Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>O1CCCC1>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)=[CH2:10]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
Option 2: To a 250 ml round bottom flask under argon and fitted with a stir bar was added 4-acetoxystyrene (15.00 g, 92.6 mmol), tetrahydrofuran (0.97 M), and 5 M solution of sodium hydroxide (aq.) (93 ml), all of which were freshly sparged with argon. The reaction flask was sealed and the reaction was stirred at room temperature for one hour or until the reaction was complete as indicated by TLC (SiO2: Rf=0.7, 30% ethyl acetate/hexanes). The crude reaction mixture was chilled to 0° C., at which time 6 N HCl (aq.) (90 ml) was added slowly until a pH of neutral was reached. The product was extracted into ethyl acetate, washed with water three times, dried over MgSO4, filtered, and concentrated by rotary evaporation. Further drying under vacuum yielded 4-vinylphenol 21 (11.72 g, 99%) which was immediately used. A 100 ml schlenk flask under argon was charged with deoxygenated (via the freeze-pump-thaw method, 3 times) t-butanol (0.23 M), 4-vinylphenol 21 (0.50 g, 4.16 mmol), 6-bromohexanenitrile (0.81 g, 4.58 mmol), and potassium t-butoxide (0.56 g, 4.58 mmol). The reaction flask was heated to 97° C. at which time the reaction flask was sealed and the reaction stirred for 18 hours. The crude reaction mixture was then chilled to 0° C., at which time 6 N HCl (aq.) (0.1 ml) was added slowly until a pH of neutral was reached yielding compound 22. Or, with the addition of more acid, in situ-polymerization occurred yielding compound 19. The crude product was extracted into ethyl acetate and washed with water until reaching a pH of neutral. The organic layer was dried over MgSO4, filtered, and then concentrated by rotary evaporation and further dried under vacuum to yield compound 19 (0.61 g, 68%) which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 6.65 (br, 4H), 3.87 (br, 2H), 2.35 (br, 2H), 1.69 (br, 7H), 1.25 (br, 2H). 13C NMR (60 MHz, acetone-d6): δ 157.71, 138.00, 129.08, 120.49, 114.62, 67.88, 41.29, 41.28, 29.15, 25.88, 25.79, 17.
Reaction SMILES: [H-].[Na+].[I-].[CH:4]([C:6]1[CH:7]=[C:8]([C:19]([NH:21][CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5].[CH3:30]S(C)=O>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH:11]=[C:6]([CH:4]3[CH2:30][O:5]3)[CH:7]=[C:8]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:20])[CH:9]=2)=[CH:17][CH:16]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(-c2cc(C=O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C3CO3)c2)cc1
Temperature: -10 °C

Procedure:
A mixture of sodium hydride (60% in mineral oil, 0.85 g, 21.2 mmol) in dimethyl sulfoxide (75 mL) was cooled to −10° C. Trimethylsufoxonium iodide (4.66 g, 21.2 mmol) in DMSO (25 mL) was added dropwise over a 10 mM period. The mixture was warmed to room temperature and stirred for an additional hour. The mixture was cooled to 0° C. and 5-formyl-4′-methyl-N-((6-methylpyridin-3-yl)methyl)biphenyl-3-carboxamide (3.65 g, 10.6 mmol) in DMSO (25 mL) was added dropwise over a 10 minute period. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was poured onto ice and extracted with ethyl acetate (3×150 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The mixture was purified by column chromatography using methylene chloride:methanol gradient (2-10%) to afford the title compound as a yellow oil. LC-MS: 358.8 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)[N:19]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>CCO.[Pd]>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:20]2[N:19]=[C:18]([N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[CH:12]=[CH:13]3)[CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: OC1CCC(Nc2nccc(-n3ccc4cc(OCc5ccccc5)ccc43)n2)CC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(ccn2-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 4-[4-(5-benzyloxyindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (70 mg) and Pd/C (15%, 38 mg) in EtOH was stirred under H2 (balloon pressure) at RT for 4 days. The reaction mixture was then filtered through a CELITE™ pad, the filter cake washed with EtOH, and the filtrate evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH, 95:5) to give trans-1-[2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-5-ol (51 mg) as an off-white solid. MS=325 [M+H]+; MP=246.5-248.0° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:37])([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([C:28](=[O:36])[NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22][C:23]([CH3:27])=[N:24]3)=[CH:19][CH:18]=2)=[CH:13][N:12]=1)[C:5]([O:7]C)=[O:6].O1CCCC1.Cl>CO>[CH3:3][C:4]([CH3:37])([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([C:28](=[O:36])[NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22][C:23]([CH3:27])=[N:24]3)=[CH:19][CH:18]=2)=[CH:13][N:12]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)Nc4ccccc4)cc(C)nc3c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2n1
Reaction time: 12 h
Yield: 60 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (2.0 mL) was added to a solution of methyl 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoate B-16 (94.0 mg, 0.20 mmol) in a 1:1 mixture of tetrahydrofuran:methanol (5.0 mL) at room temperature. After 12 h of stirring, the aqueous layer was acidified to pH 0 with a 1 N aqueous hydrogen chloride solution and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoic acid B-17 (54.7 mg, Yield=60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (s, 6H), 2.75 (s, 3H), 4.30 (s, 2H), 6.93 (d, J=8.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.41 (t, J=9.5 Hz, 1H), 7.64 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.29 (s, 1H), 8.51 (s, 2H), 8.67 (m, 1H), 10.86 (s, 1H); MS (ESI) [M+1]+ 456.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1([CH2:20][CH:21]=O)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].NC1C=CC=CC=1>ClCCCl.C(Cl)Cl.CO>[CH3:10][O:11][C:12]([C:14]1([CH2:20][CH2:21][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: Cc1cc(Br)ccc1N
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C1(CCNc2ccc(Br)cc2C)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-Methyl-4-bromo-aniline (1.20 g, 6.45 mmol) was dissolved in DCE (30 mL); to this solution was transferred a solution of 4-(2-oxo-ethyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (1.20 g, 6.44 mmol in DCE (30 mL). The flask was submerged in a water bath at rt. To this clear solution was then added acetic acid (1.2 g, 20 mmol, 3.1 equiv), followed by addition of powder NaBH(OAc)3 (24.1 g, 19.3 mmol, 3 equiv. in 2 portions under N2 at r.t. The yellowish milky suspension was stirred at r.t. overnight. LC/MS showed m/z 356/358 at t=3.955 min. along with small amount of aniline sm at 2.078 (186/188). There was no di-alkylated product detected (MW 526.47). TLC (5% of MeOH in DCM) showed no SM aldehyde, but aniline. The reaction was diluted with DCM (30 mL), cooled to ice-water bath, and quenched with an aqueous solution of 10 mL of conc. NH4OH (7.45M) in 30 mL of water. (2 M of NH4OH). 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 (20 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The product was purified on a 40-g silica gel column (0-5% B: 0-4 min; 5-15% B 4-13 min; 20% B: 13-25 min (B is 10% MeOH in DCM) to get 2.00 g (87%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N+:6]=1[O-])=[O:4].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: COC(=O)c1c2ccccc2cc[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(Cl)cc2ccccc12
Temperature: 100 °C
Yield: 49 %

Procedure:
A mixture of 1-(methoxycarbonyl)isoquinoline 2-oxide (9.5 g, 46.75 mmol) and POCl3 (50 mL) was heated at 100° C. for 4 hours. The reaction mixture was subsequently cooled and concentrated, and the crude product was purified by silica gel chromatography eluting with petroleum ether and EtOAc (15:1) to give the title compound as a white solid (5.1 g, 49%). ESI-MS m/z [M+H]+ 222.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 109 %

Procedure:
4-bromo-2-chlorophenol (1.0 g, 4.82 mmol) was dissolved in MC (30 ml), followed by addition of tert-butyldimethylsilyl chloride (1.09 g, 7.23 mmol) and imidazole (492 mg, 7.23 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 24 hours. The resulting reaction liquid was sequentially washed with distilled water (15 ml) and a saturated aqueous NaHCO3 solution (15 ml), and then dried over anhydrous magnesium sulfate, followed by filtration and concentration. The residue thus obtained was subjected to MPLC (5% EtOAc/Hexanes), to obtain 1.69 g of colorless oil (99%).
Reaction SMILES: [CH:1]1([NH:9][NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24]>>[Br:21][C:22]([CH3:27])([CH3:26])[C:23]([N:9]([CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:24]
Reactant: O=C(NNC1CCCCCCC1)OCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Product: CC(C)(Br)C(=O)N(NC(=O)OCc1ccccc1)C1CCCCCCC1

Procedure:
Benzyl 2-cyclooctylhydrazinecarboxylate and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-cyclooctylhydrazinecarboxylate was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].F[C:16]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:17]=1[CH:18]=[O:19]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:16]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:17]=2[CH:18]=[O:19])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
(4-Chloro-3-hydroxy-phenyl)-acetic acid ethyl ester was reacted with 2-fluoro-5-nitrobenzaldehyde as outlined in Example 21, Step 5, to provide [4-chloro-3-(2-formyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: c1cncc(C2CCNC2)c1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3cccnc3)C2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (15 mg, 0.068 mmol) in dichloromethane (1 mL) was added 3-pyrrolidin-3-ylpyridine (11 mg, 0.074 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1471.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:18]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1NCCCCO
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Reaction time: 4 h
Yield: 17 %

Procedure:
To a stirred solution of methyl 3-amino-2-[(4-hydroxybutyl)amino]benzoate (29.8 g, 125 mmol) in dichloromethane (500 mL) was added N-chlorosuccinimide (33.3 g, 250 mmol) at room temperature. After 4 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate and purified by flash column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane mixture to give the title compound as a pale red solid (5.81 g, 21.3 mmol, 17%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:17]([O:3][C:4]1[CH:9]=[C:8]([O:10][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][N:5]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Solvent: ClCCl
Product: O=C(Oc1ccnc(OC(=O)c2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To 4.0 g of 2,4-bis(trimethylsilyloxy)-pyridine in 50 ml of dichloromethane were added 2.65 g of benzoyl chloride and 0.2 ml of stannic chloride, and the mixture was stirred at room temperature for one hour. The solvent was distilled off and the residue was subjected to silica gel chromatography using ethyl acetate-benzene (2:3) as an eluent to produce 0.74 g of the title compound in a yield of 14.8%.
Reaction SMILES: [C:1]([O:4][CH:5]([C:36]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=1)[C@H:6]([CH:33]([CH3:35])[CH3:34])[CH2:7][C@H:8]1[C@H:12]([CH2:13][NH:14][C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[O:11]C(C)(C)[N:9]1C(OC(C)(C)C)=O)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([O:4][CH:5]([C:36]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=1)[C@H:6]([CH:33]([CH3:34])[CH3:35])[CH2:7][C@H:8]([NH2:9])[C@@H:12]([OH:11])[CH2:13][NH:14][C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(OC(C)=O)c1ccc2cnn(CCCOC)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(OC(C)=O)c1ccc2cnn(CCCOC)c2c1
Reaction time: 2 h
Yield: 61 %

Procedure:
(4S,5S)-tert-butyl 4-((S)-2-(acetoxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-5-((2,2-dimethylhexanamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate (25 mg, 0.036 mmol) was dissolved 20% TFA/CH2Cl2 (6 mL) at 0° C. and the stirred for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give (2S,4S,5S)-4-amino-6-(2,2-dimethylhexanamido)-5-hydroxy-2-isopropyl-1-(1-(3-methoxypropyl)-1H-indazol-6-yl)hexyl acetate (12 mg, 52%). 1H NMR (400 MHz, CD3OD): 0.84-1.00 (m, 9H), 1.11-1.32 (m, 10H), 1.58 (m, 3H), 1.95 (m, 1H), 2.14 (m, 6H), 3.12 (m, 2H), 3.45 (m, 1H), 3.83 (m, 1H), 4.50 (m, 2H), 5.91 (m, 1H), 7.12 (m, 1H), 7.53 (m, 1H), 7.75 (t, 3H), 8.04 (m, 1H). MS: 644 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(OCC(=O)c2ccc(Br)cc2)c1

Procedure:
11.5 g of 4-bromophenacyl bromide are dissolved in 250 ml of acetone and, after the addition of 5.75 g of potassium carbonate and 4.5 ml of 3-methoxyphenol, the reaction mixture is stirred and subsequently filtered. The filtrate is concentrated and the residue is chromatographed over silica gel with ethyl acetate/hexane (5:95 to 10:90). There are obtained 7.3 g of 1-(4-bromo-phenyl)-2-(3-methoxy-phenoxy)-ethanone, MS: m/e 320 (M+, 1 Br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](C)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:3]=2)=[CH:20][CH:19]=1)[CH2:16][CH3:17]
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2cccc(Br)c2)nc1
Product: CCCc1ccc(-c2cccc(-c3ccccn3)c2)cc1
Yield: 128.5 %

Procedure:
2-(3-bromophenyl)-5-methylpyridine (20.0 g, 81.1 mmol) was reacted with 4-n-propylphenylboronic acid (15.9 g, 96.7 mmol) under standard Suzuki coupling condition. Kugelrohr distillation at 230° C. yielded 28.5 g of a viscous yellow liquid that was then purified by silica gel column chromatography with 15/85 ethyl acetate/hexane as the eluent, affording 14.0 g of pure material plus an additional impure fraction.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([OH:19])[CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[CH:3]=[CH2:4]>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[OH:19][CH:8]([CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH3:13])[CH2:7][CH2:6][CH2:5][C:2](=[O:1])[CH:3]=[CH2:4]
Reactant: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: C=CC(=O)CCCC(O)CCCC(C)OC(C)(C)C
Reaction time: 2 h

Procedure:
Crude 3,7-dihydroxy-11-(t-butoxy)-dodec-1-ene (5.8 g., prepared as described above) was dissolved in benzene (200 ml.) and the reaction mixture was then stirred for 2 hours at 25° after addition of activated manganese dioxide (58 g.). Filtration and evaporation of the filtrate at 30° in vacuo afforded crude 7-hydroxy-11-(t-butoxy)-dodec-1-en-3-one.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[C:15]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[S:13][C:12]=2[CH:11]=1)(=[O:17])[CH3:16]
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 2 h

Procedure:
Phenoxathiin (22.9 g) and acetyl chloride (8.8 ml) were dissolved in carbon disulphide (120 ml) and mechanically stirred while aluminum chloride (15.5 g) was added in small portions. The red mixture was stirred for 2 hr. at room temperature, then boiled under reflux on the water bath for a further 221/4 hr. The mixture was cooled and poured on to ice and hydrochloric acid, and the precipitated product filtered off, washed with water, and recrystallised once from ethanol and twice from petroleum ether (b.p. 80°-100° C.) to give the product m.p. 112° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])(=[O:23])=[O:22]>N1C=CC=CC=1>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[S:21]([CH3:20])(=[O:23])=[O:22])(=[O:32])=[O:31])[CH:17]=3)[NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(C(=O)Nc3ccccc3)c2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C(=O)Nc3ccccc3)c2c1
Yield: 67.7 %

Procedure:
N-Phenyl-5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 2 from 40 mg of N-phenyl-5-amino-1H-indazole-3-carboxamide, 4 ml of pyridine and 40 mg of 2-methylsulfonylbenzenesulfonyl chloride. 50 mg of N-phenyl-5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of a pale yellow solid melting at 258° C. (analysis C21H18N4O5S2.0.48H2O, % calculated C, 53.61; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.17; H, 3.48; N, 11.58; S, 14.08).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCCCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
In 32 ml of water and 32 ml of ethanol, 27.2 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 9.0 g of sodium hydroxide were added. To this solution, 45.2 g of 1-iodoheptane was added, and the mixture was stirred at 60° C. for 2 hours. After cooling, water was added to the mixture and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/n-hexane (1:1) mixture. Thus 36.1 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained. m.p. 112°~113° C. Yield 78%.