Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].I([O-])(=O)(=O)=[O:30].[Na+]>CO.O>[CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16](=[O:30])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCSc3ccccc32)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCS(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a suspension of 4-[4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-1,4-benzothiazine (0.5 g) in methanol (15 ml) is added an aqueous solution of sodium metaperiodate (0.28 g) in water (2.5 ml) and the mixture is stirred at room temperature for 72 hours. Water is added to the reaction solution and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=100:1), and recrystallized from dichloromethane/diethyl ether to give 4-[4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-1,4-benzothiazin-1-oxide (0.34 g) as white powder, m.p. 240°-241° C.
Reaction SMILES: [CH2:1]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[C:35](=[O:37])=[O:36].Cl>O1CCCC1>[CH2:22]([C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:21]2[CH:20]=[C:19]([C:35]([OH:37])=[O:36])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Into a flask fitted with a nitrogen inlet and rubber septum were introduced 2-bromo,-9,9-dioctylfluorene (34.18 g, 72.8 mmole) and dry tetrahydrofuran (300 mL). The solution was cooled to −60° C. and n-butyl lithium (29.1 mL, 2.5M in hexanes, 72.8 mmole) added via a syringe. The reaction mixture was observed to turn red. After stirring for 1 hour at −60° C., the reaction mixture was poured onto powdered dry-ice and left to stand overnight. The mixture was acidified with 1M HCl and extracted with chloroform. The chloroform extract was washed with water, dried over magnesium sulfate and concentrated to give the required acid as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7](=[O:18])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2cccnc2n(C)c1=O
Product: CCOC(=O)c1c(Cl)c2cccnc2n(C)c1=O

Procedure:
A stirred mixture of 1.7 g. of 4-hydroxy-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 25 ml. of phosphorus oxychloride was heated under reflux for 2 hours. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured into 100 ml. of ice water. The precipitate which formed was collected, air dried and a small amount of the 1.9 g. was recrystallized from heptane twice to give the analytical sample of the title compound, m.p. 132°-135° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Br:29])=[CH:26][CH:25]=1>>[Br-:29].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH2:22][SH+:21][CH2:20][C:11]2([OH:19])[CH2:12][CH2:13][CH:14]([OH:18])[CH:15]([O:16][CH3:17])[CH:10]2[C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Product: COC1C(O)CCC(O)(C[SH+]CCc2ccc(Cl)cc2)C1C1(C)OC1CC=C(C)C
Product: [Br-]
Yield: 70.3 %

Procedure:
As in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) was allowed to react with 4-chlorobenzyl bromide (1.24 g) to give 1-(4-chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (228 mg: yield 70%) as colorless powder.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[Br-:6].[K+].S(=O)(=O)(O)O.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O>[Br:6][CH2:2][C:3]([O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCl
Reactant: [Br-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CBr)OCc1ccccc1

Procedure:
94.5g (1 mol) of chloroacetic acid, 154.7g (1.3 mol) of potassium bromide, 127.4g (1.3 mol) of c.-sulfuric acid, 75 ml of water, 200g of toluene and 108g (1 mol) of benzylalcohol were used and treated in a similar way as described in Example 3. 214g (93.4% of theory) of benzyl bromoacetate were obtained. Bp. = 145° C/ 4 mmHg. 176.5g (99.7%) of potassium hydrogen sulfate was isolated.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[CH:11](OCC)=[O:12]>>[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][CH:11]=[O:12]
Reactant: CCOC=O
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Product: CN(C)[C@@H]1CCCC[C@H]1NC=O
Yield: 85 %

Procedure:
A solution of the trans-2-(dimethylamino)cyclohexylamine prepared as in Procedure VIII (5.12 g.; 0.036 mole) and 100 ml. of ethyl formate (distilled over K2CO3) was refluxed for 17 hours and evaporated. The titled product (A) was distilled at 0.1 mm, b.p. 104°, 5.2 g. (85% yield). ir NH 3280, 3040; CH2930, 2860; N-alkyl 2770; C=O 1670; amide II 1540; other 1450, 1385. nmr in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 170.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C>[Br:1][C:2]1[C:3]([NH:9][C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[NH:16])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: N#Cc1ccco1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: N=C(Nc1ncc(Br)nc1Br)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of 3,5-dibromo-pyrazin-2-ylamine (608 mg, 2.4 mmol), furan-2-carbonitrile (297 uL, 3.39 mmol) and AlCl3 (320 mg, 2.4 mmol) in dichloroethane (6 ml) was heated at 115° C. overnight. The reaction was cooled to room temperature and water (5 ml) was added. After 30 minutes, the resulting precipitate was collected and purified by column chromatography (SiO2, THF) to afford 595 mg (72%) of N-(3,5-dibromo-pyrazin-2-yl)-furan-2-carboxamidine as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J=3.4, 1.8 Hz, 1H), 7.3 (dd, J=3.1 Hz, 1H), 7.98 (s, 1H), 8.49(s, 1H), 8.69 (br. s, 1H).
Reaction SMILES: [Si]([O:8][CH:9]1[C@H:22]([CH:23]=[CH:24][CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@@H:12]([CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[C:11](=[O:32])[CH2:10]1)(C(C)(C)C)(C)C.F.[C:34](=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]([OH:31])/[CH:24]=[CH:23]/[C@@H:22]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:34])=[O:20])[C:11](=[O:32])[CH2:10][C@H:9]1[OH:8]
Reactant: O=C([O-])[O-]
Reactant: CCCCCC(O)C=C[C@H]1C(O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CC=CCCCC(=O)[O-]
Agent: F
Agent: [Na+]
Solvent: CC#N
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C/CCCC(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
(−)-methyl(11R, 15S, 5Z, 13E)-11-tert-butyldimethylsilyloxy-15-hydroxy-9-oxoprost-5,13-dien1-oate (518 mg, 1.08 mmol) and acetonitrile (10 ml) were placed into a Teflon container and cooled to 0° C., whereby 46% hydrofluoric acid (1.0 ml) was added and stirred for 2 h. The reaction mixture was poured into a saturated aqueous sodium carbonate cooled with ice and extracted with ethyl acetate (150 ml) two times. The combined organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove solvent. The residue was purified by silica gel column chromatography [ethyl acetate/hexane (2/1)] to give 345 mg (88% yield) of prostaglandin E2 methyl ester;
Reaction SMILES: C([CH:8]([NH2:32])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:29])[CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:13][C:12]=1[O:30][CH3:31])(OC(C)(C)C)=O.[ClH:33].C(OCC)C>O1CCOCC1>[ClH:33].[NH2:32][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:29])[CH2:20][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])=[CH:13][C:12]=1[O:30][CH3:31]
Reactant: COc1cc(CCC(=O)CC(=O)c2ccccc2)ccc1OCC(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(CCC(=O)CC(=O)c2ccccc2)ccc1OCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 5-(4-(2-boc-aminoethoxy)-3-methoxyphenyl)-1-phenylpentane-1,3-dione (211 mg, 0.48 mmol) dissolved in dioxane (5 ml) was added drop wise dry HCl in dioxane (4 M, 0.36 ml, 1.43 mmol) and stirred at RT for 1 h. After this time diethyl ether (20 ml) was added and an off-white emulsion was visible. The solvents were removed by evaporation in vacuo to give a brown gum residue. Residual dioxane was removed by azeotroping with methanol and then drying the product on high pressure line to give 5-(4-(2-aminoethoxy)-3-methoxyphenyl)-1-phenylpentane-1,3-dione hydrochloride (163 mg, 99%) as a brown powdery solid: mp 80° C.; LCMS 342 [M+H]+, 364 [M+Na]+, 1H NMR (400 MHz, MeOD) δ 2.79-2.82 (2H, m, CH2), 2.99-3.02 (2H, m, CH2), 3.33-3.34 (2H, m, NHCH2+solvent signal), 3.90 (3H, s, OCH3), 4.20 (2H, t, J=5.0 Hz, NHCH2CH2), 6.37 (1H, s, enol CH), 6.84-6.98 (3H, m, 3×ArH), 7.48-7.60 (3H, m, 3×ArH), 7.93 (2H, d, J=8.0 Hz, 2×ArH) ppm; 13C NMR (100 MHz, MeOD) δ 33.04, 41.40, 41.83, 57.31, 68.16, 98.35, 114.54, 117.51, 122.73, 128.84 (2×CH), 130.58 (2×CH), 134.34, 136.75, 137.93, 147.75, 151.73, 184.57, 198.44 ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.ClC(Cl)(Cl)Cl>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[CH3:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)cccc1OC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(OC)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of ethyl 6-methyl-2-methoxybenzoate (8.4 g, 43.2 mmol), bromine (6.9 g, 43.2 mmol) and tetrachloromethane (170 ml) is stirred at room temperature for 60 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated. The crude product is obtained as a yellow oil, 10.3 g (87%) and is used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([O:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:16]=[CH:15][N:14]=2)[C:4]([CH3:27])=[N:3]1.[CH:28](OC)=[O:29].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH3:11][O:10][C:8](=[O:9])/[C:7](/[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[C:5]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[N:16]=[CH:15][N:14]=1)=[CH:28]/[OH:29]
Reactant: COC=O
Reactant: COC(=O)Cc1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)/C(=C/O)c1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.5 g (9.3 mmol) of methyl {1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}acetate and 10 ml of methyl formate in 10 ml of dimethyl formamide is slowly added dropwise to a suspension of 0.5 g (20.0 mmol) of sodium hydride (95%) in 40 ml of dimethyl formamide, while keeping the temperature below 30° C. The reaction mixture is stirred for 2 hours at room temperature, acidified with acetic acid and, after addition of 200 ml of ice-water, extracted with 200 ml of ethyl acetate. The organic phase is washed with water and sodium chloride solution, dried and concentrated under vacuum, giving E-methyl-2-{1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}-3-hydroxyacrylate as a brown resin, which is stirred together with 1.8 g (13.0 mmol) of potassium carbonate and 0.9 ml (6.7 mmol) of dimethyl sulfate in 40 ml of acetone for 3 hours at room temperature. The reaction mixture is filtered, the filtrate is diluted with 50 ml of water and extracted with 100 ml of ethyl acetate. The organic phase is washed with sodium chloride solution, dried and concentrated under vacuum. The residue is chromatographed over silica gel tetrahydrofuran/n-hexane (1:1) as eluant, giving E-methyl-2-{1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}-3-methoxyacrylate as a yellow resin; MS: 414 (M+, 44%), 75 (100).
Reaction SMILES: C[OH:2].O.[Si]([O:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([F:50])=[C:17]([CH:23]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:48]=[C:47]([CH3:49])[O:46][N:45]=3)=[CH:40][CH:39]=2)[C:24]2[NH:28][C:27](=[O:29])[N:26]([C:30]3[C:31](=[O:36])[NH:32][CH:33]=[CH:34][N:35]=3)[N:25]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)(C(C)(C)C)(C)C>[Fe].C(O)(=O)C>[C:47]([OH:2])(=[O:46])[CH3:49].[F:50][C:16]1[C:15]([O:14][CH2:13][CH2:12][OH:11])=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=1[CH:23]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([NH2:48])=[NH:45])=[CH:40][CH:39]=1)[C:24]1[NH:28][C:27](=[O:29])[N:26]([C:30]2[C:31](=[O:36])[NH:32][CH:33]=[CH:34][N:35]=2)[N:25]=1
Reactant: CO
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 34 mg of 3-(3-{{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)-1H-pyrazin-2-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-[5-oxo-1-(3-oxo-3,4-dihydropyrazin-2-yl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]methyl}amino)benzamidine acetate (5.9 mg).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].Br[C:14](Br)([F:16])[F:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C)C(=O)C.[Zn]>[F:15][C:14]([F:16])=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: FC(F)(Br)Br
Reactant: C=CCCCCCCCCC=O
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
Under an argon atmosphere, a stirred mixture of 101.0 grams (0.60 mole) of 10-undecenal and 251.9 grams (1.20 moles) of dibromodifluoromethane was cooled to 0° to -5° C., and a solution of 314.9 grams (1.20 moles) of triphenylphosphine in 1100 ml of N,N-dimethylacetamide was added dropwise during a five to ten minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for two hours. After this time a small portion from 70.5 grams (1.20 mole) of zinc powder was added to the reaction mixture. The reaction mixture was warmed to approximately 34° C. with an external heat source to initiate further reaction. Upon commencement of the reaction, the reaction mixture temperature rose to 44° C. The remainder of the 70.5 grams of zinc powder was added portionwise during a ten to twenty minute period. Upon completion of addition, the reaction mixture was warmed to 85°-90° C. where it stirred vigorously for two hours. After this time the reaction mixture was cooled to ambient temperature, and 400 ml of water was added. The reaction mixture was stirred for 30 minutes and then was allowed to stand for 18 hours. After this time the reaction mixture was subjected to a steam distillation using pentane as the extraction solvent. The pentane distillate was concentrated under reduced pressure to a residual oil. The residual oil was heated at 94° C. to remove any N,N-dimethylacetamide. The remaining oil was distilled under reduced pressure, yielding 24.3 grams of 1,1-difluoro-1,11-dodecadiene; b.p. 133° C./66 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH2:16][C:10]=2[CH:9]=1)(=O)=O.Cl.[CH2:24]([NH:26]O)[CH3:25].CC(C)([O-:31])C.[K+]>C(O)C>[CH:9]1[C:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][O:12][C:11]=2[CH:21]=[CH:22][C:8]=1[CH:7]([OH:31])[CH2:6][NH:26][CH2:24][CH3:25]
Reactant: CC(C)(C)[O-]
Reactant: CCNO
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)Cc1ccccc1CO2
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCNCC(O)c1ccc2c(c1)Cc1ccccc1CO2
Yield: 14.1 %

Procedure:
2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate (13.5 g) was taken up in 20 ml of absolute ethanol and added to a solution containing ethyl hydroxylamine hydrochloride (11.03 g) and potassium t-butoxide (12.7 g) in 600 ml of absolute ethanol. The mixture was stirred at reflux under a nitrogen blanket for 18 hours then evaporated. The residue was taken up in chloroform and washed with brine, dried, and evaporated. Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane. Recrystallization from ether-cyclohexane gave 1.7 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p 102-103° C., with softening at 88° C.
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[Cl:23].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:15]([Cl:23])=[CH:16][C:17]([C:18]#[N:19])=[CH:20][C:21]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-chloropyridine-3-carbaldehyde (2.0 g, 10.95 mmol), 4-amino-3,5-dichlorobenzonitrile (2.05 g, 10.95 mmol) and triethylamine (4.6 mL, 6.57 mmol) in DCM (48 mL) was added titanium tetrachloride (1M in DCM, 6.6 mL, 6.57 mmol) dropwise over 10 minutes. The reaction mixture was stirred for 20 minutes, warmed to room temperature, and stirred for an additional 30 minutes. The resultant mixture was concentrated to dryness under reduced pressure to afford the title compound which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][C:8]=2[CH3:16])=[O:6])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[C:20]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:21]2[N:25]=[CH:24][NH:23][C:22]=2[CH:26]=1.[N+]1([O-])C=CC=CC=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2].O>[Br:17][C:18]1[CH:19]=[C:20]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:21]2[N:25]=[CH:24][N:23]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[C:8]([CH3:16])[CH:9]=3)[C:22]=2[CH:26]=1
Reactant: FC(F)(F)CCNc1cc(Br)cc2[nH]cnc12
Reactant: Cc1cc(B(O)O)ccc1C(=O)NC1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(-n2cnc3c(NCCC(F)(F)F)cc(Br)cc32)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 48 h
Yield: 22.8 %

Procedure:
To a solution of 751 mg [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid in 68.6 mL dichloromethane were added 528 mg (1.71 mmol) 6-bromo-N-(3,3,3-trifluoropropyl)-1H-benzimidazol-4-amine which was prepared according to intermediate example 1b, 623 mg copper(II)diacetate, 179 mg pyridine 1-oxide and 416 μL pyridine. The mixture was stirred at 23° C. for two days. Water was added and the mixture was extracted with dichloromethane and methanol. The organic layer was washed with water and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 188 mg (22%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].[C:16]1([S:22](Cl)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.ClC(Cl)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:12]([S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:23])=[CH:11][C:9]=2[O:10]1)=[O:5])[CH3:2]
Reactant: O=S(Cl)c1ccccc1
Reactant: CCOC(=O)C1Oc2ccc(C)cc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1Oc2cc(C)c(S(=O)c3ccccc3)cc2O1
Temperature: 0 °C

Procedure:
20.8 g (0.1 mol) of 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester Example 2b) and 19.2 g (0.125 mol) of phenylsulphinic acid chloride are dissolved in 200 ml of 1,2-dichloroethane and cooled to 5° using an ice-bath. 13.3 g (0.1 mol) of aluminium chloride are introduced in the course of approximately 15 minutes at from 5°-10° while stirring. The mixture is stirred for a further hour in the ice-bath and is then poured out onto ice-water. The resulting emulsion is diluted with 200 ml of dichloroethane and filtered across a layer of a filter aid (for example Hyflo). The filtrate is introduced into a separating funnel and the layers are separated. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness by evaporation. A light brown honey-like product, 5-phenylsulphinyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester, is obtained.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]5)=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)CN1CCC(O)CC1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OC1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 7.3 %

Procedure:
A solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (521 mg, 1.63 mmol), N-amino-2-(4-hydroxypiperidyl)acetamide (850 mg, 4.9 mmol), and sodium methoxide (1.2 mL, 4.9 mmol) in methanol (8 mL) was taken up in a sealed tube and allowed to stir at room temperature for 25 minutes and then heated at 95° C. overnight. The reaction was acidified with hydrochloric acid to neutral pH. The product was extracted using ethyl acetate. The material was concentrated and purified by semipreprative HPLC. The purified material was taken up in ethyl acetate and washed with an aqueous solution of sodium bicarbonate to yield the title compound (47 mg, 7% yield). 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.6 (s, 1H), 8.0 (m, 3H), 7.6 (m, 1H), 7.4 (t, 2H), 3.6–3.8 (m, 2H), 3.4 (m, 2H), 3.2 (d, 1H), 2.4 (m, 2H), 2.0 (s, 4H)H, ES-MS (m/z) 393 [M+1]+.