Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.Cl.[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:20]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CCCN1C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol) was dissolved in anhydrous DMSO. To this solution was added 2-(2R)-methyl-[1,3′]bipyrrolidinyl hydrochloride (2.30 g, 15 mmol), followed by powdered potassium carbonate. The suspension was heated on an oil bath to 85° C. for 3 h when the starting material was consumed as determined by TLC (5% MeOH/DCM) and LC/MS. To the suspension was added 20 mL of water and 50 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% MeOH in DCM to obtain the title compound as a yellow solid after drying, 2.70 g (93%). MS: 290 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1

Procedure:
The 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid obtained in the above is caused to react with benzyl bromide in the presence of potassium hydroxide, to obtain 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid. The compound thus obtained is heated under reflux in the presence of an acid catalyst to obtain 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[N+:8]([CH3:10])[CH:7]=[CH:6]1.[Cl-].CO.[F-:14].[K+]>O>[F-:14].[CH2:4]([N+:5]1[CH:6]=[CH:7][N:8]([CH3:10])[CH:9]=1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCn1cc[n+](C)c1
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCC[n+]1ccn(C)c1
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
10.3 grams of [BMIMCl] prepared as described above were added to a mixture of 28 mL methanol and 0.06 mL water. After complete dissolution of the [BMIMCl], 5.0 grams of dry potassium fluoride (KF) were added, and the reaction mixture was stirred at 22° C. for 20 minutes. The mixture was filtered. 4.4 grams of KF was added to the filtrate, and the mixing continued for additional 20 minutes. After filtration, the methanol was evaporated under vacuum at room temperature, and the mixture was then filtered and centrifuged. The resulting yellowish liquid was determined by elementary analysis to be the titled compound [BMIMF] in 94% yield.
Reaction SMILES: [CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl>C1COCC1>[CH:1]1([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(OC2CCCCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(OC2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Dissolve 4-cycloheptyloxy-benzonitrile (2 g, 9.29 mmol) in anhydrous THF (20 mL) and cool to 0° C. Add borane dimethylsulfide complex (2.8 mL, 27.9 mmol, 10-12 M solution), stir at 0° C. for 0.5 h and then heat at reflux for 1 h. Cool the mixture to 0° C., add methanol (5 mL) and stir for 15 min. Add 2M aqueous HCl (15 mL) and stir for 30 min at room temperature. Concentrate the mixture in vacuo and purify the residue by chromatography on silica gel (45 g RediSep column) eluting with a gradient of dichloromethane in chloroform/methanol/concentrated ammonium hydroxide (80:18:2) over 30 min (80 ml/min) to provide the title compound as a colorless oil (1.87 g, 97%). MS (APCI) m/z: 220 (M+H)+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19]/[N:20]=[C:4]2\[C:2](=[O:3])[N:1]([CH2:2][CH2:4][CH2:6][CH2:7][CH2:8][CH3:9])[C:11]3[C:6]\2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:18])=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccc(Cl)cc2)c2ccccc21
Yield: 80 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and 4-chlorobenzhydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 80%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.25-1.38 (m, 6H), 1.64 (m, 2H), 3.76 (t, J=7.2 Hz, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.64-7.72 (m, 3H), 7.91-7.94 (m, 2H), 13.85 (br s, 1H). 13C NMR (DMSO-d6): δ 14.32 (CH3), 22.41 (CH2), 26.37 (CH2), 27.38 (CH2), 31.31 (CH2), 39.80 (CH2), 110.69 (CH), 119.56 (C), 121.33 (CH), 123.72 (CH), 129.75 (CH), 131.20 (C), 132.35 (CH), 138.23 (C), 143.52 (C═N), 161.55 (C═O). HRMS (ES+) calcd for C21H23N3O2Cl (M+H+), m/e, 384.1484; found, 384.1473.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=1[CH3:12].[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:31]=[C:32]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=3[CH3:12])[CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2[N+](=O)[O-])c1

Procedure:
Following the procedure used for Example 295, step h, reaction of 4-bromo-3-methyl-5-nitro-phenylamine (350 mg, 1.5 mmol, as prepared in Example 135, step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (1.0 gm, 2.27 mmol, as prepared in Example 140, step a), tetrakis(triphenylphosine)palladium(0) (433 mg, 0.375 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (6 mL, 2M), and toluene/EtOH mixture (2:1, 18 mL) at 80° C. for 24 h afforded 250 mg (30%) after purification (SiO2, flash elution: 5% to 50% EtOAc in hexanes) of the title compound as a yellow solid. ESI-MS (m/z): Calcd. for C24H26N4O6S3: 563.1 (M+H); found: 562.8, 463.1 (M−Boc).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH3:22][N:8]1[C:3]([C:2]([F:1])([F:20])[F:21])=[CH:4][C:5](=[O:19])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7]1=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cn2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
A solution of 3.0 grams (0.01 mole) of 6-trifluoromethyl-3-(4-methoxy-phenylmethyl)-2,4(1H,3H)-pyrimidinedione in 25 mL of N,N-dimethylform-amide was stirred and 1.4 grams (excess) of potassium carbonate was added. To this was then added 0.7 mL (0.01 mole) of methyl iodide. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, then poured into a mixture of 100 mL of ice and 100 mL of aqueous 10% hydrochloric acid. The resultant solid was collected by filtration and washed with water. The solid was then dissolved in 200 mL of ethyl acetate and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 2.1 grams (66.9% yield) of 1-methyl-6-trifluoromethyl-3-(4-methoxyphenylmethyl)-2,4(1H,3H)-pyrimidinedione, mp 79°-80° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH3:12].C([O-])(=O)C.[Na+].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH2:27])[CH3:23]>C(#N)C>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][N:27]1[CH:10]([CH:11]([N+:13]([O-:15])=[O:14])[CH3:12])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:16])[CH3:23]
Reactant: COC(=O)c1ccccc1C=C(C)[N+](=O)[O-]
Reactant: CCOC(CN)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(CN1C(=O)c2ccccc2C1C(C)[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-nitro-1-propenyl)-benzoic acid methyl ester (1.6 g, described in Example 28), sodium acetate (1.1 g) and 2,2-diethoxyethanamine (1.25 ml) in acetonitrile (20 ml) is stirred at 25° C. for 18 hr and evaporated. The residue is dissolved in ethyl acetate. The organic solution is washed with 1 N hydrochloric acid and brine, dried and evaporated to give the title compound as a mixture of two isomers (2.5 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)CC(=O)c2c(-c3ccccc3)cn(-c3ccccn3)c2C1
Yield: 61.2 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (100 mg, 0.31 mmol), phenylboronic acid (153 mg, 1.25 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) and Na2CO3 (197 mg, 1.9 mmol) in ethylene glycol dimethyl ether (10 mL) and water (4 mL) was heated at reflux for 8 h. The solvent was evaporated and the residue partitioned between DCM and aqueous K2CO3 (10% (w/v)). The organic layer was separated and the aqueous phase re-extracted with DCM (2×). The combined organic layers were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with isohexane: EtOAc (9:1), to afford the title compound (60 mg, 61%) as a yellow solid. mp 160-162° C. Found: C, 78.23; H, 6.26; N, 8.57%. Calc. C21H20N2O.0.35(H2O): C, 78.16; H, 6.47; N, 8.68%. 1H NMR (360 MHz, CDCl3) δ 1.13 (6H,s), 2.45 (2H,s), 2.99 (2H,s), 7.17 (1H,s), 7.24-7.38 (5H,m), 7.67 (2H,d, J=7.2 Hz), 7.86 (1H,d of t, J=7.9 and 1.9 Hz), 8.56-8.61 (1H,m). MS (ES+) 317 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:4]([C@H:5]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:8]([C@H:9]([CH3:20])[C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH2:7][CH2:6]3)[CH2:3]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>>[OH:1][C@@H:2]1[C:30]2[C@:25]([CH3:32])([CH:26]=[CH:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:4]([C@H:5]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:8]([C@H:9]([CH3:20])[C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: CC[C@@H](C(C)C)[C@H](O)[C@@H](O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: CC[C@@H](C(C)C)[C@H](O)[C@@H](O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 70.3 %

Procedure:
50 mg of (22S,23S)-6α,22,23-trihydroxystigmast-4-en-3-one are treated with DDQ following the procedure described in Example 6. After purification by silica column chromatography (eluting solvent: hexane/ethyl acetate 8:2) of the crude product obtained, 35 mg of (22S,23S)-6α,22,23-trihydroxystigmasta-1,4-dien-3-one are isolated.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8]1([C:14]2([CH2:27][O:28][CH2:29][C:30]3[CH:31]=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:33]=[C:34]4[C:38]=3[NH:37][CH:36]=[CH:35]4)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:5][N:37]1[C:38]2[C:34](=[CH:33][C:32]([C:39]([F:41])([F:42])[F:40])=[CH:31][C:30]=2[CH2:29][O:28][CH2:27][C:14]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:35]=[CH:36]1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cc[nH]c23)(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Dimethyl sulfate (0.020 ml, 0.209 mmol) was added to a solution of tert-butyl 4-phenyl-4-(((5-(trifluoromethyl)-1H-indol-7-yl)methoxy)methyl)piperidine-1-carboxylate (93 mg, 0.190 mmol) and potassium tert-butoxide (23.5 mg, 0.209 mmol) in tetrahydrofuran (5 ml). The reaction was stirred 1 h at ambient temperature. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 8% to 66% ethyl acetate/hexanes. The product tert-butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (63 mg, 0.125 mmol, 65.9% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.83 (s, 1H), 7.22-7.36 (m, 6H), 6.95 (s, 1H), 6.50 (s, 1H), 4.66 (s, 2H), 3.66 (s, 3H), 3.62 (m, 2H), 3.41 (m, 2H), 2.99 (m, 2H), 2.09 (m, 2H), 1.77 (m, 2H), 1.40 (s, 9H); Mass spec.(MH)+: 503.19.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8]C(=O)[NH:6]1)[CH:2]([CH3:4])[CH3:3].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O1CCOCC1.O>[NH2:6][C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C@@H:9]([OH:8])[CH2:10][CH2:11][S:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCSCCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](N)[C@@H](O)CCSCCc1ccccc1
Yield: 76.7 %

Procedure:
A solution of 4(S)-isobutyl-5(S)-[2-(phenethylmercapto)ethyl]-2-oxazolidinone (0.52 g, 1.69 mmol) and barium hydroxide octahydrate (1.06 g, 3.38 mmol) in dioxane (60 mL) and water (40 mL) was heated at reflux under N2 for 21 hours. The solid barium carbonate was filtered and the filtrate was partially evaporated. The residue was diluted with water and the resulting solution was extracted with ether. The organic extract was washed with brine solution, dried over MgSO4 and evaporated to a residue. Trituration with cold hexane gave 365 mg (77%) of product, m.p. 95°-96° C.
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43](O)=O)=[CH:36][CH:35]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:11]([CH:25]2[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methoxy-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (10 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Benzylbromide (8.0 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-4-nitro-1H-pyrrole-2-carboxylate (14.3 g, yield 97%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 73° C.
Reaction SMILES: [BH4-].[Na+].C1COCC1.[Br:8][C:9]1[CH:10]=[C:11]([O:18][CH3:19])[C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15].Cl>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([O:18][CH3:19])[C:12]([OH:17])=[C:13]([CH2:14][OH:15])[CH:16]=1
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Br)cc(CO)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Sodium borohydride (0.28 g, 6.9 mmol) was added to a THF solution (30 ml) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.2 g 13.8 mmol) under ice cooling and the mixture was stirred at 0° C. for 2 hours. Acetic acid was added to the reaction solution to set pH at 3. 10% hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The extracted material was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1) and concentrated to dryness under reduced pressure to obtain 4-bromo-2-hydroxymethyl-6-methoxyphenol (3.23 g) as light yellow oil.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br>C(O)C>[CH2:9]([NH:5][NH:4][C:1](=[O:3])[CH3:2])[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:7]=1
Reactant: CC(=O)NN
Reactant: BrCc1ccccc1Br
Solvent: CCO
Product: CC(=O)NNCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
Acetic hydrazide (1.78 g, 24 mmol) was dissolved in ethanol (20 mL) and cooled to 0° C. A solution of 2-bromobenzyl bromide (2 g, 8 mmol) in ethanol (10 mL) was added slowly and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography with ethyl acetate-hexane as eluent to give acetic acid N′-benzyl-hydrazide (1.7 g, 87%) as a white solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCC(=O)c1cccs1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1cccs1)c1ccc(F)cc1
Yield: 94.4 %

Procedure:
20.8 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride, 40.0 g of sodium bicarbonate and 18.5 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 29 g of N-(4-fluorobenzoyl)-N-[(2-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:19][CH2:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][O:17][CH:18]=1)[C:7]([O:9]C)=[O:8])[CH3:2].Cl>CO.C1COCC1.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:19][CH2:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][O:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnoc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 3,5-diethoxy-4-(isoxazol-4-yl)benzoate (91 mg) was dissolved in a mixed solvent of methanol/THF (8 mL, 3/5), aqueous 1 M NaOH solution (1.2 mL) was added to it, and stirred at room temperature for 5 hours. Aqueous 1 M HCl solution (1.2 mL) was added to it, and the solvent was concentrated under reduced pressure. The formed solid was taken out through filtration, washed with water, and dried under reduced pressure to obtain the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]3[N:21]=[N:22][NH:23][N:24]=3)=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:27]1[C:31]([C:32](O)=[O:33])=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:19][C:20]3[N:21]=[N:22][NH:23][N:24]=3)=[CH:25][CH:26]=2)[C:32]([C:31]2[S:27][C:28]3[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=3[CH:30]=2)=[O:33])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)c2cc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
To the above resin bound 4-[(4-tert-butylcyclohexylamino)methyl]-N-(2H-tetrazol-5-yl)-benzamide was added a solution of benzo[b]thiophene-2-carboxylic acid (400 μmol) in a mixture of NMP, DCP and diisopropylethylamine (4.5:4.5:1, 1 mL) followed by a solution of PyBrOP (400 μmol) in DCP (500 μL). The mixture was allowed to react 3 hours at 50° C. The resin was cooled to 25° C. while washed with NMP (4×1 mL), and DCM (10×1 mL).