Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C@H:9]([S:22][CH2:23][C:24]2([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:25]2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([OH:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1>CCOC(C)=O.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([C@H:9]([S:22][CH2:23][C:24]2([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:26]2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([OH:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CO)c2)CC1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=O)c2)CC1

Procedure:
To the dihydroxy ester from Step 15 (6.8 g, 15.4 mmol) in EtOAc (150 mL) at 50° C. was added MnO2 (6.7 g, 76.8 mmol). After stirring for 30 minutes at 50° C. more MnO2 (6.7 g) was added, and 30 minutes later, a third portion of MnO2 (6.7 g) was added. An hour later, the warm reaction mixture was filtered through celite and the cake was washed with additional EtOAc. Evaporation of the solvents gave the title aidehyde 5.62 g (83%). 1H NMR (CD3COCD3): δ5 10.4 (1H, s), 7.9 (1H, br s), 7.8 (2H, m), 7.58 (1H, t), 7.38 (1H, br d), 7.1 (3H, m), 4.1 (1H, t), 3.54 (3H, s), 3.13 (1H, ddd), 2.85 (1H, ddd), 2.51 (2H, s), 2.49 (2H, d), 2.2 (2H, m), 1.51 (6H, s), 0.52-0.32 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:30][N:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (3.90 g, 13.3 mM) and 4-methylphenyl hydrazine hydrochloride (14.8 g, 93.2 mM) in ethanol (140 mL) was added triethylamine (14.8 mL, 106.4 mM). The resulting brown solution was refluxed for 16 hours during which time a precipitate formed. The resulting suspension was cooled to room temperature and filtered to give the 4-methylphenyl hydrazine salt of the title compound as a grey powder (2.30 g). This material was refluxed in glacial acetic acid (45 mL) for 2 hours and cooled to room temperature. The resulting brown suspension was filtered to give the title compound (1.60 g, 34%) as a tan powder, mp 380-382° C.; MS(CI): 354 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: ClCCOC1CCCCO1
Reactant: Cc1cccc2c1NC(=O)C2(C)C
Product: Cc1cccc2c1N(CCO)C(=O)C2(C)C

Procedure:
Prepared from 3,3,7-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:26]([F:29])([F:28])[F:27])=[CH:18][C:19]=4[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:13]3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(OCC)(=O)C>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:26]([F:29])([F:27])[F:28])=[CH:18][C:19]=4[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:13]3)[CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc2ccn(Cc3ccc4c(c3)CNCC4)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(F)(F)F)cc2ccn(Cc3ccc4ccncc4c3)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 61.3 %

Procedure:
To a mixture of ethyl 1-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (0.14 g) and ethyl acetate (10 mL) was added manganese dioxide (0.30 g) at room temperature. The reaction liquid was stirred for 6.5 hours under the condition for heating with reflux. In addition, to the reaction liquid were added toluene (10 mL) and manganese dioxide (0.30 g) at room temperature, followed by stirring at 110° C. for 1 day and then at 130° C. for 1 day. The reaction liquid was left to be cooled to room temperature, and filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-30:70) to obtain ethyl 1-(isoquinolin-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: COc1ccc(N)cc1
Product: CCCCNc1ccc(OC)cc1
Yield: 96.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-methoxyaniline (500 mg, 4.06 mmol) and butyraldehyde (360 μL, 4.06 mmol) were converted to the title compound (700 mg, 88%). 1H NMR (CDCl3) δ 6.89-6.73 (m, 2H), 6.69-6.50 (m, 2H), 3.76 (s, 3H), 3.10 (t, J=7.2 Hz, 2H), 1.70-1.28 (m, 4H), 1.02-0.90 (m, 3H); MS(ESI+) m/z 180.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(M/e): 423(M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[O:27])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: OC1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(O)CC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and 4-hydroxypiperidine were coupled to give 118bp. 1H NMR (400 MHz, DMSO-d6), δ: 7.68 (m, 1 H), 7.46 (m, 1 H), 7.21-7.25 (m, 3 H), 6.93 (m, 1 H), 6.69 (m, 1 H), 5.16 (s, 2 H), 3.65 (m, 3 H), 3.29 (s, 3 H), 3.17 (m, 2 H), 1.73 (m, 2 H), 1.36 (m, 2 H). LCMS (ESI) m/z: 485.1
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH2:4][CH2:3]1.Cl.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[O:14]=[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:3][CH2:4]1
Reactant: O=C1CCC(n2ccccc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccccc3=O)CC2)C1

Procedure:
A solution of 1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step, 150 mg, 0.79 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide HCl salt (as prepared in Example 2 Step C, 400 mg, 1.18 mmol) in DCM (10 mL) was treated with TEA (340 μL, 2.40 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 510 mg, 2.40 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: a less polar isomer, and a more polar isomer.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[CH:24]=[N:25][N:26]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:27]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cc(C(F)(F)F)cn3)nc2c1
Temperature: 50 °C
Yield: 91.1 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 4-(trifluoromethyl)pyrazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2-{3-[4-(trifluoromethyl)pyrazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 62”).
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH3:9])[S:7](=[O:11])(=[O:10])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].[C:13]1([S:19][CH2:20]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:13]1([S:19][CH2:20][N:6]2[C:5](=[O:12])[CH:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH3:9])[S:7]2(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1C(=O)NS(=O)(=O)N1C
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Yield: 57.7 %

Procedure:
A mixture of 4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9 g), phenylthiomethyl chloride (7.43 g) and tetrabutylammonium bromide (1 g) suspended in 200 ml of toluene was refluxed for 8 hours, cooled, and concentrated in vacuo. The residue was purified by flash chromatography (15-20% ethyl acetate in hexane) to afford 8.5 g (88%) of 2-phenylthiomethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].C[C:22](=[O:25])[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:23][CH2:22][OH:25])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Compound 5 (0.32 mL, 3.54 mmols) was mixed with 4-(3,4-dichlorophenyl)piperazine (0.58 g, 2.5 mmols) and potassium carbonate (0.78 g, 5.6 mmols) in 15 ml 2-butanone overnight at 85° C. as described in General Procedure B to yield compound 7p and was used as is for the next reaction. MS (LC/MS, ESI): 289 (M+H).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[ClH:5].[Al+3:6].[Cl-].[Cl-].[Cl-]>>[C:2]([Cl:5])([CH3:3])([CH3:1])[CH3:4].[Al+3:6].[Cl-:5].[Cl-:5].[Cl-:5]
Reactant: Cl
Reactant: C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)Cl

Procedure:
A continuous process for preparing low molecular weight polyisobutylene having an Mn in the range of 700 to 3,000 and a molecular weight distribution less than about 2.0 from a feedstream mixture of C4 hydrocarbons containing at least about 6% by weight isobutylene in a continuous stirred reactor maintained at a reaction temperature of about -50° to +30° C., the reactor having a feedstream inlet and a separate AlCl3 catalyst inlet, which comprises injecting gaseous HCl, in an amount of 25 to 200 ppm parts by weight of feedstream and in the absence of AlCl3, into said feedstream at a point prior to its entry into the reactor in a manner sufficient to permit substantially complete reaction of the HCl with isobutylene to form t-butyl chloride before contact with AlCl3 such that the resulting pre-reacted feedstream at the point of reactor entry contains less than 1.0 ppm HCl, and simultaneously adding the pre-reacted feedstream and the AlCl3 catalyst to the reactor and contacting the pre-reacted feedstream with said catalyst in the reaction mixture to form the polyisobutylene, withdrawing the reaction mixture from the reactor, quenching the reaction with aqueous alkali and separating therefrom the polyisobutylene product.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:37])[C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:37])[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Product: CC(Cc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1)C(=O)O

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxyphenyl)-2-methyl-propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.71 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 2.93-2.98 (m, 1H), 2.63-2.74 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H17ClF3NO3S, 454.0 (M−H). found 454.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[N:4][C:5]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[Cl:19][C:6]1[C:5]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[N:4][C:3]([F:25])=[C:2]([Cl:1])[C:7]=1[S:8]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:17])[CH3:18])[CH:10]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1cc(Sc2c(Cl)c(F)nc(NCC(=O)O)c2Cl)ccc1O
Solvent: ClCCl
Product: CC(C)c1cc(S(=O)c2c(Cl)c(F)nc(NCC(=O)O)c2Cl)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
To a solution of 3,5-dichloro-2-fluoro-4-(3-isopropyl-4-hydroxyphenylthio)-6-hydroxycarbonylmethylaminopyridine (25 mg, 0.06 mmol) in CH2Cl2 (1.5 mL) was added 3-chloroperoxy-benzoic acid (11 mg). The mixture was left to stir overnight (ca. 15 h) at ambient room temperature. The product was extracted with EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The isolated crude product was purified by preparative HPLC (from 50% B to 100% B for 10 min, Solvent A=90% H2O-10% MeOH-0.1% TFA Solvent B=10% MeOH-90% H2O-0.1% TFA, at 20 mL/min using column YMC ODS S5 20×100 mm) to afford 16.5 mg (64%) of title compound as a white solid.
Reaction SMILES: C(O[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br)CCC.C([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:6]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)N1CCNCC1
Reactant: CCCCOc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Yield: 157.1 %

Procedure:
Part A: To a solution of n-butyloxybromobenzene (5.00 g, 21.82 mmol) in toluene (50 mL) was added tert-butyl piperazine (4.88 g, 26.18 mmol) and sodium tert-butoxide (2.94 g, 30.55 mmol). After stirring at ambient temperature for several minutes, BINAP (0.408 g, 0.655 mmol) and tris(dibenzyldeneacetone)-dipallidium (0) (0.200 g, 0.218 mmol) were added. The resulting mixture was heated to eighty degrees Celsius for 21 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with diethyl ether and dichloromethane. Chromatography (on silica, ethyl acetate/hexanes) provided the phenyl-piperazine as a tan solid (5.56 g, 76%).
Reaction SMILES: [OH:1][CH:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.O1CCC[CH2:24]1.[H-].[Na+].CI>CN(C)P(=O)(N(C)C)N(C)C>[CH3:24][O:1][CH:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: C1CCOC1
Reactant: CC(=CCOc1ccc2c(c1)OCC2)CCC(O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(CCC(C)=CCOc1ccc2c(c1)OCC2)C(C)(C)C
Temperature: 40 °C
Reaction time: 12 h

Procedure:
0.4 g. of 6-[(6-hydroxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran are dissolved in 10 ml. of absolute tetrahydrofuran and, while stirring, warmed to 40° C. for 2 hours with 0.5 g. of a 55% by weight sodium hydride suspension in oil. Then 2 ml. of hexamethylphosphoric acid triamide and 1 ml. of methyl iodide are added and the mixture is stirred for 12 hours at room temperature. For the working up, the mixture is poured onto ice-water and extracted twice with diethyl ether. The ether extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/diethyl ether (19:1 parts by volume) there is obtained 6-[(6-methoxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran; nD25 = 1.5170.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:22]([Cl:21])=[O:24])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Clc1cccc(Nc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 258.1 %

Procedure:
To a solution of 3-chlorodiphenylamine (3.0 g) and pyridine (1.43 mL) in CH2Cl2 (30 mL) was added triphosgene (1.75 g) at 5° C. After stirring at room temperature for 6 hours, the mixture was evaporated, diluted with EtOAc, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 15:1) to give N-(3-chlorophenyl)-N-phenylcarbamoyl chloride (4.05 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:19](=[O:20])[NH:18]/[C:17](=[N:21]\[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])/[C:4]2=[C:5]([S:9]CCC(OCC)=O)[S:6][C:7]=1[CH3:8].[OH-].[K+].Cl>C1COCC1.CO>[SH:9][C:5]1[S:6][C:7]([CH3:8])=[C:2]([CH3:1])[N:3]2[C:19](=[O:20])[NH:18]/[C:17](=[N:21]\[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])/[C:4]=12
Reactant: CCOC(=O)CCSc1sc(C)c(C)n2c(=O)[nH]/c(=N\S(=O)(=O)c3ccc(C)cc3)c1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)/N=c2\[nH]c(=O)n3c(C)c(C)sc(S)c2-3)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
After ethyl 3-[[(1Z)-5,6-dimethyl-1-[[(4-methylphenyl)sulfonyl]imino]-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]sulfanyl]propanoate (5.00 g, 10.4 mmol) synthesized in (iii) described above was dissolved in THF (50 ml) and methanol (50 ml), potassium hydroxide (2.74 g, 41.5 mmol) was added to the solution. The mixture was stirred at room temperature for 45 minutes. 1N Hydrochloric acid (42 ml) was added to and mixed with the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The formed precipitate was filtrated, washed with 50% methanol-water and dried to give red powders of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2ccc(OCc3ccccc3)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
A mixture of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (10.0 g, 19.5 mmol), triethylsilane (15.6 mL, 97.5 mmol) and trifluoroacetic acid (15.0 mL, 195 mmol) was mixed and stirred for 20 min at 0° C. The mixture was concentrated under vacuum. The residue was triturated with diethyl ether to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (7.40 g, 76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.25 (m, 14H), 7.23-7.17 (m 2H), 7.11-7.02 (m, 2H), 6.95 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.55-6.49 (m, 1H), 6.46 (dd, J=8.6, 2.6 Hz, 1H), 5.09 (s, 1H), 4.99 (s, 2H); MS (ES+) m/z 498.3 (M+1).