Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[S:25][C:26]([C:32]2[C:37]([F:38])=[CH:36][C:35]([C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][C:33]=2[F:43])=[CH:27][C:28]=1[C:29]([NH2:31])=[O:30]>>[CH:14]1([NH:13][C:11](=[O:12])[CH2:10][N:9]([CH2:8][C:6]2[N:7]=[C:2]([NH:23][C:24]3[S:25][C:26]([C:32]4[C:33]([F:43])=[CH:34][C:35]([C:39]([OH:42])([CH3:40])[CH3:41])=[CH:36][C:37]=4[F:38])=[CH:27][C:28]=3[C:29]([NH2:31])=[O:30])[CH:3]=[CH:4][CH:5]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CS(=O)(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CN(CC(=O)NC4CCCC4)S(C)(=O)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using N2-[(6-bromopyridin-2-yl)methyl]-N-cyclopentyl-N2-(methylsulfonyl)glycinamide (0.15 g, 0.38 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) as the starting materials.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)cc(C)c1Br
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-phenylamine (130 mg) in CH2Cl2 (4 mL) was added acetic anhydride (0.123 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=10:90 to 60:40) to give N-(4-bromo-3,5-dimethyl-phenyl)-acetamide: MS (m/z) 244 (M+1); 1H NMR (CDCl3, 400 MHz) δ 7.24 (s, 2H), 2.35 (s, 6H), 2.13 (s, 3H).
Reaction SMILES: [ClH:1].[C:2]([C:10]1[CH:11]=[C:12]([N:16]([CH3:37])[C:17]([CH:19]2[CH2:23][S:22][CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:20]2C(OC(C)(C)C)=O)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[C:2]([C:10]1[CH:11]=[C:12]([N:16]([CH3:37])[C:17]([CH:19]2[CH2:23][S:22][CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:20]2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)C1CSC(c2cccnc2)N1)c1cccc(C(=O)c2ccccc2)c1
Yield: 81 %

Procedure:
Hydrochloric acid in dioxane (4M, 10 mL) was added to N-(3-benzoylphenyl) N-methyl 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxamide (0.64 g) in dioxane (3 mL). The reaction mixture was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was washed with saturated aqueous sodium carbonate and dried over magnesium sulfate. The solvent was removed in vacuo and the residue chromatographed on silica gel, eluting with ethyl acetate to give the desired compound as a colorless oil (417 mg, 81%). This was converted to the dihydrochloride salt using the method of example 3. NMR (CDCl3, 300 MHz): δ2.72-3.28 (c, 3H), 3.42-3.97 (c, 4H), 5.57 (s, 0.6H), 5.61 (s, 0.4H), 7.21-7.48 (c, 6H), 7.81 (m, 1H), 8.51 (dd, 0.4H, J=1.0, 8.0), 8.56 (dd, 0.6H, J=1.0, 8.0), 8.72 (m, 1H). Mass Spectrum (DCI/NH3): 286 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].CN(C=O)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=1>O1CCCC1>[CH3:28][C:22]1[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=[C:18]([C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:2][CH3:1])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CS
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1SC
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a solution of methyl mercaptan-DMF solution (methylmercaptan 66 g/DMF 306 g) (3.8 ml) and methyl 4-(2-chloro-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (1.5 g) in tetrahydrofuran (25 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on silicagel eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from n-hexane to afford methyl 6-methyl-4-(2-methylthio-5-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.2 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[C].[Pd].CO>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)c1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(CC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
The compound (4267.9 g, 13.929 mol) obtained in Example 3, 10% palladium carbon (889.4 g, ca. 50% water-containing product) and methanol (38.4 L) were charged, and a hydrogenation reaction was conducted at normal pressure at 50° C. for 5 hrs. After the reaction, the reaction mixture was separated by filtration without cooling to remove the insoluble material and washed with methanol (3 L). The reaction mixture was concentrated under reduced pressure to about 10 L, and ethyl acetate (15 L) was added, followed by concentration again under reduced pressure to about 10 L, which step was conducted twice. The residue (ca. 10 L) was stirred under reflux for 2 hrs., and cooled to room temperature. The crystals were collected by filtration, washed with ethyl acetate (2 L) and dried in vacuo at 40° C. to give the title compound (2619.2 g, yield 86.1%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH2:21])=O)[CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.C(O)(=O)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH2:21])[CH2:8]2)=[CH:22][CH:23]=1
Reactant: N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 20 h
Yield: 89.6 %

Procedure:
[(S)-3-(4-Fluoro-benzyl)-piperidin-1-yl]-[(3S,4R)-3-aminotetrahydro-pyran-4-yl]-methanone (367 mg, 1.14 mmol) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 46 mL, 46 mmol) and stirred for 20 h . The mixture was treated slowly with 20% acetic acid in methanol (25 mL), and the resulting mixture was stirred at room temperature for 3 h . The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated to provide a gum (313 mg). A portion of this material (175 mg) was purified by flash column chromatography (5% methanol/dichloromethane, containing 0.5% ammonium hydroxide) to provide the product (103 mg, 52%) as an oil which solidified on standing. 1H NMR (300 mHz, CD3OD) δ7.15 (m, 2H), 6.98 (m, 2H), 3.87 (dd, J=10.3, 3.6 Hz, 1H), 3.78 (dd, J=11.1, 4.4 Hz, 1H), 3.37 (dd, J=12.0, 2.4 Hz, 1H), 3.03 (bd, 1H), 3.00 (dd, J=11.0, 10.2 Hz, 1H), 2.78 (bd, 1H), 2.59 (m, 1H), 2.49 (d, J=6.6 Hz, 2H), 2.42 (dd, J=12.8, 8.8 Hz, 1H), 2.23 (dd, J=12.8, 4.4 Hz, 1H), 1.9-1.4 (8H), 1.2 (m, 1H), 1.0 (m, 1H), ESI MS: (M+H)+=307.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=1)[CH3:13])(OCC)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[OH-].[K+]>O1CCCC1>[CH3:13][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=1)[CH3:7]
Reactant: CCOC(=O)c1csc(CN(C)C(=O)OCC)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)Cc1nc(CO)cs1
Yield: 34.8 %

Procedure:
To a cooled suspension of lithium aluminum hydride (8.4 g; 0.22 mole) in 80 ml of dry tetrahydrofuran was added a solution of 2-(N-carbethoxy-N-methylamino)methyl-4-carbethoxythiazole (20.0 g; 0.07 mole) [prepared in Step C] in 160 ml of dry tetrahydrofuran over a 1 hour period. The reaction mixture was heated at reflux temperature for 8 hours, then cooled and decomposed with Na2SO4 and 40% aqueous potassium hydroxide. The mixture was filtered, dried and evaporated under reduced pressure to give 4.2 g of the title compound as an oil; TLC (aluminum oxide/CH3CN) gave RF=0.45. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 7.17 (s, 1H); 4.73 (d, 2H); 3.43 (s, 2H); 3.35 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29]C(=O)OC(C)(C)C)=[CH:28][C:22]=2[S:21](=[O:38])(=[O:37])[N:20]=1.Cl.O1CCOCC1>ClCCl>[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:20][S:21](=[O:38])(=[O:37])[C:22]=2[CH:28]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 93.5 %

Procedure:
To a solution of the product of Example 39-5 (407 g, 0.754 mol) in dichloromethane (550 mL) was added 4 M HCl in dioxane (760 mL, 3.04 mol) and the solution was mixed at RT for 3.5 h. The reaction was quenched by addition of ethyl acetate (1.5 L) and pH 7 phosphate buffer (1.7 L) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (400 mL) and the combined organic layers were concentrated and chased with ethanol to a final volume of approximately 2500 mL. The product precipitated and was isolated by filtration and dried to give the title compound (309.7 g, 93.4%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.Cl.CCOCC.[CH3:20][C:21](=[O:24])[CH2:22][CH3:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:22]([CH3:23])[C:21](=[O:24])[CH3:20])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CCC(C)=O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.5 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 2.0 ml of butanone was saturated with gaseous hydrogen chloride. After standing over night ether was added to the solution and it was filtered. The product was crystallized from isopropanol, yield 0.2 g (30%), m.p. 139°-141° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6]S(O)(=O)=O.C(CNC(CO)(CO)CO)CNC(CO)(CO)CO.OCC(NC[CH2:42][S:43]([OH:46])(=[O:45])=[O:44])(CO)CO.C(NC(CO)(CO)CO)C(O)CS(O)(=O)=O.NC(CO)(CO)CO.N(CCO)(CCO)CCO>>[CH2:5]1[NH+:4]([CH2:3][CH2:2][CH2:42][S:43]([O-:46])(=[O:45])=[O:44])[CH2:11][CH2:12][O:13][CH2:6]1
Reactant: O=S(=O)(O)CCNC(CO)(CO)CO
Reactant: O=S(=O)(O)CCN(CCO)CCO
Agent: NC(CO)(CO)CO
Agent: O=S(=O)(O)CC(O)CNC(CO)(CO)CO
Agent: OCC(CO)(CO)NCCCNC(CO)(CO)CO
Solvent: OCCN(CCO)CCO
Product: O=S(=O)([O-])CCC[NH+]1CCOCC1

Procedure:
N,N-bis [2-Hydroxyethyl]-2-aminoethanesulfonic acid; (1,3-bis[tris(Hydroxymethyl)methylamino]propane); (N,N-bis[2-Hydroxyethyl]-2-aminoethanesulfonic acid; 2-[bis(2-Hydroxyethyl)amino]ethanesulfonic acid); (N-tris[Hydroxymethyl]methyl-2-aminoethane-sulfonic acid; 2-([2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]amino) ethanesulfonic acid; 3-[N,N-bis(2-Hydroxyethyl)methylamino]-2-hydroxypropanesulfonic acid); (3-[N-tris(Hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid); (tris[Hydroxymethyl]aminomethane), (2-amino-2-(hydroxymethyl)-1,3-propanediol); (N-[2-Hydroxyethyl]piperazine-N'-[2-hydroxypropanesulfonic acid]); (Piperazine-N,N'-bis[2-hydroxypropanesulfonic acid]); (N[2-Hydroxyethyl]piperazine-N'-[3-propane-sulfonic acid]); Triethanolamine, (2,2'2"-Nitrilotriethanol); and mixtures thereof.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl[C:12]1[C:17]([CH2:18][CH:19]([CH3:21])[CH3:20])=[N:16][CH:15]=[CH:14][N:13]=1.Cl>CO.CCCCCC.O>[CH2:18]([C:17]1[C:12]([S:10][C:9]2[CH:8]=[CH:7][O:6][C:5]=2[CH3:4])=[N:13][CH:14]=[CH:15][N:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cc1nccnc1Cl
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: Cc1occc1Sc1nccnc1CC(C)C
Temperature: 65 °C

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, and reflux condenser with calcium chloride drying tube is placed a solution of 0.15 g (0.0028 moles) of sodium methoxide in 2 ml absolute methyl alcohol. To the sodium methoxide solution, while maintaining the temperature at 22° - 25° C, is added 0.32 g (0.0028 moles) of 2-methyl-3-furan thiol dissolved in 2 ml absolute methanol. The reaction mass is stirred for a period of 10 minutes at 22° - 25° C at which time a solution of 0.43 g (0.0025 moles) of 2-chloro-3-isobutyl-pyrazine in 2 ml absolute methanol is added dropwise over a period of 2 minutes. The reaction mass is then heated to reflux at 65° C under nitrogen and maintained at reflux for a period of 4 hours. At the end of the 4 hour reflux period, the reaction mass is cooled to room temperature. 10 ml of water is added to the reaction mass which is then neutralized to a pH of 5 with dilute hydrochloric acid. Two 7 ml portions of n-hexane are then used to extract the reaction mass. The hexane layers are separated, combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to a red amber oil weighing 0.51 g. The major material is isolated using GLC techniques (conditions: 8 feet × 1/4inche SE-30 column) and is confirmed by NMR, IR and Mass Spectral Analysis to be a material having the structure: ##SPC15##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43](CO)=[CH:42][CH:41]=1>C(Cl)Cl>[Br:24][CH2:20][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:41][CH:42]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)cc1
Reaction time: 8 h

Procedure:
Triphenylphosphine (2.54 g, 9.7 mmol) is added to a solution of carbon tetrabromide (3.22 g, 9.7 mmol) and the title B compound, {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-methanol (2.0 g, 6.46 mmol) in DCM (24 mL) at RT. The mixture is stirred overnight and then concentrated under vacuum. The residue is chromatographed on silica gel using 15% EtOAc in hexane as the eluent to provide 4-[2-(4-bromomethyl-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl.C(OCC)C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][O:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:8]=[CH:9][C:2]1=2
Reactant: OCCOCC(O)c1ccc2sccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
In 54 ml of pyridine was dissolved 9.0 g of 1-(benzo[b]thiophen-5-yl)-2-(2-hydroxyethoxy)ethanol. To the solution was added, at -25° C, 7.2 g of p-toluenesulfonyl chloride. The mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 30 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.7 g of colorless oily 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[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>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(B(O)O)cc1
Reactant: COc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2ccc(OC(C)(C)C)cc2)c1
Yield: 101.2 %

Procedure:
A solution of 4-tert-butoxybenzeneboronic acid (0.50 g), 3-bromoanisole (0.44 g), and tetrakis(triphenylphosphine)palladium(0) (0.09 g) in toluene (5 ml), ethanol(1.2 ml) and aqueous sodium carbonate (2 M, 2.4 ml) was heated at 100° C. for 19 hours. After cooling the reaction mixture was added to brine (50 ml) and ethyl acetate (50 ml). The organic layer was separated and dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:toluene 9:1 to give 4-tert-butoxy-3'-methoxybiphenyl (0.61 g). (MS (EI) 256 (M)+). Trifluoroacetic acid (5 ml) was added to a solution of 4-tert-butoxy-3'-methoxybiphenyl (0.60 g) in dichloromethane (20 ml) and the resulting solution stirred for 1 hour. The solution was then concentrated under reduced pressure. The residue was partitioned between a solution of saturated aqueous sodium hydrogen carbonate (25 ml) and ether (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane to give the sub-title compound as a solid (0.25 g).
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:31]=[CH:30][C:19]([CH2:20][NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[S:23])=[CH:18][CH:17]=1>C1C=CC=CC=1>[F:27][C:26]([F:28])([F:29])[CH2:25][N:24]=[C:22]1[N:21]([CH2:20][C:19]2[CH:30]=[CH:31][C:16]([C:15]([F:33])([F:14])[F:32])=[CH:17][CH:18]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:23]1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Solvent: c1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1
Yield: 60 %

Procedure:
1.00 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.45 g of 1-(4-trifluoromethylbenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of benzene, and the solution was heated under reflux for 4 hours. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography [silica gel; eluent: hexane/ethyl acetate (10/1)] to give 1.27 g of the captioned compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C@@H:20]([NH:29][C:30](=[O:43])[CH2:31][C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:34])[CH3:33])[C:19]2=[O:44])=[CH:13][CH:12]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C@@H:20]([NH:29][C:30](=[O:43])[CH2:31][C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:34])[CH3:33])[C:19]2=[O:44])=[CH:15][CH:16]=1
Reactant: CC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of 469 mg (0.87 mmol) of the intermediate obtained in Step F in 25 mL of methanol at room temperature was treated with 5 mL ofaqueous 5N sodium hydroxide. After stirring at room temperature for 1 hour, the reaction mixture was evaporated under vacuum and the residue dissolved in methylene chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to yield 450 mg of crude product which was used in the next step without purification.