Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reaction time: 18 h
Yield: 64.4 %

Procedure:
DIAD (3.92 mL, 19.90 mmol) was added dropwise to a stirred solution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.67 g, 13.27 mmol) and triphenylphosphine (5.22 g, 19.90 mmol) in THF (30 mL) cooled to 0° C. under a nitrogen atmosphere. The resulting solution was stirred at 0° C. for 10 minutes then allowed to warm to room temperature and stirred overnight. The mixture was diluted with isohexane (80 mL) and EtOAc (20 mL) and then stirred vigorously. The mixture was filtered and the solid washed with isohexane (20 mL). The combined filtrates were evaporated and the residue was purified by chromatography on silica, eluting with a gradient of 20-50% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (3.63 g, 92% yield); 1H NMR spectrum: (300 MHz, DMSO) 1.42 (9H, s), 1.79-1.84 (2H, m), 2.01-2.05 (2H, m), 2.87-2.98 (2H, m), 4.40-4.47 (1H, m), 8.28 (1H, s), 8.95 (1H, s). b) A mixture of tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (3.63 g, 12.25 mmol) and 10% palladium on carbon (0.326 g, 0.31 mmol) in EtOH (200 mL) were stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through Celite and the filtrate loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (2.100 g, 64% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.41 (9H, s), 1.65-1.74 (2H, m), 1.89-1.92 (2H, m), 2.81-2.93 (2H, m), 3.75 (2H, s), 3.99 (2H, d), 4.09-4.16 (1H, m), 6.91 (1H, s), 7.06 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=211.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH3:20])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH4+].[Cl-]>[Zn].CO.C1COCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[C:7]#[N:8])=[CH:12][C:13]=1[CH3:20]
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Reaction time: 0.17 h

Procedure:
Intermediate (24t) (14.3 g, mmol) and zinc dust (17.2 g, 263 mmol) were suspended in mixed solvent of MeOH/THF (1:1, 125 mL) and saturated NH4Cl (125 mL) was added. The reaction mixture became warm. There was an obvious change in the zinc suspension. The reaction was finished in 10 minutes. The reaction mixture was filtered through a silica plug and diluted with EtOAc and saturated NaHCO3. The layers were separated and the combined organics dried over MgSO4 and concentrated under reduced pressure. The crude residue (25t) was pure enough on NMR spectra. 1HNMR (400 MHz, d6-DMSO) δ 7.83 (dd, J=8.5, 3.1 Hz, 1H), 7.47 (td, J=8.9, 3.1 Hz, 1H), 6.83-6.77 (m, 2H), 6.74 (dd, J=8.6, 2.3 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.88 (s, 1H), 2.06 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[CH:14]=O.C(O)CCC.[NH2:29][CH2:30][CH:31]([NH2:33])[CH3:32].II.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[C:14]1[NH:29][CH2:30][CH:31]([CH3:32])[N:33]=1
Reactant: CC(N)CN
Reactant: N#Cc1c(N2CCOCC2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC1CNC(c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)=N1
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To 4-(2,4-dichlorophenyl)-5-formyl-2-morpholin-4-ylthiophene-3-carbonitrile (52.0 mg, 0.000142 mol) in tent-butyl alcohol (0.75 g, 0.010 mol) was added 1,2-diaminopropane (12.9 mg, 0.000174 mol) and the mixture was stirred for 30 min. Iodine (51 mg, 0.00020 mol) and potassium carbonate (65.7 mg, 0.000475 mol) was added the mixture was stirred at 70° C. for 3 hr. The reaction mixture was quenched by saturated sodium bicarbonate solution and brine. The organic layer was collected and purified by column chromatography to afford 4-(2,4-dichlorophenyl)-5-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (19 mg, 32%). LCMS: (FA) ES+ 421. 1H NMR (400 MHz, d1-chloroform) δ: 7.60 (s, 1H), 7.50-7.40 (m, 1H), 7.40-7.30 (m, 1H), 4.20-4.05 (m, 1H), 3.90-3.75 (m, 5H), 3.60-3.70 (m, 4H), 3.38-3.20 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1.Cl[C:39]1C=C2C(C3N=C(NC4CCC[C@H](O)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.S([O-])([O-])(=O)=O.[Ca+2]>[Ag]=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][CH3:39])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCC[C@H](O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CI
Product: COC1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of methyl iodide (0.20 g, 0.41 mmol) and 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanol, 27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol and calcium sulfate (0.28 g, 2.04 (mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to afford 120 mg of the desired product, 27b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[C:9]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:20]=1.[BH4-].[Na+].[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([OH:12])[C:9]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:20]=1
Reactant: O=C1Cc2ccc(F)cc2Sc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)C(O)Cc1ccc(F)cc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 6.9 g of the foregoing ketone in 90 ml of dioxane was treated dropwise with a solution of 9.8 g of sodium borohydride in 3 ml of water containing 1 drop of a 20% sodium hydroxide solution. The mixture was stirred for 2 hours at room temperature and after standing overnight, dioxane evaporated. The residue was diluted with water, acidified with hydrochloric acid and the product extracted with chloroform. Processing of the extract and crystallization of the crude product from benzene yielded 4.1 g pure 3-fluoro-8-nitro-10,11-dihydrodibenzo(b,f)thiepin-10-ol, m.p. 133°-135° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2nccs2)cc1

Procedure:
Using 2-bromothiazole (0.5 g, 3.05 mmol) and (4-chlorophenyl)boronic acid (0.57 g, 3.65 mmol) and following the procedure described in Example 7, Step 1, the title compound was obtained after purification by column chromatography (15% ethyl acetate in hexane) as colorless viscous liquid (0.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, 2H), 7.92 (d, 1H), 7.80 (d, 1H), 7.55 (d, 2H); LC-MS m/z calculated for [M+H]+195.99. found 195.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20](OCC)=[O:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([CH2:20][OH:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(Sc2cc(Cl)cc(Cl)c2)c(CO)nn1CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of Example 46 (65 mg, 0.17 mmol) in tetrahydrofuran (2.5 ml) was cooled to −78° C. and treated with lithiumaluminium hydride (1M in THF) (170 μL, 0.17 mmol). After stirring at −78° C. for 2 hours the reaction mixture was allowed to warm to 0° C. for 1 hour and was then allowed to warm to room temperature. After stirring at this temperature for 18 hours, water (1 ml) was added. The reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (42 mg) as a colourless oil, which solidified on standing, m.p. 89-90° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](=O)[CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:19].O>CN(C)C=O>[CH3:19][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:31])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:17]
Reactant: CC(=O)c1ccc2c(c1)CCCN2C(C)C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2.0 g (60%, 51 mmol) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide, and 11.3 g (51 mmol) of ethyl diethylphosphonoacetate was dropped into the suspension under cooling with ice. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 5.5 g (25 mmol) of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanone. The obtained mixture was stirred at 60° C. for 48 hours, followed by the addition of water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (4% ethyl acetate/n-hexane) to give 4.0 g of the title compound as a colorless oil.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][CH3:6].[F:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>C(#N)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:3][CH2:4][NH:5][CH3:6])=[CH:10][CH:9]=1
Reactant: Fc1ccc(S)cc1
Reactant: CNCCBr
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCSc1ccc(F)cc1
Yield: 61.6 %

Procedure:
Reflux a mixture of (2-bromoethyl)methylamine hydrobromic acid salt (500 mg, 2.28 mmol), 4-fluorobenzenethiol (0.243 mL, 2.28 mmol), and potassium t-butoxide (512 mg, 4.56 mmol) in acetonitrile (10 mL) for 17 hours. Remove the solvent under vacuum and dissolve the residue in ether and 5 N sodium hydroxide solution. Extract the organic layer with 1 N hydrochloric acid solution. Neutralize the acidic aqueous layer with 5 N sodium hydroxide solution and extract twice with ether. Dry the combined ether extracts over magnesium sulfate and reduce under vacuum to give 260 mg of the titled compound as an oil.
Reaction SMILES: [F:1][C:2]([F:30])([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[F:1][C:2]([F:30])([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
26 g (60.4 mmol) of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-phenyl)prop-2-enoate is dissolved in 400 ml of dioxane. 30 ml of NaOH (30%) diluted in 250 ml of water is added to the solution. The mixture is heated to 55° C. for 2 hours. The mixture is cooled to room temperature and is carefully acidified to pH=2 with a HCl solution (25%) and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 20 g of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-phenyl)prop-2-enoic acid as a colourless powder.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[OH:14]O>C(O)(=O)C.O>[S:10]([C:2]1[S:1][C:5]2=[N+:6]([O-:14])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)(=[O:12])(=[O:11])[NH2:13]
Reactant: NS(=O)(=O)c1cc2cccnc2s1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of thieno[2,3-b]pyridine-2 Sulfonamide (0.43 g, 2 mmol) and 30% hydrogen peroxide (1.0 ml) in acetic acid (5.0 ml) was stirred at 55° C. for 24 hours. The reaction mixture was diluted with water, chilled and the resulting solid was collected and dried; 0.35 g (76% yield); m.p. 278°-279° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1COCC1.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OCC
Yield: 43 %

Procedure:
To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min), the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 7.78 (dd, 1H, J=1.9, 7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.52 (d, 1H, J=7.2 Hz); 7.17 (t, 1H, J=7.7); 6.97 (d, 1H, J=8.5 Hz); 6.75 (d, 1H, J=7.7 Hz); 4.19 (m, 4H); 3.65 (t, 2H, J=8.9 Hz); 3.45 (tr, 2H, J=8.9 Hz); 1.7 (broad s, 1H+H2O); 1.49 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O>>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][C:5]2[S:4][C:3]([CH2:1][CH3:2])=[CH:7][CH:6]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CCc1cccs1
Product: CCc1ccc(Cc2ccc(OC)c(Br)c2)s1

Procedure:
2-Ethylthiophene and 3-bromo-4-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([OH:12])[CH3:11])=[N:6][CH:7]=1.[CH2:13](N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([O:12][CH3:13])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(O)C#Cc1ccc(Br)cn1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(C)C#Cc1ccc(Br)cn1
Reaction time: 1 h
Yield: 34 %

Procedure:
5-Bromo-2-(3-hydroxy-1-butynyl)pyridine (5.426 g) was dissolved in tetrahydrofuran (60 ml), followed by the sequential addition of triethylamine (10 ml) and methanesulfonyl chloride (2.2 ml) under ice-cooling, and the resulting mixture was stirred for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was dissolved in methanol (16 ml), and under ice-cooling, 28% sodiummethoxide/methanol solution (4.6 ml) was added thereto and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound as a brown oil (1.968 g, yield; 34%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
1-(2-Bromo-ethyl)-4-nitro-benzene (0.9 g, 3.9 mmol) was added to a mixture of 1-methyl-piperazine (520 μL, 4.7 mmol) and potassium carbonate (1 g, 4.7 mmol) in 5 mL of DMSO. The mixture was stirred at 100° C. for 2 hour. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 850 mg of 1-methyl-4-[2-(4-nitro-phenyl)-ethyl]-piperazine, which was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (780 mg, 91%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.98 (d, J=8.3 Hz, 2H), 6.61 (d, J=8.3 Hz, 2H), 3.57 (br, 2H), 2.71 (br, 12H), 2.43 (br, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>C(#N)C>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=2)=[O:4])=[O:25])=[CH:22][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.3 g, 4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN (30 mL) was added TEA (0.72 ml, 5.2 mmol). After stirring overnight, the mixture was poured onto aq. citric acid and EA then stirred for 10 min before the solid was collected by filtration. The cake was washed with water and iso-hexanes then dried to provide 905 mg (57%) of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate. LCMS-ESI (m/z) calculated for C22H25BrO4, 432.1. found 433.2 [M+H]+, tR=3.24 min (Method 8).
Reaction SMILES: [F:1][C@H:2]1[O:10][C@H:9]([C:11]([O-:13])=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[F:1][C@H:2]1[O:10][C@H:9]([C:11]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Sodium 1-deoxy-1-fluoro-α-D-glucuronate (6.22 g, 28.51 mmol) was suspended in DMF (350 ml), and benzyl bromide (4.89 g, 28.59 mmol) was added. The reaction mixture was stirred at 60° C. for 24 h and then evaporated. The residue was dissolved in 3:1 chloroform/methanol, and magnesium sulfate (12 g) was added. The suspension was stirred for 2 h and then filtered, and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (160 g) with 4:1 dichloromethane/acetone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:6]=1)=[O:4].[CH3:32]I.[Na]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH3:32])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(CCCCNS(=O)(=O)c2ccccc2)c2ccc(C(C)C)ccc1-2
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CCCCN(C)S(=O)(=O)c2ccccc2)c2ccc(C(C)C)ccc1-2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 6-Isopropyl-3-[4-(benzenesulfonylamino)butyl]-azulene-1-carboxylic acid methyl ester (0.50 g) in DMF (10 ml) was added to the suspension, and the mixture was stirred at 0° C. for 10 min. Then, methyl iodide (5 ml) was dropped into the solution of the sodium salt, and the mixture was stirred at the same temperature for 30 min. The reaction was quenched by the addition of saturated aqueous NH4Cl, followed by extraction with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, and dried over MgSO4. Removal of the solvent and the purification by silica gel column chromatography (ethyl acetate-n-hexane, 1:1) afforded the sulfonamide (0.51 g 99%) as a violet oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(=O)(O)O.[BH4-].[Na+]>C(O)(C)C>[CH2:17]([NH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)c2ccccc2)c(NCc2ccccc2)c1
Reaction time: 6 h

Procedure:
To a mixture of 21.1 g. of 2-amino-4-methylbenzophenone, 58.4 g. of benzaldehyde and 35 ml. of isopropanol is added dropwise 5.5 ml. of 46% sulfuric acid while maintaining at temperature of 20°-25° C. There is then slowly added 2.7 g. of sodium borohydride while maintaining 20°-25° C. Thereafter three additional separate and alternate additions of 5.5 mls. of 46% sulfuric acid and 2.7 g. of sodium borohydride are effected while maintaining 20°-25° C. and controlling the foaming caused by the borohydride additions. After stirring for 6 hours there is added with cooling 58 g. of sodium bisulfite in 200 ml. of water followed by the addition of 100 ml. of toluene and stirring for 1.5 hours. The toluene layer is separated, washed twice with water and distilled to remove toluene and benzaldehyde. The cooled residue is treated with heptane which is flashed off and the residue cooled to obtain crystals of 2-benzylamino-4-methylbenzophenone.