Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[NH4+:28]>CO.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Yield: 26 %

Procedure:
A solution of the 9-[(phenyl)methyl]-4-hydroxy-5-Carbomethoxy carbazole (200 mg, 0.6 mM) in 4 mL MeOH and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 30 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 50 mg (26%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.1 (m, 9H), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3428, 3198, 3063, 1631, 1599, 1579, 1562, 1496, 1442, 1330, 1261, 1215, 775, and 697. MS (ES) m/e 315, 317.
Reaction SMILES: [CH:1]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25]Cl)([O-:22])=[O:21].CN(C)C=O>C1C=CC=CC=1>[C:8]([C:1]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:25][C:24]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:23]=1[N+:20]([O-:22])=[O:21])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)CC(Cc1c(C)cccc1[N+](=O)[O-])(C(=O)OCC)C(=O)OCC

Procedure:
The title compound was prepared by the same procedure as described in example 1 for 1a (R2 = R3 = H), using triethyl 1,1,2-ethanetricarboxylate (9.85 g; 0.04 mole), NaH (1.6 g; 0.04 mole) and 2-nitro-6-methylbenzyl chloride (7.4 g; 0.04 mole) in 20 ml. 10% dimethylformamide (DMF) in benzene. The crude product so obtained was used directly in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (140 mg, 60% in mineral oil, 3.5 mmol) in anhydrous DMF (10 mL) was added 2-chloro-1H-benzoimidazole (460 mg, 3 mmol) at 0° C. The reaction mixture which resulted was allowed to warm to rt and stir at rt for 30 min then was cooled to 0° C. and (2-Chloromethoxy-ethyl)trimethyl-silane was added to this mixture at 0° C. After warming to rt, the mixture was allowed to stir at rt for 16 h. and then was poured onto 100 mL ice-water solution. This solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product, which was purified by silica gel flash chromatography to afford the title product (660 mg, 80%); 1H NMR (400 MHz, CDCl3); δ 0.03 (s, 9H), 0.89-0.97 (m, 2H), 3.56-3.64 (m, 2H), 5.57 (s, 2H), 7.26-7.35 (m, 2H), 7.45-7.48 (m, 1H), 7.69-7.72 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(Cl)(Cl)(Cl)Cl.[OH2:14]>CC#N>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:14])=[O:8]
Reactant: OCC1CCCCO1
Reactant: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1CCCCO1
Reaction time: 0.33 h

Procedure:
To a vigorously stirred solution of tetrahydropyran-2-methanol (2.32 g, 40 mmol) in a mixture of CH3CN (20 ml), CCl4 (20 ml) and water (10 ml) at 0° C. was added NaIO4 (9.42 g, 44 mmol) and then RuCl3H2O(414 mg, 2 mmol). After 20 min, the cooling bath was removed. After 40 min at room temperature, TLC showed reaction was complete. The reaction mixture was partitioned into ethyl acetate and ice-cold Na2S2O5 solution. More Na2S2O5 was added until all the brown material dissolved and a greenish mixture was obtained. The aqueous portion was extracted with more ethyl acetate and combined layer was washed with 10% Na2S2O5, H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using methylene chloride/methanol/acetic acid=95:5:0.5 to afford the product as an oil (1.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:12]I.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(O)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
1-(3,5-Dihydroxyphenyl)ethanone (3 g) and methyl iodide (2.80 g) were dissolved in DMF (40 ml), and sodium hydride (568 mg) was added. After stirring at RT for 2 h, the DMF was drawn off. The residue was taken up in EA and washed with water, dried, filtered and concentrated. The residue was purified using silica gel (89 g cartridge, n-heptane/EA 0-50% within 30 min). 1.12 g of the title compound were obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][Br:20])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Yield: 59.9 %

Procedure:
A solution of 54.8 g (192 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylbenzenesulfonamide in 420 ml of tetrachloromethane is heated at reflux for 6-8 h under a nitrogen protective-gas atmosphere, following addition of 36 g (202 mmol) of N-bromosuccinimide and 0.5 g of azobisisobutyronitrile (AIBN) with simultaneous irradiation with a daylight lamp. The solution is then filtered and then washed in succession with sodium disulphide solution, sodium hydrogen carbonate solution and water, dried over Na2SO4 and evaporated to dryness i.v. Crystallization of the residue from diisopropyl ether/ethyl acetate yields 41.9 g (57%) of N-tert-butyl-5-bromomethyl-2-methoxycarbonylbenzenesulfonamide of mp. 88-90 °C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[NH:4][C:5](=[NH:8])[S:6][CH3:7].[C:11]([N:15]=[C:16]=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:1][N:2]([CH3:10])[C:3]([N:4]=[C:5]([S:6][CH3:7])[NH:8][C:16]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:9]
Reactant: CSC(=N)NC(=O)N(C)C
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CSC(=NC(=O)N(C)C)NC(=O)NC(C)(C)C
Reaction time: 8 h

Procedure:
A mixture of 7 parts methyl 4,4-dimethylthioallophanimidate, 8 parts of t-butylisocyanate and 50 ml methylene chloride is refluxed for 2 hours. After standing overnight at room temperature, the solution is evaporated under vacuum to give a viscous oil, which solidified after trituration with petroleum-ether. Recrystallization from petroleum-ether gives methyl N-dimethylcarbamoyl-4-tert-butylthioallophanimidate, (a compound of formula I), m.p. 74°-78° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].C[O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O.[Cu]I>[CH:18]([N:12]1[C:13]2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[CH:10]=[CH:11]1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: C[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Temperature: 120 °C
Yield: 178.6 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and CuI (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Br:20])(=O)C>C(O)(=O)C>[Br:20][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: CC(=O)Br
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Solvent: CC(=O)O
Product: [O-][n+]1ccc(Br)cc1-c1ccccn1
Yield: 95 %

Procedure:
To 4-nitro-2,2′-bipyridyl-N-oxide (Wenkert, D.; Woodward, R. B. J. Org. chem. 48, 283(1983)) (5 g) dissolved in 30 mL acetic acid in a 100 ml round bottom flask was added 16 mL acetyl bromide. The yellow mixture was refluxed for 1.5 h and then rotovaporated to dryness. The resulting light yellow solid was sufficiently pure enough for the next step without further purification. Yield: 95%
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:6]=2[C:5](=[O:17])[CH:4](C(OC)=O)[CH2:3]1.O>CN1C(=O)CCC1>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:11]=[CH:12][C:6]2[C:5](=[O:17])[CH2:4][CH2:3][C:2](=[O:1])[NH:8][C:7]=2[CH:9]=1
Reactant: COC(=O)C1CC(=O)Nc2cc(C(F)(F)F)ccc2C1=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(=O)c2ccc(C(F)(F)F)cc2N1
Temperature: 135 °C
Reaction time: 15 h
Yield: 96.7 %

Procedure:
A 22 L reactor was charged with a solution of methyl 2,5-dioxo-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate [670 g, 2.22 mol] in NMP (4 L, 6 vol). Water (67 mL, 0.1 vol) was added and the resulting solution was slowly heated to 135° C. The reaction was continued for 15 h when HPLC analysis indicated >99% conversion. The reaction was cooled to ambient temperature. Water (8.7 L, 13 vol) was added slowly with vigorous stirring resulting in a suspension. The suspension was stirred at ambient temperature overnight. The solid was collected by filtration and the filter cake was washed with water (1.5 L). The solid was dried to a constant weight in a vacuum oven at 45° C. to obtain 8-(trifluoromethyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (522 g, 97% recovery) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm: 10.28 (s, 1H), 8.00 (d, 1H, J=8.0 Hz), 7.54 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 3.00-2.94 (m, 2H), 2.78-2.70 (m, 2H); ESI-MS m/z: 244 (M+H, 100%).
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])([O-:5])=[O:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=1
Reactant: COc1ccccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 87 %

Procedure:
Bromine, Br2 (16 ml, 311 mmol) was added in small portions to a solution of 2-nitroanisole (17.1 ml, 140 mmol) in glacial acetic acid (80 ml). The reaction mixture was then heated at 60° C. for one hour. The reaction was poured into 400 ml water, and extracted with 600 ml diethyl ether/600 ml saturated NaHSO3 (aqueous). The organic layer was washed with NaHSO3 solution, then with water, dried over sodium sulfate, and concentrated under vacuum. The residue was recrystallized from diethyl ether to give 28.4 g (87%) of 4-bromo-2-nitroanisole. 1H NMR (300 MHz, CDCl3) δ7.970 (1H, d, J=2.5 Hz), 7.64 (1H, dd, J=8.9, 2.4 Hz), 7.00 (1H, d, J=8.9 Hz), 3.96 (3H, s).
Reaction SMILES: [Na+].[Br-:2].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])[CH:7]=[CH:8][CH:9]=1>CC(C)=O.CCCCCC>[Br:2][CH:12]([CH3:13])[C:11](=[O:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: [Br-]
Reactant: CC(Cl)C(=O)Cc1cccc(Br)c1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(Br)C(=O)Cc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of NaBr (197 mg, 1.9 mmol) and 1-(3-bromophenyl)-3-chlorobutan-2-one (100 mg, 0.38 mmol) in acetone (2 ml) was stirred at 70° C. for 3 h. The mixture was diluted with hexane and filtered to remove the solid. The solvent was removed under reduced pressure and the residue was used for the next step without further purification. MS (ES+) C10H10Br2O requires: 303, 305 found: 304, 306 [M+H]+(1:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([N+:20]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.[C:23]([C:25]1[O:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1)#[N:24].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([NH:20][C:30]([C:28]3[O:29][C:25]([C:23]#[N:24])=[CH:26][CH:27]=3)=[O:31])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CN1CCN(c2ccc(N3CCCCC3)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(N3CCCCC3)c(NC(=O)c3ccc(C#N)o3)c2)CC1
Yield: 71 %

Procedure:
The title compound was prepared following the procedure of Example 4, step (c) using 28.1 mg (0.0923 mmol) of 1-methyl-4-(3-nitro-4-piperidin-1-yl-phenyl)-piperazine (as prepared in the previous step), 28 mg of 10% palladium on carbon (Degussa type E101-NE/W, 50% by weight water), 12.7 mg (0.0923 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 16.2 μL (0.185 mmol) of oxalyl chloride, and 24.1 μL (0.138 mmol) of DIEA. The resulting residue was chromatographed on a 10-g silica SPE column with 1-4% MeOH-dichloromethane to afford 25.8 mg (71%) of the title compound as a beige crystalline solid: 1H-NMR (CDCl3; 400 MHz): δ 9.97 (br s, 1H), 8.18 (d, 1H, J=2.8 Hz), 7.23, 7.25 (AB q, 2H, J=3.7 Hz), 7.11 (d, 1H, J=8.7 Hz), 6.67 (dd, 1H, J=8.7, 2.8 Hz), 3.22-3.25 (m, 4H), 2.75-2.85 (m, 4H), 2.56-2.58 (m, 4H), 2.35 (s, 3H), 1.76-1.81 (m, 4H), and 1.5-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O2, 394.2 (M+H), found 394.2.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.N(OCCC(C)C)=O.[ClH:40]>C(#N)C.[Cu](Cl)Cl>[Cl:40][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
9 g (19.762 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile are initially charged in 200 ml of acetonitrile, 7.98 ml (59.285 mmol) of isoamyl nitrite and 7.97 g (59.285 mmol) of copper(II) chloride are added and the mixture is stirred at 60° C. for 4 hours. 1N Hydrochloric acid is added to the mixture, and the precipitated solid is filtered off. It is purified on a silica gel column (mobile phase: toluene). This gives 5.98 g (63% of theory) of the target compound.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].C[O:15][B:16](OC)[O:17]C.Cl>C1COCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[B:16]([OH:17])[OH:15]
Reactant: Fc1ccccc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
Butyllithium (2.5 M in hexanes, 88 ml, 0.219 mol) was added dropwise to a stirred, cooled (−78° C.) solution of difluorobenzene (25.0 g, 0.219 mol) in dry THF (400 ml) under a stream of dry nitrogen. The reaction mixture was maintained under these conditions for 2.5 h and then trimethylborate (45.5 g, 0.438 mol) was added dropwise to the reaction mixture and left overnight to reach room temperature. The reaction mixture was stirred for 1 h with 10% HCl (100 ml) at room temperature. The product was extracted into ether (2×200 ml) and the combined ethereal extracts were washed with water and dried (MgSO4), the solvent was removed under reduced pressure to give white crystals.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C@:20]([CH3:24])([C@@H:21]([CH3:23])[CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]3)[CH2:9][CH2:8]2)(=O)C.[Br:26]N1C(C)(C)C(=O)N(Br)C1=O>O1CCOCC1.O>[Br:26][C@@H:22]1[C@H:21]([CH3:23])[C@@:20]2([CH3:24])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])=[CH:6][C:5]1=[O:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1[C@@H](Br)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 193.6 %

Procedure:
Under ice cooling, a suspension of 5.18 g of 3-acetoxy-1α-methylandrosta-2,4-dien-17-one in 50 ml of dioxane and 100 ml of water is combined in portions with 2.2 g of 1,3-dibromo-5,5-dimethylhydantoin and stirred for one hour at room temperature. Subsequently, the mixture is precipitated into 1 liter of water saturated with sodium chloride, 2.7 g of sodium sulfite is added, and the mixture is stirred for 60 minutes. The precipitated residue is filtered off, washed free of chloride with water, and dried, thus obtaining 5.65 g of a mixture of 2β-bromo-1α-methyl-4-androstene-3,17-dione and 2β-bromo-1α-methyl-4-androstene-3,17-dione.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Oc1cccc(F)c1
Product: COc1ccc2c(Oc3cccc(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenol to give [1-(3-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16]O)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:23][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To dry dimethylformamide (50 ml)solution of 22.5 g (67.9 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-8)was added 25.0 ml of thionyl chloride, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the residue, ethyl acetate was added and extracted. The extract was neutralized with a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 23.7 g of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methylimidazole (28a)(yield about 100%). mp 110-111° C.
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:2].C(O)(C)(C)C.[C:19]([O:22][C:23]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:28]([C@H:29]4[C@@:33]([CH2:36][CH2:37]3)([CH2:34][CH3:35])[CH:32]=[CH:31][CH2:30]4)[CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:21])[CH3:20]>C(Cl)CCl>[C:19]([O:22][C:23]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:28]([C@H:29]4[C@@:33]([CH2:36][CH2:37]3)([CH2:34][CH3:35])[C@@H:32]3[O:2][C@@H:31]3[CH2:30]4)[CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:21])[CH3:20]
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(OC(C)=O)ccc3[C@H]1CC2
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CC[C@]12CC[C@@H]3c4ccc(OC(C)=O)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Reaction time: 18 h

Procedure:
At room temperature, a solution of 460 mg. of p-nitroperbenzoic acid in 3 ml. of tert.-butanol and 0.6 ml. of ethylene chloride is gradually added to 600 mg. of 3-acetoxy-18-methyl-1,3,5(10),16-estratetraene in 20 ml. of ethylene chloride. After 18 hours, the crude product is worked up as described in (A) and purified by preparative layer chromatography (eluent: hexane/ethyl acetate = 7 : 3). In this way, 490mg. of 3-acetoxy-16α,17α-epoxy-18-methyl-1,3,5(10)-estratriene is isolated as an oily product.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[CH2:12]1C[O:15][CH2:14][CH2:13]1>>[CH2:14]([O:15][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:13]=[CH2:12]
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOCc1ccccc1
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of isomer A product from Step 1 (1.62 g, 4.23 mmol) in THF (50 mL) was added NaH 60% (540 mg, 13.4 mmol) followed by benzylbromide (1.5 mL, 13.4 mmol) and the reaction was stirred at 55 C overnight. The cooled mixture was poured into water, extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 99:1 to 50:50) to afford 1.07 g (53%) of allylbenzylether isomer A.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][C@H:42](O)[CH3:43].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:39][O:40][CH2:41][C@@H:42]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:43]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g of 3 mmol/g loading, 155 mmol) and (R)-(−)-1-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification.