Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]2[C:8](=[O:12])[CH:9]=[CH:10][O:11][C:6]=2[C:5]=1[CH2:15][CH:16]=[CH2:17].[CH3:18][O:19][C:20](=[O:44])[CH2:21][CH2:22][C:23]1[C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]I.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20](=[O:44])[CH2:21][CH2:22][C:23]1[C:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:3][C:4]2[CH:14]=[CH:13][C:7]3[C:8](=[O:12])[CH:9]=[CH:10][O:11][C:6]=3[C:5]=2[CH2:15][CH:16]=[CH2:17])=[CH:25][CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Reactant: C=CCc1c(O)ccc2c(=O)ccoc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCCCCCCc2cccc(OCCCC(=O)OC)c2CCC(=O)OC)ccc2c(=O)ccoc12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 79 %

Procedure:
To a slurry of 202 mg(5.05 mmol) of 60% sodium hydride-mineral oil dispersion (pre-washed with penlane) in 3 mL of anhydrous N,N-dimethylformamide was added a solution of 0.77 g (3.81 mmol) of 7-hydroxy-8-(2-propenyl)-4H-1-benzopyran-4-one in 12 mL of anhydrous N,N-dimethylformamide, over a 1 min period. The mixture was stirred at room temperature for 15 min whereupon a solution of 2.1 g (4.29 mmol) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (example 17) in 15 mL of anhydrous N,N-dimethylformamide was added over a 1 min period. The resulting mixture was stirred at room temperature for 3 hr before being treated with ice-water, and worked-up with ethyl acetate in the usual manner. The oily product was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 1.7 g (79.1%) of the title compound as a yellow oil.
Reaction SMILES: [OH-].[NH4+:2].C[O:4][C:5]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([OH:14])=[C:9]([Br:15])[N:8]=1)=O>>[Br:13][C:11]1[C:10]([OH:14])=[C:9]([Br:15])[N:8]=[C:7]([C:5]([NH2:2])=[O:4])[CH:12]=1
Reactant: COC(=O)c1cc(Br)c(O)c(Br)n1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc(Br)c(O)c(Br)n1
Reaction time: 48 h
Yield: 80 %

Procedure:
Concentrated ammonium hydroxide, 180 ml, was added to 10 g of 4,6-dibromo-5-hydroxy-2-pyridinecarboxylic acid methyl ester and heated at 45°-60° C. for 1 hour. After the mixture was kept for 2 days at room temperature, the solid was filtered and successively washed with dilute HCl (to neutralize the ammonia) and then with methanol and benzene to remove any unreacted starting material. The product was isolated in 80% yield; m.p. 261-266° C. (best sample: m.p. 275° C.).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25].[OH-].[Na+]>N1C=CC=CC=1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH:20][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:21][CH:22]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CC(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 59.5 %

Procedure:
A solution of 1.5 g of 2-(4-carboxybenzamido)-4-aminobenzoic acid in 50 ml of pyridine was mixed with 3.2 g of isobutyroyl chloride and the mixture was heated at 50° to 60° C. for a period of 2 hours. The reaction mixture was further mixed with a solution of 4 g of sodium hydroxide in 20 ml of water and concentrated under vacuum. The residue was diluted with water and hydrochloric acid was used to adjust the pH of the dilution between 1 and 2. The precipitating crystal was filtered, washed with water and recrystallized from a solvent mixture of methanol and water to thereby produce 1.1 g of 2-(4-carboxybenzamido)-4-isobutyramidobenzoic acid having a melting point in the range of from 312° to 314° C. (decompose).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6](S(C2C=CC=CC=2)(=O)=O)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].O1CCCC1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a mixture of the resulting 1-benzenesulfonyl-5-methanesulfonylindole-2-carboxylic acid methyl ester (3.5 g), tetrahydrofuran (45 ml) and methanol (12 ml), potassium hydroxide (0.79 g) was added at 0° C. and the mixture was stirred at the same temperature for 3 hours. 2N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2 g of a white amorphous 5-methane sulfonylindole-2-carboxylic acid methyl ester as a crude product.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].[Cl:16]N1C(=O)CCC1=O>CC(C)=O>[Cl:16][C:7]1[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Cl)c1
Reaction time: 8 h
Yield: 17.5 %

Procedure:
Under nitrogen atmosphere, a solutin of N-triisopropylsilyl-pyrrole (2.00 g) in acetone (40 mL) was cooled at 0° C., and thereto was added N-chlorosuccinimide (1.27 g), and the mixture was allowed to stand overnight. The solvent was evaporated under reduced pressure, and thereto was added hexane. The insoluble materials were removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane) to give 3-chloro-1-triisopropylsilyl-1H-pyrrole (403 mg, 18%).
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:22]([NH:24][NH2:25])=[O:23])=[N:14][C:15]3[N:16]([N:19]=[CH:20][CH:21]=3)[C:17]=2[F:18])=[C:7]([F:26])[CH:6]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[O:23][C:22]([C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([Br:4])=[CH:6][C:7]=3[F:26])=[C:17]([F:18])[N:16]3[N:19]=[CH:20][CH:21]=[C:15]3[N:14]=2)=[N:24][N:25]=1
Reactant: N#CBr
Reactant: NNC(=O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2nc3ccnn3c(F)c2Nc2ccc(Br)cc2F)o1
Reaction time: 17 h

Procedure:
Cyanogen bromide (2.02 equivalents) is added to a suspension of 6-(4-bromo-2-fluorophenylamino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid hydrazide (1.00 equivalent) in dioxane followed by an aqueous NaHCO3 solution (1.01 equivalents). After 17 hours, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product is purified by flash chromatography as necessary.
Reaction SMILES: [OH-].[Na+].CO.[C:5]1([C:11]2[CH:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[C:13]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O>[C:5]1([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[C:13]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Aqueous 2 N sodium hydroxide solution (8.4 mL) was added to an MeOH (85 mL) solution of methyl 2-phenyl-6-(tetrazol-5-yl)pyridine-4-carboxylate (3.19 g), and stirred at 50° C. for 4 hours. With cooling with ice, 2N hydrochloric acid (16.8 mL) and water were added to it, the formed precipitate was taken out through filtration, washed with water and dried to obtain the title compound as a flesh-colored powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(Cl)Cl.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:10])=[O:9]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
2-Bromobenzenesulfonyl chloride (100.9 g, 394.9 mmol) was dissolved in methylene chloride (500 mL, 8.0 mol) and cooled at 0° C. t-Butylamine (41.3 mL, 395 mmol) was added in 3 portions over approximately 1 minute. DIPEA (75.7 mL, 434 mmol) was immediately added in 3 portions over approximately 1 minute. The mixture was warmed to room temperature and stirred overnight. The product was washed with 1M H3PO4 (2×), with saturated. NaHCO3, and with saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to yield 2-bromo-N-t-butyl-benzenesulfonamide (112 g) as a light brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Yield: 47 %

Procedure:
To a 3 ml of methylene chloride solution of 772 mg of N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol synthesized in Step A, a 3 ml of trifluoroacetic acid was dropwise added under ice cooling. The resultant mixture was stirred at room temperature for 2-hours, then adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10 and extracted with ether. The extract was dried, filtered, then concentrated under reduced pressure to give a residue, which was then recrystallized from ether/methylene chloride to give 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine in an amount of 250 mg (yield 47%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>CO>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:10](=[O:11])[C:9]([F:16])([F:15])[F:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCCCO
Solvent: CO
Product: CN(CCCCO)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a 250 mL round bottom flask, charged with 10.0 g (96.9 mmol) of the amine, 4-methylaminobutanol, in 100 mL of dry methanol, was added 17.5 mL (147 mmol) of ethyl trifluoroacetate. The mixture was stirred at room temperature for 24 hours and then concentrated to afford 18.55 g of the product as a near colorless oil (96%): 1H-NMR (200 MHz, D2O); 3.63 and 3.50 (2t's, 4H), 3.20 and 3.05 (d and s, 3H), and 1.82-1.47 (m, 4H) ppm.
Reaction SMILES: [OH:1][C:2]([CH3:37])([CH2:34][O:35][CH3:36])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:39]1[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:37])([CH2:34][O:35][CH3:36])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:39]3[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cn1ccc(I)cc1=O
Reactant: COCC(C)(O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COCC(C)(O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1

Procedure:
A mixture of (S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 196.29 mmol), 4-iodo-1-methylpyridin-2(1H)-one (60.49 mg, 255.2 mmol), Pd(PPh3)2Cl2 (20 mg), and aq Cs2CO3 solution (2 mol/L, 3 mL) in 1,4-dioxane (4 mL) was stirred at reflux for 2 hours. After the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to afford two isomers of (6S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one.
Reaction SMILES: O[CH:2]=[C:3]1[C:13](=O)[C:8]2[CH:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:15][NH:16][NH2:17]>CO>[CH3:15][N:16]1[C:13]2[C:8]3[CH:9]=[N:10][N:11]([CH3:12])[C:7]=3[CH2:6][CH2:5][CH2:4][C:3]=2[CH:2]=[N:17]1
Reactant: CNN
Reactant: Cn1ncc2c1CCCC(=CO)C2=O
Solvent: CO
Product: Cn1ncc2c1CCCc1cnn(C)c1-2
Temperature: 0 °C

Procedure:
To an ice-cold solution of 4 g of 5,6,7,8-tetrahydro-5-hydroxymethylene-1-methyl-4(1H) cycloheptapyrazolone in 130 ml of methanol was added, dropwise, a solution of 1.1 ml of methylhydrazine in 20 ml of methanol and the mixture was heated at reflux for 2.5 hours. Removal of the solvent under reduced pressure left a residual dark oil. The oil was flash chromatographed (7.5% 2-propanol in methylene chloride) to give 4,5,6,7-tetrahydro-1,7-dimethyl-1H-cyclohepta[1,2-c:3,4-c']dipyrazole as a yellow crystalline solid melting at about 94°-96° C. The chromatography also gave 4,5,6-tetrahydro-2,7-dimethyl-2H-cyclohepta[1,2-c:3,4-c')]dipyrazole melting at about 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCl)CC)C.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]Cl)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Reactant: ClCCN1CCOCC1
Agent: CCN(CC)CCCl
Product: Clc1ccc(CN2CCN(CCN3CCOCC3)CC2c2ccccc2)cc1Cl

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3 (b), is akylated by following the procedure described in Example 3 (c) whereby, in place of diethylamino ethylchloride, the equimolecular amount of morpholino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 230° C./0.04 mm. Hg.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1>C(Cl)Cl>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Cc1ccc(N)nc1
Solvent: ClCCl
Product: Cc1cnc(N)c(Br)c1
Reaction time: 2 h

Procedure:
Bromine (3.19 g) was added dropwise at 0° C. to a solution of amino-5-picoline in 75 mL CH2Cl2. After about two hours at room temperature, the reaction was extracted with saturated sodium carbonate solution, then sodium thiosulfate solution. The combined aqueous extracts were washed with CH2Cl2, and the combined organic extracts washed with saturated NaCl, dried (Na2SO4) and concentrated giving 3.59 g crude material. The product was purified by flash chromatography on silica gel, eluting with petroleum ether with increasing amounts of CH2Cl2 (0-40%), giving 3.05 g 2-amino-3-bromo-5-picoline, m.p. 68°-70° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[N:13]/[OH:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=1.Cl([Na])=O>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:23][C:22]([C:20]3[CH:19]=[C:18]([C:28]([F:29])([F:30])[F:31])[CH:17]=[C:16]([Cl:15])[CH:21]=3)([C:24]([F:27])([F:26])[F:25])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: O/N=C/c1ccc(Br)c2ccccc12
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(Br)c4ccccc34)=NO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dichloromethane (100 mL), (E)-N-[(4-bromonaphthalen-1-yl)methylidene]hydroxylamine (4.5 g, 17.99 mmol, 1.00 equiv), 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.9 g, 17.84 mmol, 1.00 equiv), chlorosylsodium (30 mL). The resulting solution was stirred overnight at room temperature. The aqueous layer was extracted with 3×20 mL of dichloromethane and the organic layers combined and washed with 3×40 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and washed with ethyl acetate/petroleum ether (1/10-1/5). This resulted in 7.1 g (75%) of 3-(4-bromonaphthalen-1-yl)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a off-white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].C(O)(=O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O>[CH:13]1([NH:16][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: C=Cc1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: c1cc(CCNC2CC2)ccn1

Procedure:
4-Vinyl pyridine (50 mmol), glacial acetic acid (3 ml), cyclopropylamine (4.28 g, 75 mmol) and water (12.8 ml) were heated at 50° C. for 22 hours. The crude reaction products partitioning, the organic phase was washed with water, brine and dried. Filtered and solvents removed under vacuum. The residue was further distilled under vacuum (Kugelrohr) and the product amine collected. NMR (CDCl3) 8.45 (m, 2H), 7.05 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 2.07 (m, 1H), 1.37 (m, 2H), 1.25 (m, 2H); m/z 163.17.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:29](=S)=[S:30]>C(OCC)C>[Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:10]=[C:29]=[S:30])=[CH:7][CH:6]=1
Reactant: S=C=S
Reactant: C=C(Cl)COc1ccc(CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: C=C(Cl)COc1ccc(CN=C=S)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
6.7 g of 4-(2-chloro-2-propeneoxy)benzylamine was added dropwise to a mixture of 7.7 g of DCC, 20 ml of carbon disulfide and 100 ml of diethyl ether with stirring at -10° C. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours. The reaction solution was filtered, and the residue was washed with diethyl ether and combined with the filtrate. The solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing solvent hexane) to give 6.6 g of the desired 4-(2-chloro-2-propeneoxy)benzyl isothiocyanate as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[N:1]1([C:26]([C:15]2[N:16]([CH3:25])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=3)[N:14]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: C1CCNC1
Product: Cc1ccc(-c2nc(C(=O)N3CCCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using pyrrolidine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[O:14][CH:13]=1.[OH-].[Na+]>ClC(Cl)C>[CH:8]([C:13]1[O:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:16][C:12]=1[CH3:11])=[O:9]
Reactant: Cc1ccc(-c2cc(C)co2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cc(C)c(C=O)o2)cc1
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (12 ml) was added slowly to dimethylformamide (9.85 ml) with stirring at 0° C., and the mixture stirred at 0° C. for 30 minutes. A solution of 3-methyl-5-(4-methylphenyl)furan (22 g) in 50 ml of dichloroethane was added dropwise over a period of 15 minutes, maintaining the temperature at 0° C. The mixture was then stirred at room temperature for 11/2 hours. Ice water was then added, and the pH of the aqueous layer adjusted to about 8 with dilute sodium hydroxide. The organic layer was separated, the aqueous layer extracted with dichloromethane, the organic portions combined and solvent removed under reduced pressure. The solvent was removed from the filtrate under reduced pressure, and the residue flash chromatographed on silica gel, eluting with 10% ethyl acetate in heptane, to yield 19.2 g of 2-formyl-3-methyl-5-(4-methylphenyl)furan.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:55]1[C:62]([CH3:63])=[CH:61][C:58]([C:59]#[N:60])=[CH:57][C:56]=1[CH3:64].C(N(C(C)C)CC)(C)C.N#N>O1CCOCC1>[CH3:64][C:56]1[CH:57]=[C:58]([CH:61]=[C:62]([CH3:63])[C:55]=1[S:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[C:59]#[N:60]
Reactant: O=C1CCc2c(S)cccc21
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)cc(C)c1Sc1cccc2c1CCC2=O
Temperature: 120 °C
Yield: 87.9 %

Procedure:
4-Mercapto-indan-1-one (Step 1, 210 mg, 1.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (74 mg, 0.13 mmol), 4-bromo-3,5-dimethyl-benzonitrile (269 mg, 1.28 mmol) and diisopropylethylamine (0.88 mL, 5.1 mmol) are dissolved in 1,4-dioxane (2 mL). The mixture is degassed with N2, tris(dibenzylideneacetone)palladium(0) (117 mg, 0.13 mmol) added and heated under microwave irradiation at 120° C. for 2 hours. The solution is concentrated under vacuum. The crude product obtained is purified by flash chromatography (10-80% ethyl acetate in cyclohexane) to give the title compound (Yield: 330 mg). LC (METHOD 5): tR=1.36 min; Mass spectrum (ES+): m/z=294 [M+H]+.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:29]=[N:30][C:31]([CH3:35])=[C:32](Br)[CH:33]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:4]5[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=5)[C:7]([OH:9])=[O:8])[C:31]([CH3:35])=[N:30][CH:29]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(C(=O)O)c1

Procedure:
3-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)benzoic acid was prepared from 3-boronobenzoic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.