 2.00 mmol) in DMF (3 ml) was added sodium hydride (60% dispersion in oil) (100 mg, 2.50 mmol) in small portions at 0° C. The mixture was stirred at room temperature for 30 min, then iodomethane (1.00 ml, 16.0 mmol) was added and the stirring was continued for 1 h. The reaction mixture was partitioned between ethyl acetate and 1M hydrochloric acid, the organic layer was washed with water, dried, and the solvent was evaporated to afford the product as a white solid (620 mg, 82%). 1H NMR (300 MHz, CDCl3) 7.35 (5H, m), 6.64 (1H, s), 4.27 (2H, q), 3.51 (3H, s), 2.80 (2H, br s), 1.96 (3H, br s), 1.64 (12H, m), 1.35 (3H, t).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.ClCCl>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:24])(=[O:21])=[O:20]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)OCC(=O)N(CC)CC)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 95 °C
Yield: 63.6 %

Procedure:
Bumetanide (1.2 g, 3.29 mmol) was dissolved in dimethylformamide (12 mL) and 2-chloro-N,N-diethylacetamide (500 mg, 3.35 mmol) was added followed by triethylamine (0.68 mL) and sodium iodide (500 mg 3.33 mmol). The reaction was heated to 95° C. for 8 hours, at which time TLC and LC/MS indicated the reaction was complete. The reaction was cooled to room temperature brought up in dichloromethane and washed with water, saturated ammonium chloride and reduced to a thick slurry. To the slurry was added water (25 mL), and the resultant solids precipitated from the solution. The product was filtered and dried in a vacuum oven at 50° C. for 12 hours to yield 1.0 g of N,N-diethylaminocarbonylmethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8](B(O)O)[S:7][C:6]=2[CH:13]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=1.[Al].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:17]([C:27]([F:28])([F:30])[F:29])[CH:16]=3)[S:7][C:6]=2[CH:13]=1
Reactant: FC(F)(F)c1cc(Br)ccc1-c1ccccc1
Reactant: Cc1ccc2cc(B(O)O)sc2c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 85 °C
Yield: 54.3 %

Procedure:
To a slurry of 6-methyl-benzo[b]thiophene-2-boronic acid (0.19 g, 0.001 mol) in 10 mL of benzene is added 4-bromo-2-trifluoromethyl-biphenyl ( 0.3g, 0.001 mol). The reaction flask is then covered with aluminum foil to keep out light. To this is added 58 mg of tetrakis(triphenylphosphine-palladium(0), followed by 1 mL of 2.0N sodium carbonate solution. The biphasic mixture is heated at 85° C. for 3 hours with vigorous stirring. The mixture is cooled to room temperature and 10 mL of brine solution is added. The organic layer is separated, dried and concentrated under vacuo to afford 0.2g of 6-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=1)=[N:5]/[O:6][CH3:7].[CH3:27][NH2:28]>CO>[Cl:24][C:23]([Cl:25])=[CH:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1/[C:4](=[N:5]\[O:6][CH3:7])/[C:3]([NH:28][CH3:27])=[O:2]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1cccc(C=C(Cl)Cl)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(C=C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Methyl-(E)-2-(2-((3-(2,2-dichlorovinyl)phenoxy)methyl)phenyl)-2-methoxyiminoacetate (0.4 g, 1 mmol) obtained in Example 1 was added to 10 ml of methanol. 40% methylamine solution (0.39 g, 5 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 6 hours. The solvent was removed therefrom under a reduced pressure. After adding water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (0.35 g, 89%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 4-benzyl-2-hydroxymethylmorpholine (118.8 g.) in dry pyridine (250 ml.) toluene-p-sulphonyl chloride (120.2 g.) is added gradually at 18°-25°C. The mixture is stirred for 20 hours at ambient temperature (ca. 20°C.) and the pyridine is removed under diminished pressure. The residue is diluted with water, the mixture made alkaline by the addition of sodium hydroxide solution, and the product is then extracted into ether. The ethereal solution is dried (MgSO4) and filtered, the ether is evaporated and the residual solid is crystallised from cyclohexane or petroleum ether (b.p. 60°-80°C.) to give 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine, m.p. 78°-79°C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C(Cl)(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[C:18]1([CH:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:25]([OH:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)(Cl)Cl>[C:5]([C:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:25]([OH:27])=[O:26])(=[O:7])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(C(C)=O)(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A 500 ml reaction vessel was charged with 200 mls freshly distilled carbon tetrachloride and the CCl4 was cooled to 0°-5° C. Aluminum chloride (0.33 moles) was added, via Gooch tubing, to the CCl4 over a period of 20 minutes. Acetyl chloride (0.35 mol) was added to an addition funnel and charged to the CCl4 -AlCl3 mixture. Phenylstearic acid (0.125 moles) was then slowly added to the reaction mixture from an addition funnel while maintaining the temperature of the reaction mixture at 0°-5° C. The temperature was maintained at 0°-5° C. for one hour and at room temperature for an additional two hours. The evolution of HCl was observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1
Temperature: 25 °C

Procedure:
After 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 200.5 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]#[CH:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])/[CH:10]=[CH:11]\[CH:17]([S:18][CH:12](/[CH:11]=[CH:10]\[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]1[CH:20]=[CH:19][C:16]([CH3:17])=[CH:15][CH:14]=1)[C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(O)c(OC)c1
Reactant: Cc1ccc(CS)cc1
Agent: [Na]
Product: COc1cc(/C=C\C(SC(/C=C\c2ccc(O)c(OC)c2)c2ccc(C)cc2)c2ccc(C)cc2)ccc1O

Procedure:
A solution of 3-methoxy-4-hydroxyphenylacetylene (0.02 mol), 4-methylbenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-hydroxystyryl-4-methylbenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.