Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:35])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29]OS(C)(=O)=O)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:35])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:42]4[C:41](=[O:43])[C:40]5=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]5[C:38]4=[O:48])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)-benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.26 g), and the mixture is stirred at 110° C. for one hour. The mixture is poured into ice-water, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica gel column chromatography to give 7-chloro-1-[6-(6,7-benzo-1-oxo-4-azepin-5-on-4-yl)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g, Compound A) and 7-chloro-1-{6-[2-(2-phthalimido-ethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g, Compound B), separately.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.C([S-])C.[Na+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2cc1OC
Agent: CC[S-]
Agent: [Na+]
Product: Oc1cc2ncnc(Nc3cccc(Cl)c3)c2cc1O
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 4, 6,7-dimethoxy-4-(3'-chloroanilino)quinazoline was reacted with sodium ethanethiolate to give 6,7-dihydroxy-4-(3'-chloroanilino)quinazoline in 68% yield, m.p. 233°-235° C.
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4]1)#[N:2]>C1C=CC2C(=CC=CC=2O)C=1>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2C(C#N)(O[Si](C)(C)C)C1
Agent: Oc1cccc2ccccc12
Product: CCOC(=O)C1C=C(C#N)c2ccc(OC)cc2C1

Procedure:
Following the procedure described in Naphthol 5, Step 5, but substituting the ester from Step 1 for the mixture of alcohol ester and lactone from Step 4 in Naphthol 5, the title compound was obtained and used as such for the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][N:7]1[C:17](=O)[CH3:18].[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[C:23]#[N:24].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:21]([N:20]=[C:17]([N:7]2[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:6]2)[CH3:18])[C:22]=1[C:23]#[N:24]
Reactant: CC(=O)N1CCCc2ccccc2C1
Reactant: N#Cc1c(N)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=Nc1cccc(Cl)c1C#N)N1CCCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
Phosphorus oxychloride (2.93 mL, 32.0 mmol) was added to a stirred solution of 1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethanone (5.5 g, 29.0 mmol) in dry dichloromethane (100 mL) at 10° C. After that, the mixture was stirred for 20 minutes at room temperature. Then a solution of 2-amino-6-chloro-benzonitrile (4.43 g, 29.0 mmol) in dry dichloromethane (40 mL) was added and the resulting suspension was heated under reflux for 24 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added followed by saturated sodium bicarbonate to pH 8. The organic layer was separated and the aqueous was extracted with dichloromethane (100 mL). The organic fraction was washed with brine and dried over sodium sulfate, and then evaporated in vacuo to give a residue which was precipitated in ether. The solid was collected by filtration and dried in vacuo to give 6 g of product as a brown powder (yield was 63.7%). It was used in the next step without further purification. MS obsd. (ESI+) [(M+H)+] 324.
Reaction SMILES: [S:1](=O)(=O)(O)O.O.C(O[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=S)C.O>CO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][SH:1])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=S(=O)(O)O
Reactant: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CS)cc1
Yield: 98 %

Procedure:
Concentrated sulfuric acid--water (1:1 v/v; 17 cm3) was added to a stirred suspension of 4-nitrobenzyl thioacetate (8.0 g, 37.9 mmol) in methanol (150 cm3) and the reactants were heated, under reflux, for 3 h. The cooled products were poured into water (1.0 dm3) and the resulting mixture was extracted with diethyl ether (2×400 cm3). The combined organic extracts were washed with water (2×200 cm3), dried (MgSO4) and evaporated under reduced pressure to give 4-nitrobenzyl mercaptan 17a as a pale yellow solid (6.31 g, 98%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH2:25][O:26][C:27]4[C:32]([F:33])=[CH:31][C:30]([CH2:34][CH2:35][C:36](OCC)=[O:37])=[CH:29][C:28]=4[F:41])=[C:18]([C:21]([F:24])([F:23])[F:22])[S:19][CH:20]=3)=[CH:15][C:10]=2[O:9][CH2:8]1>>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH2:25][O:26][C:27]4[C:32]([F:33])=[CH:31][C:30]([CH2:34][CH2:35][CH2:36][OH:37])=[CH:29][C:28]=4[F:41])=[C:18]([C:21]([F:24])([F:22])[F:23])[S:19][CH:20]=3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc4c(c3)OCO4)csc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2c(-c3ccc4c(c3)OCO4)csc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((4-(benzo[d][1,3]dioxol-5-yl)-2-(trifluoromethyl)thiophen-3-yl) methoxy)-3,5-difluorophenyl)propanoate to give the desired product as off-white oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.08 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.5 Hz, 2H), 6.02 9s, 2H), 5.11 (s, 2H), 3.67 (d, J=7.5 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.86 (m, 2H), 1.55 (br, s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][C:35]1[CH:43]=[C:42]2[C:38]([CH2:39][CH2:40][CH:41]2[NH2:44])=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:44][CH:41]2[C:42]3[C:38](=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:43]=3)[CH2:39][CH2:40]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: COc1ccc2c(c1)C(N)CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(NC(=O)C1COCCN1c1nc(Cl)ncc1Br)CC2

Procedure:
The title compound was prepared in a manner similar to PREPARATION x31 using 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 500 mg, 1.550 mmol), EDC (446 mg, 2.325 mmol), HOBt (356 mg, 2.325 mmol), 6-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (464 mg, 2.325 mmol) and triethylamine (0.324 mL, 2.325 mmol) in DMF (10 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.76-1.94 (m, 1H), 2.30-2.47 (m, 1H), 2.62-2.93 (m, 2H), 3.48-3.65 (m, 2H), 3.70 (d, J=4.80 Hz, 3H), 3.87-3.96 (m, 1H), 4.24-4.43 (m, 2H), 4.89-5.01 (m, 1H), 5.26-5.41 (m, 1H), 6.70-6.82 (m, 2H), 7.08-7.18 (m, 1H), 8.45 (s, 2H). ESI-MS m/z [M+H]+ calc'd for C19H20BrClN4O3, 467.04. found 467.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](Cl)=[O:18])[CH:15]=3)[C:10]([CH3:20])=[CH:9]2)=[CH:5][CH:4]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:27][O:26][N:25]([CH3:24])[C:17]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:20])=[CH:9][N:8]2[CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)Cl)cc32)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2cc(C)c3ccc(C(=O)N(C)OC)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A stirred solution of 1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carbonyl chloride [2.8 g, Reference Example 42(b)] in chloroform (90 ml) at 0° C. was treated with N,O-dimethylhydroxylamine hydrochloride (0.982 g) and pyridine (1.55 ml). The solution was stirred at room temperature for 1 hour then evaporated. The residue was partitioned between dichloromethane (100 ml) and brine (50 ml). The organic layer was dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the title compound (2.8 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].[CH3:12][SiH:13]([CH3:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1.[Pt].ClCCl.C1CC=CC=1.[Pt](Cl)Cl>[CH3:12][Si:13]([CH3:16])([CH2:14][CH3:15])[CH2:4][CH2:3][CH2:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=1
Reactant: CC[SiH](C)C
Reactant: C=CCCc1ccc(Br)cc1
Agent: Cl[Pt]Cl
Agent: [Pt]
Agent: C1=CCC=C1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[Si](C)(C)CCCCc1ccc(Br)cc1
Reaction time: 3 h
Yield: 67.9 %

Procedure:
About 20.0 g (95 mMol) of 4-(3-butenyl)-1-bromobenzene [which can be prepared, for example, by the method of P. E. Peterson et al, J. Org. Chem. 33, 972 (1968)] were dissolved in 40 ml of toluene, 2 ml of a platinum catalyst solution (0.5 percent solution of cyclopentadiene-platinum dichloride in dichloromethane) were added, and the mixture was added dropwise to a stirred solution containing 16 g (0.18 Mol) of commercially available dimethylethylsilane in 20 ml of toluene. The mixture was stirred at 50° to 70° C. for 3 hours and then cooled, and the solvent was removed by distillation. The residue was fractionated under reduced pressure. Approximately 19.4 g of 4-[4-(dimethylethylsilyl)butyl]-1-bromobenzene (67.9 percent yield) were obtained at a pressure of 0.05 hPa and at a temperature of 110° to 112° C. A mixture containing 18 g (0.06 Mol) of this derivative, 6.3 g (0.07 Mol) of CuCN and 10 ml of dimethylformamide was heated at 160° C. for 8 hours. The mixture, still hot at 80° C., was poured into a mixture containing 30 g of iron(III) chloride, 7.5 ml of concentrated hydrochloric acid and 90 ml of water, and the full mixture was stirred at 70° C. for 75 minutes. The product was then extracted with tert-butyl methyl ether, the extract was washed, dried and evaporated, and the residue was fractionated. About 9.9 g of 4-[4-(dimethylethylsilyl)butyl]benzonitrile were obtained at 0.02 hPa and at 114° to 116° C. (66.6 percent yield).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])#[N:2].C[Si]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C=CC=CC=1>[CH:25]1([NH:24][C:22]([C:7]2[N:8]=[N:9][N:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=3)[C:6]=2[CH2:5][CH2:4][CH2:3][C:1]2[NH:34][N:33]=[N:32][N:2]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2nnn[nH]2)cc1
Yield: 26.9 %

Procedure:
A solution of 5-(3-cyanopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (183 mg, 0.5 mmol) obtained in Example 1207, trimethylsilyl azide (58 mg, 0.5 mmol) and di-N-butyltin oxide (12.5 mg, 0.05 mmol) in toluene (5 ml) was boiled under reflux for 24 hr and the solvent was evaporated. Methanol (5 ml) was added to the residue, and the solvent was evaporated again. Ethyl acetate (10 ml) and 6% aqueous sodium bicarbonate solution (10 ml) were added to the residue and, after partitioning, the aqueous layer was adjusted to pH 4-5 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and dried to give the title compound as a colorless powder (55 mg, 27%).
Reaction SMILES: [CH2:1]([C@H:5]1[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:9]2[CH:16]=[CH:17][C:18]([N+:20]([O-])=O)=[CH:19][C:8]=2[O:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]>C(OCC)(=O)C.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:9]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[C@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][O:7][C:8]=2[CH:19]=1
Reactant: CC(C)C[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H]1COc2cc(N)ccc2N1CC(F)(F)F
Yield: 65.3 %

Procedure:
This compound was prepared according to General Method 4 (EXAMPLE 1) from (3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (0.22 g, 0.69 mmol) and 10% Pd/C (0.075 g) in 5 mL ethyl acetate to afford 0.13 g (65%) of (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine. Data for (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine: Rf 0.3 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.63 (d, 1H, J=8.5), 6.27 (dd, 1H, J=8.5, 2.6), 6.23 (d, 1H, J=2.5), 4.10 (dd, 1H, ABx, J=10.6, 1.8), 3.97 (dd, 1H, ABx, J=10.6, 2.3), 3.70-3.51 (m, 2H), 3.38 (broad s, 2H), 3.19-3.13 (m, 1H), 1.75-1.63 (m, 1H), 1.47-1.25 (m, 2H), 0.93 (d, 3H, J=6.6), 0.89 (d, 3H, J=6.6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](SC)=[N:7][C:6]=2[CH:12]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].N1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:19]3[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]3)=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(Br)ccc2s1
Reactant: CC(C)N1CCNCC1
Solvent: c1ccncc1
Product: CC(C)N1CCN(c2nc3cc(Br)ccc3s2)CC1
Temperature: 160 °C
Yield: 76.3 %

Procedure:
A mixture of 5-bromo-2-(methylthio)benzothiazole (200 mg, 0.77 mmol), 1-isopropylpiperazine (985 mg, 7.7 mmol) and pyridine (610 mg, 7.7 mmol) was heated at 160° C. for 36 h. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluent: 2% EtOAc in Petroleum ether) to give 200 mg (77%) of 5-bromo-2-(4-isopropylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1(N2C(=[O:41])N=NC2=O)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][C@@H:20]2[OH:41])=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: O=C1N=NC(=O)N1c1ccccc1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
140.3 g of the 1α,2α-epoxide of the 1,4-cyclic adduct of cholesta-1,5,7-triene-3β,25-diol and 4-phenyl-1,2,4-triazoline-3,5-dione obtained in Example 2 was dissolved in 15 ml of tetrahydrofuran, and 142 mg of lithium aluminum hydride was added little by little to the solution under agitation. Then, the mixture was mildly refluxed and boiled for 1 hour and cooled, and 20 ml of tetrahydrofuran was added to the reaction mixture. A saturated aqueous solution of Glauber salt was added to the reaction mixture until generation of bubbles was stopped, whereby excessive lithium aluminum hydride was decomposed. The reaction mixture was then filtered, and the residue was washed 3 times with 10 ml of tetrahydrofuran. The organic solvent layer was dried and the solvent was distilled off. The residue was purified by using a column packed with 20 g of Sephadex LH 20, and a fraction eluted by chloroform-hexane (65 : 35 V/V ratio) was collected and recrystallized from ether-hexane to obtain 49.9 mg of cholesta-5,7-diene-1α,3β,25-triol in the form of needles melting at 149° to 152° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:52])([F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:51])([F:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 6804236; 28.9 mg, 0.0393 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane, and the solvent was again distilled off under reduced pressure. This operation was repeated twice and the residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5513213; 20.1 mg, 75% yield, white powder).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.O1CCOCC1>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.O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:25]([C:26]2[S:30][N:29]=[CH:28][N:27]=2)[S:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[C:49]2[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=2)=[N:13][CH:14]=[CH:15]3)(=[O:24])=[O:23])=[CH:33][CH:34]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)cc1
Reactant: OB(O)c1ccncc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccncc4)nccc3c2)cc1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
A microwave vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.157 mmol), potassium carbonate (109 mg, 0.787 mmol), 4-pyridineboronic acid (77 mg, 0.629 mmol), tetrakis(triphenylphosphine)palladium(0) (18.18 mg, 0.016 mmol), dioxane (1049 μl) and water (525 μl). The vial was purged with argon, sealed and heated in a microwave at 100° C. for 35 min. The reaction was cooled to room temperature, diluted with 60 mL of EtOAc, dried over MgSO4, filtered and concentrated. The material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 100% (90:10 MeOH:DCM) in DCM, to provide a yellow glass, N-(4-methoxybenzyl)-1-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.158 mmol). This material was carried on to the next step. MS (ESI): 634.0 [M+H]+.
Reaction SMILES: ON1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([C:19]2([CH:27]=[CH:26][CH:25]=[CH:24][CH2:23]2)C[O:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O-:21][OH:22].[CH:19]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1.[CH:34]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: OOCC1(C2CCCCC2)C=CC=CC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc(C2CCCCC2)cc1
Product: [O-]O
Reaction time: 8 h

Procedure:
0.3 mmol of N-hydroxyphthalimide and 0.6 mmol of 1-cyclohexylbenzyl hydroperoxide are added at a temperature of 110° C. to 30 mmol of cyclohexylbenzene in a round-bottomed flask having an attached reflux condenser. The reaction mixture is stirred for 8 hours at said temperature under an oxygen atmosphere of 1 bar. 1-cyclohexylbenzene hydroperoxide is obtained at a selectivity of 96.2% at a cyclohexylbenzene conversion rate of 28.6%.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[C:12]([CH3:31])[CH:11]=2)[CH2:6][CH2:5]1.[N:32]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45]I)=[N+:33]=[N-:34].O>CN(C=O)C>[N:32]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[C:12]([CH3:31])[CH:11]=2)[CH2:6][CH2:5]1)=[N+:33]=[N-:34]
Reactant: Cc1cc(N2CCC(O)CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: [N-]=[N+]=NCCOCCOCCOCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC(OCCOCCOCCOCCN=[N+]=[N-])CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 21.3 %

Procedure:
NaH (13.2 mg, 60% in mineral oil, 0.330 mmol) was added to a 0° C. solution of N-(4-(4-(4-hydroxypiperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (14.8 mg, 0.0362 mmol) in dry DMF (0.5 mL); the mixture was then stirred at 50° C. for 20 min. After that, the mixture was cooled to 0° C., and a solution of 1-azido-2-(2-(2-(2-iodoethoxyl)ethoxy)ethoxy)ethane (14.3 mg, 0.0435 mmol)6 in DMF (0.15 mL) was added dropwise. The mixture was stirred at rt overnight. Water (2 mL) was added to quench the reaction, and the mixture was extracted with DCM (4×2 mL). The combined organic layer was washed with brine and concentrated. The residue was briefly purified on a short silica column (EtOAc) to furnish N-(4-(4-(4-(2-(2-(2-(2-azidoethoxyl)ethoxy)ethoxy)ethoxy)piperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (4.7 mg, 21.3%). MS (ESI) m/z 632.4 (M+Na+).