Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O[Li].O>CO.O>[CH2:7]([O:6][P:4]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 7-f (100 mg, 0.33 mmol) in methanol (2 mL) and water (2 mL) was treated with LiOH—H2O (14 mg, 0.33 mmol), and the resulting reaction solution was stirred at room temperature overnight. The resulting mixture was concentrated and extracted by EA. The aqueous layers was added HCl (1 M) until pH 1˜2. The mixture was extracted by EA. Combined organic layers was washed by brine, dried over Na2SO4 and concentrated to afford the title compound, 7-g, as oil (35 mg, 37%). 1H NMR (300 MHz, CDCl3) δ1.30-1.34 (m, 6H), 1.52 (d, J=7.2 Hz, 3H), 3.79 (q, J=7.2 Hz, 1H), 4.07-4.17 (m, 4H), 7.39-7.43 (m, 2H), 7.71-7.78 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15]C(C)(C)[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:17])[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(F)cc4F)ncnc31)O[C@@H]2c1nc(C(C)(C)C)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1noc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(F)cc5F)ncnc43)[C@H](O)[C@@H]2O)n1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
A solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-(2,4-difluorophenyl)-9H-purin-6-amine (18.3 mg) in a cold mixture of trifluoroacetic acid:water (9:1; 1 ml) was kept at 4° C. for 18 h. The resulting solution was basified in an ice bath with a saturated solution of sodium bicarbonate (20 ml), extracted with ethyl acetate (2×20 ml), the extracts dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound (14.3 mg) as a purple solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[BH4-].[Na+].Cl>O.CO>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCc2cc(C(O)c3ccccc3)ccc2N1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a suspension of 27.3 parts of intermediate 18, namely 6-benzoyl-3,4-dihydro-2(1H)-quinolinone, in 790 parts of methanol were added 115 parts of an aqueous sodium hydroxide solution 1N. After stirring for 10 min., there were added at once 4.54 parts of sodium tetrahydroborate. Stirring was continued over weekend at room temperature. There were added 110 ml of HCl 1N and 1000 parts of water. The precipitate was filtered off, stirred in water for 15 rain and then taken up in a mixture of methanol and methylbenzene. This solution was evaporated and the residue was co-evaporated with methylbenzene. The product was filtered off and dried at 70° C., yielding 21.9 parts (78.6%) of 3,4-dihydro-6-(hydroxyphenylmethyl)-2(1H)-quinolinone; mp. 175.0° C. (interm. 19).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(Br)cc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Br)cc1
Yield: 71 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-bromo-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 71% of theory; LC (method 1): tR=4.06 min; Mass spectrum (ESI+): m/z=426/428 (Br) [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:14][CH:15]=[C:16]([CH3:25])[CH2:17][CH2:18][CH:19]=[C:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[OH-].[Na+]>O1CCCC1.CN(C)C=O>[CH2:23]([C:20]([CH2:21][CH3:22])=[CH:19][CH2:18][CH2:17][C:16]([CH3:25])=[CH:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:24]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCC(=CCCC(C)=CCBr)CC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(=CCCC(C)=CCOc1ccc2c(c1)OCC2)CC
Temperature: 0 °C

Procedure:
10.9 g. of 6-hydroxy-2,3-dihydrobenzofuran are dissolved in 80 ml. of anhydrous dimethylformamide and treated, while stirring and with ice cooling at 0° C. with 5.3 g. of freshly powdered potassium hydroxide. The mixture is stirred for 1 hour at 0° C. under a nitrogen atmosphere and then added dropwise within 1 hour to a solution of 19.6 g. of 1-bromo-7-ethyl-3-methyl-2,6-nonadiene in 10 ml. of absolute tetrahydrofuran. The mixture is allowed to stir for 2 hours at 0° C. and for 2 hours at room temperature and then poured onto a mixture of 100 ml. of 10% by weight aqueous sodium hydroxide and 100 ml. of ice-water. The mixture is extracted three times with pentane, the extracts are washed successively with 10% by weight aqueous sodium hydroxide, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/diethyl ether (19:1 parts by volume) there is obtained pure 6-[(7-ethyl-3-methyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran which is distilled in a bulb-tube at 132° C./0.02 mmHg; nD20 = 1.5350.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][N:5]([CH2:17][C:18]1[CH:37]=[CH:36][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O.Cl>CO.O1CCCC1.[OH-].[Na+]>[CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][N:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=2)=[CH:36][CH:37]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Methyl 3-{4-[(4-{[(3-methylbutyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}propanoate (240 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated to give the title compound (220 mg, yield 90%) as a pale-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([NH:10]C(=O)OCC=C)[CH2:9][CH2:8]1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([NH2:10])[CH2:9][CH2:8]1
Reactant: C=CCOC(=O)NC1(c2cnccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: NC1(c2cnccn2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of allyl 1-(pyrazin-2-yl)cyclopropylcarbamate (0.12 g, 0.547 mmol, 1 eq) and morpholine (0.47 ml, 5.47 mmol, 10 eq) in THF (3 ml) was added Pd(PPh3)4 (0.038 g, 0.033 mmol, 0.06 eq), and the yellow mixture was stirred at 50° C. for 3 h. The solvent was removed under a stream of N2 and the residue was purified by flash chromatography using 4-7% of methanol in dichloromethane to give the compound as a yellow oil. Yield: 0.05 g (68.5%). 1H NMR (400 MHz, CD3OD): δ 1.17-1.20 (m, 2H), 1.36-1.38 (m, 2H), 8.36-8.37 (d, J=2.4 Hz, 1H), 8.49-8.50 (q, 1H), 8.85-8.85 (d, J=1.6 Hz, 1H). LCMS: (ES+) m/z=136.2 (M+H)+
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]>C(O)(=O)C>[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12]([Br:1])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Yield: 81.2 %

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.139 moles) in glacial acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H), 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3) δ3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was colleced and dried to yield 5.6 g of the title compound; mp >290° C.; NMR (DMSO-d 6) δ4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Reactant: OB(O)c1ccsc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccsc2)c1
Yield: 26 %

Procedure:
By carrying out the operation analogously to example 13, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 3-thiopheneboronic acid, the expected product is obtained in the form of white crystals with a yield of 26%.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:29])[CH2:27][CH3:28]>C(O)C>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][NH:29][CH2:26][CH2:27][CH3:28])[CH2:7]1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCCNCC1CCOC1

Procedure:
A mixture comprising 3.00 g of (tetrahydro-3-furanyl)methyl tosylate, 0.20 g of sodium iodide, 3.50 g of potassium carbonate, 4.00 g of propylamine and 30 ml of ethanol was refluxed for 8 hours. After separation of insoluble matters by filtration, the reaction fluid was concentrated under a reduced pressure to obtain crude N-{(tetrahydro-3-furanyl)methyl}propylamine. To this were added 1.90 g of 1,1-bis(methylthio)-2-nitroethylene and 16 ml of acetonitrile. The resulting mixture was refluxed for 4 hours. The reaction fluid was concentrated under a reduced pressure, and purified by silica gel column chromatograpy (eluent: ethyl acetate/hexane=1/2) to obtain 1.00 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-propylamino]-1-methylthio-2-nitroethylene. A mixture comprising 0.25 g of the 1-[N-{(tetrahydro-3-furanyl)methyl}-N-propylamino]-1-methylthio-2-nitroethylene obtained above and 3 ml of 40% methylamine in methanol solution was stirred for 40 minutes at room temperature. The reaction fluid was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/methanol=7/1) to obtain 0.22 g of 1-[N-{(tetrahydro-3-furanyl)methyl}propylamino]-1-methylamino-2-nitroethylene.
Reaction SMILES: Cl[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H-].[CH2:15]([Al](CC)CC)[CH3:16].[Na+].C[O-].[Na+].Cl>CCCCC>[CH3:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:15][CH3:16]
Reactant: CCCCCCCCCCC#CCl
Reactant: CC[Al](CC)CC
Agent: C[O-]
Agent: Cl
Agent: [H-]
Solvent: CCCCC
Product: CC/C=C\CCCCCCCCCC
Temperature: 50 °C

Procedure:
In a manner similar to that described in Example 10, 1.00 g (5.00 mmol) of 1-Chloro-1-dodecyne was hydroaluminated with sodium triethylaluminum hydride and then treated with sodium methoxide. After heating the reaction mixture overnight at 50° C., it was slowly poured into a mixture of 3N HCl and pentane. The aqueous layer was extracted with pentane and the combined organic phase was washed sequentially with 3N HCl, saturated NaHCO3, and saturated NaCl. Analysis by GC (using n-nonane as an internal standard) showed the presence of 4% 1-dodecene, 28% 1-dodecyne, and 68% cis-3-tetradecene. Short-path distillation provided a pure sample of cis-3-tetradecene: bp=57./0.1 torr; IR (neat) 3020 (w), 2960 (s), 2920 (s), 2850 (s), 1655 (w), 1470 (m) cm-1 ; 1H--NMR (CDC13, TMS) 0.85 (t, 3H), 0.95 (t, 3H), 1.2-1.4 (br s, 16H), 2.05 (m, 4H), 5.35 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[NH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.96 g, 5.95 mmol) was reacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.10 g (70%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[N:14]=[CH:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[C:12]=2[CH:11]=[CH:10][N:9]=1)=[O:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[N:14]=[CH:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([C:37]([F:39])([F:38])[F:40])[CH:30]=4)=[O:36])=[CH:19][CH:18]=3)[C:12]=2[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CN(C)CCNC(=O)c1nccc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid (2-(dimethylamino)ethyl)amide and 4-chloro-3-(trifluoromethyl)phenyl isocyanate in the same manner as in Steps B and C of Example 1.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]C1C=CC=CC=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20](F)[CH:19]=1.[OH-].[Na+]>CN(C=O)C>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:19]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
Sodium hydride (12 g, 300 mmol) (60% by wt) was weighed into a flask and washed free of oil with several hexane rinsings. The hexanes were decanted and discarded and DMF was added to the flask. A DMF-solution of phenol (23.5 g, 250 mmol in 100 mL DMF) was added dropwise to the NaH mixture and stirred at room temperature. To the phenoxide was added a solution of 4-bromo-2-fluoro-benzonitrile (50 g, 250 mmol in 100 mL DMF), dropwise. Upon complete addition, the reaction was refluxed for 20 h. The reaction was cooled to room temperature, and poured into cold 1 N NaOH. A fine, tan precipitate formed and was collected by vacuum filtration to give 62.04 g (226 mmol) of Compound 1a. MS m/z (MH+) 277.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2]([C:34](=[O:36])[CH3:35])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 7.9 %

Procedure:
A stirred suspension of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.33 mmol) from Step 5 of Example 108 and tributyl(1-ethoxyvinyl)tin (177 mg, 0.5 mmol) in DMA (1.5 mL) was purged with a stream of argon for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 110° C. for 3 h. The mixture was cooled to rt. To the mixture was added 0.5 M aq HCl (500 μL) followed by stirring at rt for 12 h. The mixture was filtered, and the filtrate was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and a Varian Pursuit XRs C18 column as the stationary phase. The product was further purified by silica gel flash chromatography eluting with 5% MeOH in CH2Cl2 to afford 1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)ethanone (11 mg, 8%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.32 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.64-7.72 (m, 2H), 7.30 (m, 1H), 7.20 (m, 1H), 5.52 (s, 2H), 4.73 (d, J=5.1 Hz, 1H), 3.52 (m, 1H), 3.34 (m, 1H), 2.62 (s, 3H), 2.02 (m, 1H), 1.90 (m, 1H), 1.55-1.69 (m, 2H), 1.10-1.35 (m, 4H); LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2cccc3ccccc23)CCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2cccc3ccccc23)CCC(=O)CC1
Yield: 76 %

Procedure:
A mixture of 16.73 g. (0.055 mole) of methyl 5-cyano-5-(1-naphthyl)-2-oxocyclohexanecarboxylate (prepared in Example 11) in 400 ml. of acetic acid and 200 ml. of 10% sulfuric acid is stirred mechanically for about 44 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is successively washed with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from acetone to give 10.3 g. (76% yield) of 4-cyano-4-(1-naphthyl)cyclohexanone, having a melting point of 213° to 215°C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Cl-].[Mn+2].[Cl-].C(#N)C>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: [Mn+2]
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 61.7 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, and 7.84 g (76 mmol) of tert-butyl nitrite, 31 mg (0.25 mmol) of manganese(II) chloride, 120 mL of acetonitrile and 4.65 g (50 mmol) of aniline at 70° C. The crude product is purified by vacuum flash chromatography (heptane) to give 3.6 g of the title compound as a colorless oil in a 62.1% yield.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:4]/[N+:5]([O-:7])=[O:6].C=CC>>[OH:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][N+:5]([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C(/CO)c1ccccc1
Solvent: C=CC
Product: O=[N+]([O-])CC(CO)c1ccccc1
Yield: 55 %

Procedure:
The same procedure as Example 17, except that (E)-3-hydroxy-1-nitro-2-phenyl-1-propene was used in place of (E)-1-nitro-2-(pyridin: 2-yl)-1-propene, provided optically active 3-hydroxy-1-nitro-2-phenylpropane.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=1)=O.Cl>CN(C)C=O.O>[N+:9]([C:5]1[CH:4]=[C:3]([CH:2]=[CH:37][C:39]2[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=2)[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(C=Cc2cccc([N+](=O)[O-])c2)cs1
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 1-(bromomethyl)-3-nitrobenzene (276 mg) in N,N-dimethylformamide (7 mL) was added triphenylphosphine (335 mg) at room temperature. After the mixed solution was stirred for 4 hours, potassium tert-butoxide (172 mg) and N-(4-formyl-1,3-thiazol-2-yl)acetamide (217 mg) were successively added to the solution at the same temperature. After the whole solution was stirred at room temperature for 5 hours, the mixture was poured into water, the pH of the aqueous layer was adjusted to 7 with 1N-hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of n-hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give brown powder of the title compound (E-Z mixture) (323 mg, 87.4%).