Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22](O)=[O:23])[CH:10]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[C:60]2[C:73](=[CH:74][CH:75]=1)[CH2:72][C@@:62]1([C:70]3[C:65](=[N:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]1=[O:71])[CH2:61]2>CN(C=O)C>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:10]2[N:11]([CH2:21][C:22](=[O:23])[NH:57][C:58]3[CH:59]=[C:60]4[C:73](=[CH:74][CH:75]=3)[CH2:72][C@:62]3([C:70]5[C:65](=[N:66][CH:67]=[CH:68][CH:69]=5)[NH:64][C:63]3=[O:71])[CH2:61]4)[C:12](=[O:20])[C:13]3([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(C2CN(C(=O)OC(C)(C)C)C3(COCCOC3)C(=O)N2CC(=O)O)c1
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc(C2CN(C(=O)OC(C)(C)C)C3(COCCOC3)C(=O)N2CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.44 g (0.81 mmol) 80% 2-(1-(tert-butoxycarbonyl)-3-(3-methoxyphenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)ethanoic acid in 10 ml DMF were combined with 0.75 g (2.0 mmol) HATU and 0.34 ml (2.4 mmol) TEA and stirred for 10 min at RT. Then 0.25 g (0.98 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20]C1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH:38]([C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:50])[CH3:49])[C:42]=1N)([CH3:40])[CH3:39]>>[CH:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:41]([CH:38]([CH3:40])[CH3:39])[C:42]=1[NH:20][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])([CH3:50])[CH3:49]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with 2,6-diisopropylaniline, mp 202°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14]CC2C=CC=CC=2)[CH:11]=[C:10]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H][H]>[Pd]>[Cl:1][C:2]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Product: OCCCCOc1c(Cl)cc(O)cc1Cl

Procedure:
This compound was prepared in a manner analogous to that of Step A of this example, using 12.2 grams (0.036 mole) of 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butan-1-ol and 0.5 gram (catalyst) of 10% palladium on carbon and a theoretical amount of hydrogen gas in a Parr Hydrogenator. The yield of the subject compound was 9.3 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O.S(=O)(=O)(O)O>O>[CH3:18][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)ccc1C(=O)O
Temperature: 10 °C
Reaction time: 144 h

Procedure:
A stirred mixture of 2-hydroxy-4-methylbenzoic acid (75 g, 0.50 mol), sodium hydroxide (42 g, 1.0 mol) and water (250 ml) was cooled to 10° C. and treated dropwise with dimethyl sulphate (126 g, 1.0 mol). The mixture was stirred for 6 days, poured into water (4000 ml), acidified with sulfuric acid and extracted with dichloromethane (4×600 ml). The extracts were combined, washed with water, dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The resulting oil was treated with aqueous sodium hydroxide (1000 ml of 2M) and heated under reflux for 2 hours. The mixture was acidified with hydrochloric acid and extracted with dichloromethane (3×300 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to give the crude product as an oil. The crude product was purified by column chromatography (silica gel, chloroform) and recrystallized from chloroform-hexane to yield 2-methoxy-4-methylbenzoic acid as a colorless crystalline solid, having a melting point of 108°-109° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[CH:17]=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCn1cnc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Yield: 38.2 %

Procedure:
A mixture of 8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.035 g, 0.094 mmol), Pd\C (10%) (0.025 g), in ethanol (20 ml) were stirred under hydrogen atmosphere for 20 hours. Reaction mixture was filtered through celite bed washed with methanol (20 ml), and the solvents were removed under vacuum. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.012 g, 39%) as off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:43][C:44]([NH2:46])=[O:45]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[CH:14][N:13]2[CH2:43][C:44]([NH2:46])=[O:45])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc([N+](=O)[O-])c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 111.5 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridin-2-amine (2.70 g, 11.7 mmol), p-toluenesulfonyl chloride (2.67 g, 14.0 mmol) and pyridine (20 mL) was stirred at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 92%) as a white solid. A mixture of 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 10.7 mmol) thus-obtained, N,N-diisopropylethylamine (2.44 mL, 14.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr, iodoacetamide (2.59 g, 14.0 mmol) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.28 g, 99%) as a white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].O1CCOCC1>O>[CH2:26]([N:29]([CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]
Reactant: CCCNCCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCCN(CCC)CC1CCn2c(nc3ccccc32)S1
Yield: 14.3 %

Procedure:
To 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole were added 4 ml of di-n-propylamine and 20 ml of dioxane. The mixture was reacted in a sealed tube, at 120° C. and for 67 hours. After cooling down the temperature of the reaction mixture, it was condensed under reduced pressure. Water was added to the condensed reaction mixture, followed by an extraction with chloroform and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 0.13 g (yield: 14.3%) of the intended product, m.p. 82°-84° C.;
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:13]=2)=[CH:5][C:4]=1[C:27]1[O:28][C:29]2[C:35]([CH2:36][OH:37])=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CC(O)C>[NH2:2][C:3]1[C:4]([C:27]2[O:28][C:29]3[C:35]([CH2:36][OH:37])=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(CO)c5o4)c3)cn2)CC1
Agent: Cl
Solvent: CC(C)O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(CO)c2o1
Temperature: 78 °C
Yield: 62.1 %

Procedure:
7N Hydrogen chloride in propanol-2 (1083 μl) was added to tert-butyl 4-[4-[6-amino-5-[7-(hydroxymethyl)-1,3-benzoxazol-2-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (93 mg). The mixture was heated at 78° C. for 1 hour. The solvent was evaporated under reduced pressure. A solution of 7N methanolic ammonia was added to the mixture at 0° C. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 2 to 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [2-[2-amino-5-[1-(4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazol-7-yl]methanol (46.0 mg) as a pale yellow solid. NMR Spectrum: (DMSOd6) 2.04-2.17 (m, 2H), 2.17-2.28 (m, 2H), 2.94-3.08 (m, 2H), 3.33-3.39 (m, 2H), 4.42-4.51 (m, 1H), 4.92 (d, 2H), 5.51 (t, 1H), 7.41 (dd, 1H), 7.46 (d, 1H), 7.65 (bs, 2H), 7.72 (d, 1H), 7.99 (s, 1H), 8.29 (s, 1H), 8.47 (d, 1H), 8.54 (d, 1H); Mass spectrum: M+H+ 391.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCCCC1.[S:14]1[CH:18]=[CH:17][C:16](C=O)=[CH:15]1.Cl>N1C=CC=CC=1>[S:14]1[CH:18]=[CH:17][C:16](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:15]1
Reactant: O=Cc1ccsc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccsc1
Temperature: 100 °C

Procedure:
46 g of malonic acid and 2 ml of piperidine are added to 25 g of 3-thienaldehyde in solution in 100 ml of pyridine, and the mixture is heated at 100° C. for 4 hours. The reaction medium is cooled to 30° C. and it is poured over an aqueous hydrochloric acid solution (2N). The precipitate formed is filtered and it is rinsed with isopropyl ether to give, after drying, 30 g of a white solid.
Reaction SMILES: [CH:1]12[O:7][C:6]1([C:8]1[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=1)[CH2:5][CH2:4][O:3][CH2:2]2.S(=O)(=O)(O)[OH:36].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[OH:7][CH:1]1[C:6]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=2)([OH:36])[CH2:5][CH2:4][O:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C45CCOCC4O5)nc3)cc(-c3ccccn3)c2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C4(O)CCOCC4O)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Yield: 42 %

Procedure:
Compound iii (20 mg; 0.042 mmol) was dissolved in THF-H2O (10:1, 11 mL). Conc. sulfuric acid (20 μL) and p-toluenesulphonic acid (0.7 mg, 4 mmol) were added and the mixture stirred at RT. The mixture was concentrated in vacuo and purified over silica (0-100% 0.1% FA (aq)-MeCN) yielding Compound 8 (8.8 mg, 42%).
Reaction SMILES: [NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
7,5 g of a chloromethylated styrene-divinylbenzene copolymer (Merrifield resin, 1% cross-linked) are esterified with 1.113 g of Boc-D-Tyr(Bzl)-OH (3 mmoles) by refluxing for 45 hours in 60 ml of ethyl acetate in the presence of 0.42 ml of triethylamine. The resin is separated by filtration, washed successively with ethyl acetate, ethanol and water, and dried under vacuum at 25° C. 8.09 g of Boc-D-Tyr(Bzl)-resin are obtained having an esterification degree of 0.201 mmoles of D-Tyr/g calculated on the basis of the difference between the total amount of D-Tyr derivative employed and the one remained in mother liquors and in washings (determination by UV at 276 nm). The resin is Boc-deprotected by treatment with 70 ml of TFA/CH2Cl2 1/1 for 30 minutes at room temperature; thereafter it is filtered and suspended for 30 minutes under stirring in 70 ml of 10% triethylamine in chloroform. After filtrating, washing with chloroform and drying under vacuum, the product H-D-Tyr(Bzl)-resin is obtained.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:13]([CH3:14])[O:12][C:11](=[O:15])[C@@H:10]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][O:8][CH2:7][C@@H:6]1[O:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:2]=C.C([O-])(O)=[O:37].[Na+].O=[O+][O-].CSC>CO.C(Cl)Cl>[C:19]([O:18][C:17]([N:16]([C@H:10]1[CH2:9][O:8][CH2:7][C@H:6]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:5]([O:4][CH2:1][CH:2]=[O:37])[C@H:13]([CH3:14])[O:12][C:11]1=[O:15])[C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:23])([CH3:21])([CH3:22])[CH3:20]
Reactant: O=C([O-])O
Reactant: C=CCO[C@H]1[C@H](C)OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@@H]1OCCCC
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: CCCCO[C@H]1COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1OCC=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 907.8 %

Procedure:
A mixture of tert-butyl N-[(3S,7S,8S,9S)-8-allyloxy-7-butoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (0.350 g, 0.698 mmol) and NaHCO3 (5.86 mg, 0.070 mmol) in MeOH (0.21 ml) and DCM (6.8 ml) was treated with ozone at −78° C. until the solution became light blue in color. The mixture was purged with nitrogen until colorless and quenched by the addition of DMS (0.10 ml, 1.40 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 20 h. The mixture was concentrated and purified by flash chromatography on (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (320 mg, 91%): IR (neat) 2934, 2876, 1743, 1706, 1367, 1253, 1121, 1096 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 5.18 (dd, J=8.9, 3.8 Hz, 1H), 4.84 (dq, J=9.4, 6.3 Hz, 1H), 4.39 (dd, J=17.9, 0.9 Hz, 1H), 4.22 (dd, J=17.8, 0.5 Hz, 1H), 4.19 (dd, J=12.2, 3.8 Hz, 1H), 3.91-3.75 (m, 2H), 3.57-3.42 (m, 2H), 3.37 (dt, J=9.2, 6.5 Hz, 1H), 3.29 (dd, J=7.9, 6.9 Hz, 1H), 3.21 (t, J=9.0 Hz, 1H), 1.52-1.40 (m, 2H), 1.45 (s, 18H), 1.41 (d, J=6.3 Hz, 3H), 1.30-1.19 (m, 2H), 0.83 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 200.51, 168.79, 152.61, 86.19, 83.52, 83.08, 79.09, 75.35, 72.95, 71.99, 70.03, 57.92, 32.02, 27.94, 19.29, 18.84, 13.85; HRMS-ESI (m/z) [M]+ calcd for C24H41NO10, 503.2730; found, 503.2727.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11](=[C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.CO.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[OH:28][C@H:6]1[CH2:5][CH2:4][C@@:3]2([CH2:2][OH:1])[C:8]([CH:9]=[CH:10][C:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C:12]=3[CH2:13][CH2:14][C@@H:15]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:7]1
Reactant: CC(C)(C)C(=O)O[C@H]1CCC2=C3C=CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)O[C@H]1CCC2=C3C=CC4=C[C@@H](O)CC[C@]4(CO)[C@H]3CC[C@@]21C

Procedure:
A mixture of 5 g of 19-hydroxy-17β-pivaloxyandrosta-4,6,8(14)-trien-3-one and 50 ml of methanol was cooled below 5° C. by an ice-bath, whereupon 500 mg. of sodium borohydride was added slowly and with stirring. After 85 minutes another 50 mg of sodium borohydride was added. The mixture was stirred with cooling for another 35 minutes, whereupon 10 ml of acetic acid-water 1:10 was added dropwise. After 10 minutes of further stirring without external cooling 2 g of sodium bicarbonate was added. The mixture was then concentrated at reduced pressure to a thick paste and 50 ml of water was added. The precipitate obtained was filtered and digested with benzene to yield 3β,19-dihydroxy-17β-pivaloxyandrosta-4,6,8(14)-triene, uv max 275 (sh), 285 and 300 (sh) mμ.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:44])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19](C3C=CC=C(C(F)(F)F)C=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[Br-:46]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19]([Br:46])[CH:18]=2)=[O:44])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as a white gum (0.976 g, 58%) from N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)4hydroxy-benzamide using a procedure similar to Example 191. 1H NMR (DMSO-d6) δ9.84 (s, 1H); 8.42 (t, 1H); 8.04 (d, 1H); 7.85-7.67 (m, 5H); 7.26-7.10 (m, 5H); 3.21 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.26 (m, 8H); IR (KBr) 3330, 2950, 2850, 1620, 1550, 1495, 1470, 1330, 1220, 1170, 1120, 1100, 1080 cm−1; mass spectrum [(+)APCI], m/z 549 (M+H)+; Anal. Calcd. for C28H29F3NO2: C, 61.32; H, 5.33; N, 2.55, Found: C, 61.02; H, 5.29; N, 2.51.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.[CH3:14][O:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:18]1[CH2:19][CH2:20][C@@H:16]([O:15][CH3:14])[CH2:17]1
Reactant: CO[C@@H]1CCNC1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: Cl
Product: CO[C@@H]1CCN(c2ccnc3ccc(Br)cc23)C1
Yield: 44.8 %

Procedure:
500 mg 6-bromo-4-chloroquinoline and 300 mg (3R)-3-methoxy pyrrolidine monohydrochloride were reacted by the same method as in Production Example 82, to give 284 mg of the title compound as a yellow oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Al].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1I>[Cu]I.CN(C)C=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Fc1ccc(I)c(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: CN(C)C=O
Product: Fc1ccc(-n2cnc3ccccc32)c(F)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
0.16 g (0.836 mmol) of CuI, 1.20 g (10.15 mmol) of benzimidazole and 5.70 g (17.50 mmol) of cesium carbonate (CeCO3) were successively added into a 50 ml round bottom flask wrapped by aluminum foil, after introducing nitrogen for 15 minutes, 1 mL (8.36 mmol) of 2,4-difluoro-iodobenzene, 0.30 g (1.67 mmol) of 1,10-ortho-phenanthroline and 25 mL of anhydrous N,N-dimethylformamide (DMF) were successively added to the nitrogen stream to form a reaction mixture; after 30 minutes of continually introducing nitrogen to the reaction mixture, the system was heated in oil bath to 110° C. and stirred for 24 hours; after the reaction was cooled to room temperature, it was concentrated in vacuum, and 10 mL of ethyl acetate was added to the concentrate, the precipitate was removed by filtering, the concentrate was then washed with 30 mL of ethyl acetate, the filtrate was concentrated; the filtrate was applied to silica gel column chromatography using a mixture solution containing ethyl acetate and n-hexane in a volume ratio of 2:3 as eluant, and 0.942 g of 1-(2,4-difluorophenyl)-benzimidazole in a form of yellow liquid was obtained with the yield of 48%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(OCCCl)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(c1ccc(OCCCl)cc1)N1CCOCC1

Procedure:
4-(2-Chloroethoxy)benzoyl chloride (5.0 g) was dissolved in dry methylene chloride and stirred while cooling to 0°. Morpholine (4.0 g) was added dropwise and the mixture was stirred at room temperature for 2 days. The resultant colourless solid was filtered off and the liquors allowed to stand from which the title compound crystallised (5.5 g), m.p. 102°-104°.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.Cl[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][O-].[K+].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:11]=2)[CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:7]=1
Reactant: Nc1ncc(C2CC2)cc1Br
Reactant: CCOC(=O)C(Cl)=C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(Br)cc(C3CC3)cn12
Yield: 51.7 %

Procedure:
A mixture of 3-bromo-5-cyclopropylpyridin-2-amine (0.753 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (1.30 g), sulfuric acid (0.208 mL) and ethanol (15 mL) was heated with reflux overnight. The reaction mixture was neutralized with 1N sodium hydroxide at 0° C., and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (565 mg).