Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:34])[C:32]#[CH:33]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:33]=[C:32]([CH2:31][OH:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cc(CC4CCOCC4)cc(c1=O)c32
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide (0.185 g), PdCl2(PPh3)2 (0.012 g), and CuI (0.032 g) in 10 mL of diethylamine is added propargyl alcohol (0.02 mL). The reaction is stirred overnight. The mixture is concentrated and the resulting solid is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is recrystallized from CH2Cl2/Et2O to yield 0.09 g (56%) of N-(4-chlorobenzyl)-2-(hydroxymethyl)-6-oxo-8-(tetrahydro-2H-pyran-4-ylmethyl)-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a white solid, m.p. 196-198° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[C:7]([NH:10][C:11]1[S:12][C:13]([S:17]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)(=[O:18])=[O:19])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8]
Reactant: OC1CCNC1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N2CCC(O)C2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.3 %

Procedure:
To a stirred solution of (RS)-3-pyrrolidinol (0.51 g, 5.85 mmol) in THF (12 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield (RS)-1-(2-acetamido-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (0.82 g, 68%) as a white solid. MS (ISP) 306.3 [(M+H)+]; mp 241° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:8]([O:10][CH3:11])=[O:9])=[O:5].Cl.[CH3:24]N1C(=O)CCC1>O1CCOCC1.O>[CH:13]1([CH2:12][C@H:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:1]=[CH:24]2)[C:8]([O:10][CH3:11])=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CN1CCCC1=O
Reactant: COC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccccc1N
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC1CCCCC1)n1cnc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of Compound 22 (1 g, 3.29 mmol) in 15 mL of NMP was added triethoxyorthformate (9.87 mmol), followed by 0.5 mL of 4M HCl in dioxane. The mixture was heated to 100° C. overnight, and then diluted with water and extracted with EtOAc. After removing the solvent, the residue was dissolved in MeOH and 7.9 mL of 2 M LiOH was added. The mixture was stirred for 4 hours and acidified with con. HCl to pH=4-5. The mixture was extracted with EtOAc and dried over MgSO4. Removing the solvent gave Compound 23. [M+H] calc'd for C17H20N2O3, 301; found, 301.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH3:24])[N:18]=[C:19]([N+:21]([O-])=O)[N:20]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]>C(O)C.CO.[Pd]>[NH2:21][C:19]1[N:20]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=2)[N:17]([CH3:24])[N:18]=1
Reactant: CCO[C@@H](Cc1ccc(-c2nc([N+](=O)[O-])nn2C)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(-c2nc(N)nn2C)cc1)C(=O)OC
Reaction time: 3 h
Yield: 99.8 %

Procedure:
0.4 g (0.4 mass equivalent) of 10% palladium-on-charcoal is added to a solution of 0.9 g (2.7 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H-[1,2,4]triazol-3-yl)phenyl]propanoate in 40 ml of ethanol and 10 ml of methanol, degassed beforehand, and the reaction medium is placed under an atmospheric pressure of hydrogen for 3 hours. After filtration through Celite and washing with ethyl acetate, the filtrate is evaporated under vacuum. 0.82 g (100%) of methyl 3-[4-(5-amino-2-methyl-2H-[1,2,4]triazol-3-yl)phenyl]-2(S)-ethoxypropanoate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1.FC1C=CC([Mg]Br)=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.75 h
Yield: 35 %

Procedure:
Ethyl (1RS)-1-(4-Fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (5 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 4-fluorophenyl magnesium bromide (0.62 mmol). After stirring for 45 min, the mixture was partitioned between 3 M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (45 mg, 35%).
Reaction SMILES: C(OCCCCOC(OC1C=CC(C(O)=O)=CC=1)=O)(=[O:4])C=C.[CH:23]1([N:29]=[C:30]=[N:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C1C=CN=CC=1)C.ClCCl>[CH:32]1([NH:31][C:30]([NH:29][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:4])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C=CC(=O)OCCCCOC(=O)Oc1ccc(C(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of 4-(acryloxybutyloxycarbonyloxy)benzoic acid (2 mmol), N,N′-dicyclohexylcarbodiimide (2.2 mmol), 2,4-O-benzylidene-D-threitol (1.1 mmol; cf. Example 1c) and the catalyst 4-DMAP (0.1 mmol) in dichloromethane (5 ml) is stirred at room temperature until the reaction is complete, the N,N′-dicyclohexylurea which has been formed is filtered off and the solvent is removed under reduced pressure. The residue is finally purified by column chromatography and recrystallized from ethanol.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:35])[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]C(C)(C)C)=[O:29])=[O:22])[CH2:17][CH3:18])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl.O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:17]([N:16]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:35])[CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([OH:30])=[O:29])=[O:22])[CH3:18]
Reactant: CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 97 %

Procedure:
To a stirred solution of 85 mg (0.17 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-ethyl-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after resuspension in water and lyophilization, 63 mg (97%) of the title compound as a yellow crystalline solid. MS m/e (%): 442 ([M+OAc]−, 35), 382 ([M−H]−, 100).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18]C)=[O:17])[C:6]2=[O:20].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+].C(#[N:34])C>C(OCC)(=O)C>[NH2:34][C@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:14][CH2:15]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]3=[O:20])[CH2:22]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC#N
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(N2CCC[C@H](N)C2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (300 mg, 1 mmol), 3-S—N-(tert-butoxycarbonyl)-amino)-piperidine (413 mg, 2 mmol) and NaHCO3 (390 mg, 14.64 mmol) in ACN (13 mL) was heated in a microwave at 120° C. for 20 min, and twice at 130° C. for 30 min. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (30 mL). After extraction of the aqueous phase with ethyl acetate (2×30 mL), the organic phases were combined washed with brine, dried with magnesium sulfate, filtrated, and concentrated. The residue was dissolved in TFA (1 mL) and agitated for 1 hour prior to evaporation of the solvent. The residue was dissolved in THF (1 mL) and an aqueous 4M NaOH solution (1.4 mL) and heated in a microwave at 100° C. for 10 min and at 120° C. for 10 min. The mixture was evaporated and the residue purified by preparative HPLC. The title compound EXAMPLE 35 was obtained after lyophilization (65 mg, 19%). High-Res MS: calculated m/z 342.1812 (M+H)+. found m/z 342.1787 (M+H)+.
Reaction SMILES: C(OCC)(=O)C.[C:7]1([S:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.CC1C=CC(OC2C=CC(CN[C:41]([C:43]3[N:47]([CH3:48])[N:46]=[C:45]([CH2:49][CH3:50])[C:44]=3[Cl:51])=[O:42])=CC=2)=CC=1>O>[C:7]1([S:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:41]([C:43]3[N:47]([CH3:48])[N:46]=[C:45]([CH2:49][CH3:50])[C:44]=3[Cl:51])=[O:42])=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCc1nn(C)c(C(=O)NCc2ccc(Oc3ccc(C)cc3)cc2)c1Cl
Reactant: NCc1ccc(Sc2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1nn(C)c(C(=O)NCc2ccc(Sc3ccccc3)cc2)c1Cl
Reaction time: 1.5 h

Procedure:
Into 50 ml solution of ethyl acetate containing 3.50 g of 4-phenylthiobenzylamine and 2.2 g of triethylamine, was dropped 3.60 g of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride synthesized in Example 2. After the completion of dropping, the mixture was stirred for 1.5 hours, poured into iced water and then extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium carbonate, water and a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solution was concentrated under a reduced pressure. The residue was purified on silica gel column chromatography to obtain 4.70 g of the titled compound (No. 76) shown in Table 1.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][S:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)C1CSCC1=O
Solvent: CCO
Product: CCOC(=O)C1CSCC1=O

Procedure:
20 parts by weight of methyl 3-keto-1,5-dihydrothiophene-4-carboxylate, 57.8 parts by weight of ethanol and 1 part by weight of p-toluenesulfonic acid are refluxed for 50 hours, and the mixture is then distilled. 17.1 parts by weight of ethyl 3-keto-1,5-dihydrothiophene-4-carboxylate of melting point 106°-109° C./1.3 mbar are obtained.
Reaction SMILES: Cl.Cl.[C@H:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(CC[N:55]2[CH2:60][CH2:59][C@H:58]([OH:61])[C@@H:57]([CH3:62])[CH2:56]2)CC1>>[OH:61][C@H:58]1[CH2:59][CH2:60][N:55]([CH2:3][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:56][C@@H:57]1[CH3:62]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6ccccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105, see example 50) and amine 14.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:33]=[C:34]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH:35]=[C:36]([Cl:39])[C:37]=1[F:38].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:31][C:32]1[CH:33]=[C:34]([C:40]2([C:41]([F:43])([F:44])[F:42])[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[C:9]3([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[O:8][CH2:7]4)[O:45]2)[CH:35]=[C:36]([Cl:39])[C:37]=1[F:38]
Reactant: O=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ccc12
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)O3)ccc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a stirred solution of tert-butyl 5′-((hydroxyimino)methyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 43) (0.5 g, 1.645 mmol, 1 eq) in DMF (6.5 mL) was added NCS (0.218 g, 1.645 mmol, 1 eq). Reaction mixture was stirred at 55° C. for 1 hour under nitrogen atmosphere. After 1 hour (chloro intermediate formation), 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (0.437 g, 1.678 mmol, 1.02 eq) was added followed by addition of sodium bicarbonate (0.140 g, 1.678 mmol, 1.02 eq) at room temperature. Resulting reaction mixture was stirred at 55° C. for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (3×50 mL). Combined organic phase was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.6 g, crude). Crude compound was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as colorless thick oil (0.33 g, impure). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 4.11 (d, J=10.04 Hz, 2H), 4.32 (d, J=9.92 Hz, 2H), 5.15 (s, 2H), 7.56-7.58 (m, 1H), 7.64-7.68 (m, 3H), 7.86 (d, J=8.04 Hz, 1H), 8.02-8.04 (dd, J1=6.12 Hz, J2=0.64 Hz, 1H). LC-MS (m/z): No ionization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N+:13]([O-])=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1.C1(C)C=CC=CC=1.CNC.[H][H]>[Ni].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Reactant: [H][H]
Agent: [Ni]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 67 %

Procedure:
24.1 g (0.1 mol) of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide, 9.6g of Raney nickel (produced by Kawaken Fine Chemical Co., Ltd.), 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had bee completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 67% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 12.4 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole (yield, 55%; melting point, 128° to 130° C.).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].[H][H].Br[C:10]1[S:11][C:12]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])=[CH:13][N:14]=1>CN(C)C=O.O>[CH2:3]([O:6][C:10]1[S:11][C:12]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])=[CH:13][N:14]=1)[CH:4]=[CH2:5]
Reactant: [H][H]
Reactant: C=CCO
Reactant: CN(C)C(=O)c1cnc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ncc(C(=O)N(C)C)s1
Reaction time: 18 h

Procedure:
To a stirred suspension of 0.5 g (10 mmol) of sodium hydride in 5 ml of dry N,N-di-methylformamide under N2, there can be added 0.6 g (10 mmol) of sieve-dried allyl alcohol. After hydrogen evolution ceases, the stirred solution can be treated with 2-bromo-5-(N,N-dimethylcarbamoyl)thiazole (2.35 g, 10.0 mmole). The mixture can then be stirred at 40° under N2 for 18 hours, diluted with four volumes of water and extracted with ether. The ether extracts can be washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give an oil which can then be distilled to give pure title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][N:6]=1.Cl.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)C.NCCCC1C(C)=CC(Br)=CN=1>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][N:16]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Reactant: Cc1cc(Br)cnc1CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 197.5 %

Procedure:
2-(3-Aminopropyl)-5-bromo-3-methylpyridine (5 g), 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (4.45 g) and triethylamine (10 ml) were refluxed together in ethanol (200 ml) for 5.5 hr. A further addition of 2-(3-aminopropyl)-5-bromo-3-methylpyridine (0.5 g) was made and refluxing was continued for a further 2.5 hr. The reaction mixture was then concentrated to dryness giving a yellow oil (13.59 g). The oil was chromatographed on silica in first methanol/chloroform 1:19 increasing the polarity to 1:9. The product was recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (5.11 g), m.p. 105°-106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.O[O:24][S:25]([O-:27])=O.[K+].OS([O-])(=O)=O.[K+].[CH3:35]O.O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:16]=[CH:17][C:18]([S:25]([CH3:35])(=[O:27])=[O:24])=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C2=C(c3ccc(F)cc3)CC(C)(C)C2)cc1
Reactant: CO
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Reaction time: 4 h
Yield: 38 %

Procedure:
A solution of 120 mg (0.39 mmol) of 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylthio)benzene (Step 9 ) in 3 mL of methanol/water (1:1) was slowly treated with 470 mg (0.76 mmol) of Oxone® [2 KHSO5.KHSO4.K2SO4 ] in 2 mL of water. After stirring for 4 h, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (5:1) and subsequent lyophilization from acetonitrile/water (1:1) gave 50 mg (38%) of 1-[2-(4-fluorophenyl)-4,4-dimethyl cyclopenten-1-yl]-4-(methylsulfonyl)benzene (41 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R10 =SO2CH3, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid: NMR (CDCl3) d 1.24 (s, 6H) , 2.71 (s, 4H), 3.4 (s, 3H), 6.92 (t, J=8 Hz, 2H), 7.05-7.12 (m, 2H) , 7.30 (d, J=9 Hz, 2H) , 7.75 (d, J=9 Hz, 3H); MS (EI) m/e (rel intensity) 344 (100) , 329 (33) , 250 (18) , 235 (20) , 109 (35) , 69 (44); HRMS. Calc'd for C20H21FO2S: 344.1246. Found: 344.1272.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19].[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:25]\[NH:24][C:21](=[NH:22])[NH2:23])/[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19]
Reactant: O=C(Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Reactant: N=C(N)NN
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: N=C(N)N/N=C(/Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a screw cap pressure vessel was added the intermediate from Step A (800 mg, 2.20 mmol), aminoguanidine hydrochloride (280 mg, 2.53 mmol), methanol (20 mL) and boron trifluoride diethyl etherate (0.63 mL, 4.95 mmol). After stirring at 100° C. for 1 hour, boron trifluoride diethyl etherate (1 mL) and aminoguanidine hydrochloride (200 mg) were added and the reaction solution heated at 100° C. for 3 hours. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed with aqueous 1N NaOH (2×), brine and dried over anhydrous sodium sulfate. The solution was then filtered and concentrated to give the indicated product. m/z=419 (M+H).