Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:35]([NH:38][NH:39][C:29]([C:27]1[NH:28][C:24]([C:14]2[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=[C:12]([O:11][C:10]3[CH:32]=[CH:33][C:7]([C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[CH:8][C:9]=3[F:34])[CH:13]=2)=[CH:25][CH:26]=1)=[O:30])(=[O:37])[CH3:36]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (126 mg, 0.27 mmol) synthesized in Example (66g) and acetohydrazide (40 mg, 0.54 mmol) were dissolved in dichloromethane (5 mL), and HATU (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (70 μL, 0.40 mmol) were added at room temperature, followed by stirring under nitrogen atmosphere for 1 hour. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=5%) to afford the desired product (87 mg, yield 62%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:10]2[C:15]([C:16]=1[N:17]=[C:18]=[O:19])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]([C:38]1[C:42]([NH2:43])=[CH:41][S:40][CH:39]=1)=[O:37].C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[C:1]([O:5][C:6]([C:8]1[N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:43][C:42]1[C:38]([C:36]([O:35][CH3:34])=[O:37])=[CH:39][S:40][CH:41]=1)=[O:19])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N=C=O)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Reactant: COC(=O)c1cscc1N
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc12
Temperature: 150 °C
Yield: 74.6 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-isocyanato-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5E (˜4.10 mmol) in trifluoromethylbenzene (10 mL) was added 4-aminothiophene-3-carboxylic acid methyl ester 5F (1.30 g, 8.28 mmol). The reaction mixture was heated in a microwave reactor at 150° C. for 30 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 1-benzyloxycarbonyl-3-[3-(4-methoxycarbonylthiophen-3-yl)-ureido]-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5G (1.89 g, 3.06 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=2[OH:12])[CH:5]=[CH:4][CH2:3]1.[H][H]>O.[Ni]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=2[OH:12])[CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CCCc1ccc2c(c1O)N(C)CC=C2
Agent: [Ni]
Solvent: O
Product: CCCc1ccc2c(c1O)N(C)CCC2
Yield: 36 %

Procedure:
Into a stainless steel autoclave, one introduces 37.3 g of paratoluenesulfonate of N-methyl-7-propyl-8-hydroxyquinoline (0.1 mole) in 120 ml of water, and 5 g of Raney nickel. The hydrogenation is carried out under an 80 kg/cm2 hydrogen pressure. After absorption of the hydrogen, one cools and filters off the catalyst; one neutralizes the filtrate with an ammonia solution, resulting in the formation of a grayish-white precipitate that one separates and distills under high vacuum. One collects 8 g of a colorless liquid that distills at 180°-110°C under a 0.5 mm Hg pressure. One obtains a yield of 36%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:13][OH:14])[O:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].N1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: COC(CO)CO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO[Si](C)(C)C(C)(C)C)OC
Yield: 99 %

Procedure:
To a solution of alcohol Compound 42 (1.1 g, 5.0 mmol) in CH2Cl2 (10 mL) was added oleoyl chloride (1.8 mL, 5.5 mmol) followed, after 5 min, by the addition of pyridine (0.44 mL, 5.5 mmol). After TLC analysis indicated that the reaction had gone to completion, the mixture was partitioned between ethyl acetate (100 mL) and H2O (30 mL), the organic extract was dried (MgSO4) and concentrated to give 1-O-t-butyldimethylsilyl-2-O-methyl-3-O-oleoyl-rac-glycerol (Compound 43) (2.4 g, 99%) as a dark brown oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13].[Br:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH2:16][CH2:15][Br:14]
Reactant: BrCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCOc1ccc2cc(Br)ccc2c1Br
Temperature: 0 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
1,6-Dibromo-2-naphthol (15.0 g, 49.67 mmol) and 1,2-dibromoethane (46.7 g, 248.37 mmol) were added to a suspension of potassium carbonate (84.8 g, 74.51 mmol) in acetonitrile (500 mL) at rt. The reaction mixture was stirred for 48 h. Additional 1,2-dibromoethane (21.5 mL, 248.37 mmol) was added and the reaction mixture was stirred for 96 h at rt. The reaction mixture was cooled to 0° C. with an ice bath and filtered through a fritted glass funnel. The resulting filtrate was concentrated under reduced pressure to give the title compound (14.2 g, 69.9% yield) as a brown solid. GC/MS m/z 406 (M)+, RT 10.25 min; 1H NMR (400 MHz, acetone-d6) δ 14-8.09 (m, 2H), 7.96 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 4.64-4.60 (m, 2H), 3.90-3.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[NH:9][CH2:8][CH2:7][C:6]2=1.Br[CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH2:33]([O:32][C:30](=[O:31])[CH:29]([N:9]1[CH2:8][CH2:7][C:6]2[C:5]3[C:13](=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:12][C:11]=2[CH:10]1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34]
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3CCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(c1ccccc1)N1CCc2c([nH]c3ccc(OC)cc23)C1CCc1ccc(C(F)(F)F)cc1
Yield: 16.3 %

Procedure:
A mixture of 90 mg (0.24 mmol) 6-methoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-2,3,4,9-tetrahydro-1H-β-carboline, 59 mg (0.24 mmol) ethyl bromophenylacetate and 28.8 mg (0.27 mmol) Na2CO3 in 4 mL methanol was heated to reflux for 16 h. After filtration DMF was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to dryness to yield 21 mg (16%) {6-methoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,3,4,9-tetrahydro-β-carbolin-2-yl}-phenyl-acetic acid ethyl ester (diastereoisomer 1)
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].C(OC([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)=O)C1C=CC=CC=1>N1C=CC=CC=1>[NH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:20][CH2:19][N:15]2[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]3[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:38](=[O:39])[C:37]4[CH:36]=[CH:35][C:34]([NH2:33])=[CH:42][CH:41]=4)[C:4](=[O:22])[CH2:5]3)[CH2:17][C:16]2=[O:18])=[O:39])=[CH:36][CH:35]=1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: O=C(Nc1ccc(C(=O)Cl)cc1)OCc1ccccc1
Solvent: c1ccncc1
Product: Nc1ccc(C(=O)OCN2C(=O)CN(CCN3CC(=O)N(COC(=O)c4ccc(N)cc4)C(=O)C3)CC2=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 114.7 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.63 g, 2.0 m mol) and pyridine (10 ml), p-benzyloxycarbonylaminobenzoyl chloride (1.27 g, 4.4 m mol) dissolved in pyridine (12 ml) was added gradually at 0° C. and then the reaction mixture was stirred for 1 hour at 0° C. and successively for 16 hours at room temperature. The residue obtained by removing the solvent from the reaction mixture under reduced pressure was added to water (50 ml) and extracted with chloroform (150 ml×2). The extract solution was washed with 10% sulfuric acid solution and successively with water, further was washed with saturated sodium bicarbonate aqueous solution and successively with water and was dried. The residue obtained by removing the solvent from the extract solution was purified by silica gel column chromatography (ethyl acetate) to give benzyloxycarbonyl derivative of the titled compound (1.27 g; yield 77.4%). The derivative (1.27 g) was dissolved in a mixture of ethyl acetate (80 ml) and ethanol (80 ml), and 10% palladium-carbon (0.13 g) was added and the mixture was stirred overnight under hydrogen at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=95:5) and recrystallized from ether to give the titled compound (0.39 g; yield 45.7%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:4][CH:14]([C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A solution of sulfuryl chloride (12.4 mmol) in toluene (5 mL) was added dropwise via an additional funnel to a solution of ethyl benzoylacetate (12.4 mmol) in toluene (20 mL) over 5 minutes at room temperature. The resulting mixture was stirred at room temperature overnight. Water was added slowly and resulting two-phase mixture was basified with saturated NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to afford 2.2 g (84%) of product as a pale yellow oil; MH+=227.0, retention time (LC-MS)=2.77 min.
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:27][CH:28]([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CC#N>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:4]2[C:3](=[O:26])[C:2]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([O:29][CH:28]([F:27])[F:37])=[CH:31][CH:32]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:5]2(=[O:14])=[O:13])=[CH:17][CH:18]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: O=C1C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
4-Chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (80 mg, 0.2 mmol) and 4-(difluoromethoxy)-aniline (64 mg, 0.4 mmol) were mixed in MeCN (2 mL).
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=3)[CH2:17][CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:38][C:36]1[CH:35]=[CH:34][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=4)[CH2:17][CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[S:13][C:6]=23)=[C:2]([F:1])[CH:37]=1
Reactant: COCCN(CCc1cccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COCCN(CCc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Yield: 85.8 %

Procedure:
To nitro compound 155 (0.44 g, 0.78 mmol) and zinc dust (0.65 g, 10 mmol) in methanol (50 mL) was added ammonium chloride (0.075 g, 1.4 mmol) in water (6 mL). The resulting mixture was heated to reflux for 2 h, then cooled, filtered through celite and concentrated. Silica gel chromatography (70% ethyl acetate/hexanes) afforded title compound 156 (0.36 g, 88% yield). MS (m/z): 538.3 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:55]1([O-:60])[CH2:56][CH2:57][CH2:58][CH:59]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:60][N:55]4[CH2:56][CH2:57][CH2:58][C@@H:59]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Reactant: [O-][N+]1=CCCC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 62.6 %

Procedure:
To a solution of 1.291 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 100 ml of toluene is added 1.5 g of 3,4-Dihydro-2H-pyrrole 1-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 8:1 ethyl acetate-hexanes to give 0.906 g of the desired product as a white foam. FAB mass spec 812 (M+Na).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1.I[CH3:20].O>CN(C=O)C>[Br:3][C:4]1[C:13]([O:14][CH3:20])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1
Reactant: CI
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reaction time: 2 h

Procedure:
720 mg (24 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 5.7 g (20 mmol) of 2-bromo-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in 75 ml of DMF was added dropwise and stirring was carried out until gas evolution had ceased. 1.5 ml (24 mmol) of iodomethane was then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane and filtered. 5.5 g (93%) of 2-bromo-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, with a melting point of 70°-71° C., were recovered.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[CH:4].Br[C:14]1[N:19]=[C:18]([CH2:20][C:21]2[O:26][C:25](=[O:27])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[C:4][C:14]1[N:19]=[C:18]([CH2:20][C:21]2[O:26][C:25](=[O:27])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C#CC(O)CCCCCCCC
Reactant: O=c1cccc(Cc2cccc(Br)n2)o1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(O)C#Cc1cccc(Cc2cccc(=O)o2)n1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-undec-1-yne (202 mg, 1.2 mmole) and 6-[1-[6-bromopyridine-2yl]methyl]pyran-2-one (270 mg, 1 mmole) are combined in 4 ml triethylamine in a 25 ml one-neck round bottom flask under argon. The mixture is treated with (bis)triphenylphosphine palladium dichloride (14 mg, 0.02 mmole), warmed to 55° C., and is treated with cuprous iodide (2 mg, 0.01 mmole). The reaction mixture is stirred one hour at 55° C., cooled to room temperature, and the volatiles are removed in vacuo. The residue is partitioned between 1×10 ml diethyl ether and 1×10 ml saturated sodium chloride/ammonium chloride (1:1). The aqueous layer is extracted with 3×10 ml diethyl ether. The combined organics are dried over magnesium sulfate and concentrated in vacuo to a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 52.5 °C
Reaction time: 24 h
Yield: 89.7 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (4.24 g, 19.48 mmol) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (6.73 g, 21.41 mmol) in DMF (21 ml) were stirred at 50-55° C. for 24 hours. The reaction mixture was allowed to return to room temperature and poured into water (90 ml), and extracted with ethyl acetate (60 ml). The aqueous layer was extracted with ethyl acetate (60 ml) again. The organic phases were combined, washed with water (90 ml) 3 times and a saturated saline solution (60 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazine-1-carboxylate (9.29 g, yield 90%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1.[H-].[Na+].CI.[C:18]([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:18][O:1][CH2:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2ncc(CO)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COCc1cnc2ccc(C#N)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(hydroxymethyl)-imidazo[1,2-a]pyridine-6-carbonitrile (7-2) (346 mg, 2 mmol) in 20 mL of THF was added sodium hydride (240 mg, 60% in oil) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then methyl iodide (615 mg, 4.3 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was treated with aqueous Na2CO3, then concentrated. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated to afford the title compound (300 mg). MS (m/z): 188.0 (M+H)+
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([S:9][CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[O:15][CH2:14][CH2:13]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.O>C(Cl)Cl>[C:27]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([S:9]([CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[O:15][CH2:14][CH2:13]2)=[O:41])[CH3:8])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(SCCN1CCOc2c(OCC(=O)O)cccc21)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(c1ccccc1)(c1ccccc1)S(=O)CCN1CCOc2c(OCC(=O)O)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid (51 mg) was dissolved in methylene chloride (5 ml), and the resultant solution was stirred at room temperature. m-CPBA (20 mg) was then added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to water (20 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by Lober® column chromatography (DIOL, type A, developing solvent: n-hexane/ethyl acetate=1/2) to obtain the object compound (43 mg, yield 81%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc[nH]1
Product: S=C(NN=Cc1ccc[nH]1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and pyrrole-2-carboxaldehyde (53 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow oil (3 mg, 2%). 1H NMR (CDCl3): 9.28 (s, 1H), 8.99 (s, 1H), 7.68 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 6.94 (s, 1H), 6.53-6.51 (m, 1H), 6.29-6.26 (m, 1H), 6.22-6.13 (m, 2H), 4.30-4.24 (m, 1H), 3.04 (s, 1H), 2.94 (s, 1H), 1.92-1.84 (m, 1H), 1.65 (d, J=9.0 Hz, 1H), 1.50 (d, J=9.0 Hz, 1H), 1.45-1.38 (m, 1H).