Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34])=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc4c(NS(=O)(=O)c5ccccc5)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)naphthalen-1-amine (50 mg, 0.144 mmol) and benzenesulfonylchloride (25 mg, 0.144 mmol) were dissolved in pyridine (0.6 mL) then stirred at RT for 3 days. The reaction mixture was concentrated under vacuum. The crude material was purified by silica gel chromatography (2% to 4% MeOH in DCM) to give N-(6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-naphthalenyl)benzenesulfonamide as a tan solid. MS (ESI pos. ion) m/z: 487.1 (+H). Calc'd for C27H22N2O5S−486.55.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]#[N:19].C>CC(Cl)(Cl)Cl.O.CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][C:18]#[N:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(C#N)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
The compound of 4-cyanophenoxyacetonitrile was prepared by heating 29.8 g of 4-cyanophenol, 44.8 g of anhydrous K2CO3, 40 ml of dimethylformamide and 18.75 g of chloroacetonitrile with stirring in a round-bottomed three-necked flask at 70°-80° C. for 3 hours, after which time the reaction mixture was poured into an ice and water mixture, which resulted in crystal formation. The crystals were separated by filtering and were then washed with water. After drying a pale tan solid was obtained which was then dissolved in methylchloroform at reflux temperature, treated with activated charcoal and filtered. The filtrate was cooled to 5° C. and the resulting crystals filtered and dried to give the 4-cyanophenoxyacetonitrile.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([CH3:12])=[N:10][C:9]2[N:5]([N:6]=[C:7]3[CH2:15][N:14]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH:26]4[F:31])=[O:17])[CH2:13][C:8]3=2)[C:4]=1[CH3:32].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:2][C:3]1[C:11]([CH3:12])=[N:10][C:9]2[N:5]([N:6]=[C:7]3[CH2:15][N:14]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][CH:26]4[F:31])=[O:17])[CH2:13][C:8]3=2)[C:4]=1[CH3:32]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1F)C3
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C)CC1F)C3
Yield: 16.8 %

Procedure:
A mixture of (6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]inden-2-yl)-[2-(3-fluoro-piperidin-4-yloxy)-phenyl]-methanone hydrochloride (124 mg; 0.26 mmol; 1 eq.), paraformaldehyde (70 mg; 0.78 mmol; 1 eq.), sodium triacetoxyborohydride (110 mg; 0.52 mmol; 2 eq.) and AcOH (30 μL; 0.52 mmol; 2 eq.) in DCE (1.5 mL) was stirred at reflux for 1.5 hour. The reaction mixture was diluted with sat. aq. Na2CO3 and extracted with EA (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (20 mg, 6%) as a white solid. HPLC (max plot) 97.0%, Rt 2.70 min. UPLC/MS: (MS+) 458.4 ([M+H]+).
Reaction SMILES: O.O.[F-].[K+].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[CH:9]=[O:10].Br[CH2:19][CH2:20]Br>CN(C)C=O>[N+:15]([C:12]1[C:13]2[O:14][CH2:19][CH2:20][O:5][C:6]=2[CH:7]=[C:8]([CH:9]=[O:10])[CH:11]=1)([O-:17])=[O:16]
Reactant: BrCCBr
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2c(c([N+](=O)[O-])c1)OCCO2
Temperature: 130 °C
Yield: 61.3 %

Procedure:
To a mixture of potassium fluoride dihydrate (2.573 g, 27.3 mmol), and 3,4-dihydroxy-5-nitrobenzaldehyde (500 mg, 2.73 mmol) in N,N-dimethylformamide (20 mL) was added 1,2-dibromoethane (3.8 mL, 43.7 mmol), and the mixture was heated at 130° C. for 17 h. The reaction mixture was quenched with water followed by a standard aqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=15:1) to give Intermediate 45 (350 mg, yield 62.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C(C)(C)OB(C(C2C=CC([C:70]([F:73])([F:72])[F:71])=CC=2)=C)O1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:70]([F:73])([F:72])[F:71])=[CH:27][CH:26]=2)=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccc(C(F)(F)F)cc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: C=C(c1ccc(C(F)(F)F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 48 %

Procedure:
Prepared according to the method for 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 4,4,5,5-tetramethyl-2-{1-[4-(trifluoromethyl)-phenyl]ethenyl}-1,3,2-dioxaborolane (Intermediate 66) in 48% yield.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:42])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:36][CH3:37])([OH:35])[CH2:33][CH3:34])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:16][C:15]=2[CH3:41])=[CH:12][CH:13]=1)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:22]([C:21]([C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([C:11]2[N:10]=[CH:9][C:8]([CH2:7][C:6]([OH:42])=[O:5])=[CH:13][CH:12]=2)=[C:15]([CH3:41])[CH:16]=1)([C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:33][CH3:34])([OH:35])[CH2:36][CH3:37])=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23]
Reactant: CCOC(=O)Cc1ccc(-c2c(C)cc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)O)cn3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.3 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.063 mL, 0.063 mmol) was added to a solution of (E)-[6-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid ethyl ester (Example 119-(1); 11.6 mg, 0.021 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for six hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (6.4 mg, 59%).
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>C(O)C.O>[I:13][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=[C:8]([NH2:3])[CH:12]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(I)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1-phenyl-1H-pyrazole (12.2 g) in ethanol/water (2/1, 180 ml) were sequentially added hydroxylammonium chloride (46.6 g) and triethylamine (9.3 ml), and the mixture was stirred at 95° C. for 72 hours. This reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added a 8M aqueous solution of sodium hydroxide (80 ml), and then the mixture was extracted with ethyl acetate (50 ml). This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to give the titled compound (9.1 g).
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)([O-])=O.C(=O)(O)[O-].[Na+]>CO>[NH2:5][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Concentrated hydrochloric acid (1.11 ml, 13.3 mmol) and anhydrous tin dichloride (1.35 g, 7.12 mmol) were sequentially added at 0° C. to a methanol (8 ml) solution of 1,2,3,4-tetrahydro-2-[2-nitro-4-(trifluoromethyl)phenyl]isoquinoline (658 mg, 2.04 mmol), obtained as described in Referential Example 21-1. The resulting mixture was warmed to room temperature and stirred for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=20/1). Thus, 2-[2-amino-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline (426 mg, 71.4%) was yielded as a red-orange colored oily material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:19](Cl)[CH:20]=[CH:21][CH3:22]>C(O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:20]=[CH:21][CH3:22]
Reactant: CC=CCCl
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC=CCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
8.6 g of 4′-hydroxy-4-biphenylcarboxylic acid was added to hydrous ethanol containing 5.3 g of potassium hydroxide dissolved therein, followed by stirring at room temperature for 30 minutes. While heating at reflux, 5.5 g of crotyl chloride was added dropwise, followed by heating at reflux for 2 hours. After the completion of the reaction, ethanol was distilled off under reduced pressure and 50 ml of 18% HCl was added to deposit a crystal. The deposited crystal was collected by filtration, washed with water and then dried under reduced pressure to obtain 5.3 g of 4′-(2-butenyloxy)-4-biphenylcarboxylic acid (XI-k). Excess thionyl chloride was added, followed by heating at reflux for 2 hours. After the completion of the reaction, excess thionyl chloride was distilled off under reduced pressure. Then, 30 ml of pyrimidine and 2.6 g of (R)-1-(3-methoxyphenyl)ethanol (XI-l) were added to the resulting crude product and the reaction was conducted at 50° C. for one hour. After the completion of the reaction, the reaction product was extracted with toluene in the presence of hydrochloric acid, washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to obtain 5.1 g of 1-(3-methoxyphenyl)ethyl (R)-4′-(2-butenyloxy)-4-biphenylcarboxylate (R-isomer of the compound represented by the formula (XI-m).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl.O.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>>[C:34]([O:18][CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15]1)(=[O:35])[CH2:33][C:32]([CH3:31])=[O:36]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
11.95 g (0.05 mole) of 1-benzhydryl-3-hydroxyazetidine and 0.5 ml of triethylamine were dissolved in 50 ml of chloroform 6.3 g (0.075 mole) of diketene were then added dropwise to the solution, after which the reaction mixture was stirred for 10 hours at room temperature, and then water was added to it. The reaction mixture was then stirred for 30 minutes. At the end of this time, the chloroform layer was separated and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The concentrate was subjected to silica gel column chromatography, and 15.07 g (93%) of 1-benzhydryl-3-azetidinyl acetoacetate were obtained, as a pale yellow oil, from the fractions eluted with a 9:1 by volume mixture of toluene and ethyl acetate.
Reaction SMILES: [C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:22]([NH:26][OH:27])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=[N+:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[O-:27])=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)NO
Reactant: CC(C)C(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)C(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 50.8 %

Procedure:
To a solution of 4-isobutanoyl-3,5-di-tert-butylbenzaldehyde (7.00 g, 0.023 mol) in benzene (200 mL) was added tert-butylhydroxylamine (2.56 g, 0.029 mol) and p-toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (Rf =0.30 for product and 0.89 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated in 50.8% yield as a white solid, m.p. 197.1-208.1° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7]CC)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:29])=[O:28])[CH:22]=1.O>CN(C=O)C>[C:27]([C:23]1[CH:22]=[C:21]([O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[F:1])[CH:26]=[CH:25][N:24]=1)(=[O:28])[NH2:29]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(C(=O)O)cc2F)ccn1
Temperature: 130 °C
Yield: 29.7 %

Procedure:
To a solution of ethyl 3-fluoro-4-hydroxybenzoate (2.0 mmol, 368 mg) in DMF (5 mL), were added cesium carbonate (Aldrich, 6.0 mmol, 1.95 g) and 4-chloropicolinamide (2.0 mmol, 312 mg). The reaction mixture was heated at 130° C. for 20 h. After cooling to room temperature, 5 mL of cold water was added. The aqueous solution was washed with EtOAc (2×20 mL), and neutralized with 1N HCl to pH 3-4. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to give the desired product (164 mg, 27% yield). MS(ESI+) m/z 277.32 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:32])=[N:22]1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=4)[N:3]=3)[CH2:35][CH2:34]2)=[O:32])=[N:22]1
Reactant: Clc1ccc(-c2nsc(Cl)n2)cc1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccc(Cl)cc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 5-chloro-3-(4-chlorophenyl)-1,2,4-thiadiazole (179 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 85.0 mg (34.7%) of the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3](=[O:5])[CH3:4].[BrH:10]>C(Cl)(Cl)Cl.[Fe]>[Br:10][CH:7]([CH3:8])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3](=[O:5])[CH3:4]
Reactant: C=CCC(C)(C)C(C)=O
Reactant: Br
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(=O)C(C)(C)CC(C)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
18.9 g (0.15 mole) of 3,3-dimethyl-5-hexen-2-one and 1.6 g (0.0054 mole) of iron-III bromide are dissolved in 150 ml of chloroform. 0.16 mole of hydrogen bromide gas are passed in at 0° C. in the course of 90 minutes. The mixture is subsequently stirred at room temperature for 2 hours and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated in vacuo. 27 g (87% of theory) of 5-bromo-3,3-dimethyl-2-hexanone of refractive index nD20 =1.4639 are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C(N(CC)CC)C>C(O)C>[OH:31][NH:30][C:22](=[NH:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:25]([F:28])([F:26])[F:27])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:24]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)NO)CC3)cc1
Yield: 414.8 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.100 g, 0.255 mmol), hydroxylamine hydrochloride (0.027 g, 0.382 mmol), and triethylamine (0.071 mL, 0.510 mmol) were dissolved in ethanol (10 mL). The reaction was refluxed overnight, concentrated, and purified by reverse HPLC and freeze-drying to afford the title compound (0.45 g, 42%): 1H NMR (CHCl3) δ 7.61 (bs, 0.5 H), 7.38 (d, j=8.5 Hz, 2H), 6.94 (d, j=8.8 Hz, 2H), 6.72 (bs, 0.5H), 3.82 (s, 3H), 3.68 (t, j=6.4 Hz, 2H), 3.48 (s, 2H), 3.01 (t, j=6.4 Hz, 2H), 3.35 (s, 3H), 1.56 (bs, 4H) ppm; Mass Spec 426.3(M+H)+.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18](=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:18](=[S:19])[NH:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=C=S
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Solvent: c1ccncc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of (2e)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (1.90 g, 8.04 mmol) and carbon disulfide (0.58 ml, 9.64 mmol) in pyridine (30 ml) was stirred at 60° C. for 3 hours. After cooling to room temperature, the solid formed was filtered and dried to yield the desired product (1.90 g, 84.9%). LCMS calculated for: C11H14N6OS (M+H) 280.1. Found: 280.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]4([NH:32]C(=O)C)[CH2:29][O:28]C(C)(C)[O:26][CH2:25]4)=[CH:18][CH:17]=3)=[C:12]([F:36])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:37]>C(O)C>[ClH:37].[NH2:32][C:24]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([S:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:11][C:12]=2[F:36])=[CH:21][CH:20]=1)([CH2:29][OH:28])[CH2:25][OH:26]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C)c(C)c4)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)cc1C
Temperature: 75 °C
Reaction time: 4 h

Procedure:
N-(5-{2-[4′-(3,4-Dimethylphenylthio)-2′-fluorobiphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.23 g) was dissolved in ethanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 75° C. for 4 hr. The reaction mixture was concentrated to dryness, and the residual solid was suspended in ethyl acetate and collected by filtration to give the title compound (141 mg) as white crystals.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]12[CH2:18][CH2:19][C:20](=[O:22])[CH:21]=[C:6]1[C:7]1[C:12](=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:13][CH2:14]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(C)=O)CCc2cc(OC)ccc2C1=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1CC2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2-butyl-6-methoxy-2-(3-oxobutyl)-3,4-dihydro-1(2H)-naphthalenone (91 mg, 0.3 mmol), pyrrolidine (0.025 mL, 0.3 mol), acetic acid (0.017 mL, 0.3 mmol), and toluene (0.5 mL) was stirred and heated in an oil bath at 100° C. for 3 hours. After standing at room temperature overnight, the mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with 5% NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 5% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2ccccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2ccccc2o1
Yield: 62 %

Procedure:
A mixture of 2-methylbenzofuran (2.0 g), N-bromosuccinimide (2.7 g) and carbon tetrachloride is heated at reflux overnight. The reaction is filtered and the solvent is removed in vacuo giving 3.8 g (52% monobrominated) of product (62% yield).