Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.[OH-].[NH4+:10]>CO>[NH2:10][C@@H:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:8]
Reactant: C1CCC2OC2CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CCCCC[C@H]1O

Procedure:
In a sealed tube, cycloheptene oxide (5.44 g; 48.50 mmol)and ammonium hydroxide solution (10 ml) in 4 ml methanol is heated to 80° C. for 72 hrs. After removal of the heat, the mixture is concentrated in vacuo to obtain trans-2-aminocycloheptanol which is used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[C:20]2[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)SC)#[N:5]>CN(C=O)C>[NH2:5][C:4]1[N:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[C:20]3[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:2]([CH3:1])[N:3]=1
Reactant: CSC(=NCCCOc1cccc2c(N3CCCCC3)nccc12)NC#N
Reactant: CNN
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc2c(N3CCCCC3)nccc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Methyl hydrazine (5.7 ml) is added to a stirred suspension of 1-cyano-3-[3-(1-piperidino-5-isoquinolyloxy)propyl]-2-methylpseudothiourea (7.77 g) in 62 ml of DMF under nitrogen. The reaction mixture is stirred at 40° C. under nitrogen for 24 hours, cooled to RT, evaporated under vacuo and the residue dissolved in warm absolute ethanol. The resulting precipitate is collected, washed with absolute ethanol and dried in air. The filtrate is evaporated in vacuo and the residue crystallized from acetonitrile and dried overnight, yielding 5.3 g of the crude product as an off-white solid, M.P. 173°-175° C. The crude product is placed on a silica gel column and eluted with methylene chloride/methanol. The combined pure fractions are evaporated and recrystallized from acetonitrile, yielding the desired product, M.P. 181°-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.I[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH2:21][CH3:22])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-bromo-2-chloro-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)benzene (2.70 g) obtained in Reference Example 46 in dichloromethane (27 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise boron tribromide (0.83 ml). The mixture was warmed to room temperature, and stirred for 30 minutes. The mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and subsequently, the reaction mixture was made acidic with a saturated aqueous citric acid solution. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from chloroform-hexane to give 5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (2.01 g) as pale green crystals. ESI-Mass m/Z 351/353 (M−H). (2) The above 5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (500 mg) was dissolved in N,N-dimethylformamide (5 ml), and thereto were added iodoethane (0.23 ml) and potassium carbonate (390 mg). The mixture was stirred at room temperature for 2 days. Added thereto was water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the desired 5-bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene (492 mg) as pale pink oil. APCI-Mass m/Z 381/383 (M+H).
Reaction SMILES: Cl.[O-:2][OH:3].[C:4]1([CH:10]([CH3:12])[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C)(C)C>[C:10]([O:2][O:3][C:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1ccccc1
Reactant: [O-]O
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Yield: 36 %

Procedure:
The fourth method is the only method relevant to this invention. The other methods and their short-comings in the preparation of cumyl peroxide are thoroughly discussed in U.S. Pat. No. 4,133,835 (Bafford). This invention is essentially an improvement over Bafford's process as taught in U.S. Pat. No. 4,133,835. Prior art pertaining to the fourth method above is: Kato et. al. (Auslegeschrift No. 2,035,127) published a process for preparing t-cumyl type peroxides by reacting a tertiary hydroperoxide with an aralkyl halide, such as t-cumyl chloride, at 0°-80° C. in the presence of an acid binding agent such as a t-alcohol or an aliphatic olefin. The mole ratio of the aralkyl halide to the hydroperoxide could vary from 1:1 to 1:1.5. In this process the hydroperoxide reacts with the aralkyl halide to form the peroxide; the HCl generated is taken up by the acid binding agent. There is no regeneration of the t-cumyl chloride. Kato's process was run with an acid sensitive aralkyl hydroperoxide, cumene hydroperoxide, with t-cumyl chloride in the presence of t-butyl alcohol (see Example XX). Although the reaction ran quite fast, only a 36% yield of dicumyl peroxide was obtained. There was a considerable amount of phenol generated during the reaction indicating the t-butyl alcohol was not a good scavenger of the hydrogen chloride; consequently a large amount of the cumene hydroperoxide underwent acid catalyzed decomposition to form phenol and acetone.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)=[O:16])[CH2:4][O:3]1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2ccsc2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a reaction flask charged with 14.7 mg (0.013 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (2.5 mL) under nitrogen was added 125 mg (0.27 mmol) of the product from Example 6. The resulting yellow solution was stirred for 10 min before the addition of 41.0 mg (0.32 mmol) of 3-thiopheneboronic acid dissolved in ethanol (0.2 mL) and the subsequent addition of 0.27 mL (0.54 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for ˜20 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the residue was purified by column chromatography (hexane/ethyl acetate) to yield 55 mg (50%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Yield: 115.2 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 9.8 g (55.0 mmol) of N-bromosuccinimide and 0.41 (2.5 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 17.8 g (purity: 72.0%, yield: 82.7%) of 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=N[CH:12]=1)(=[O:4])=[O:3].[F:13][C:14]([F:24])([F:23])[C:15]1C=C(CO)C=NC=1>>[CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:15]([C:14]([F:24])([F:23])[F:13])[CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCc1cncnc1
Reactant: OCc1cncc(C(F)(F)F)c1
Product: CS(=O)(=O)OCc1cncc(C(F)(F)F)c1

Procedure:
(5-(Trifluoromethyl)pyridin-3-yl)methyl methanesulfonate was prepared in a similar manner as used to prepare pyrimidin-5-ylmethyl methanesulfonate using (5-(trifluoromethyl)pyridin-3-yl)methanol instead of pyrimidin-5-ylmethanol. LCMS-ESI+ (m/z): [M+H]+ calc'd for C8H8F3NO3S: 256.02; found: 256.06.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)(C)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: CN=C=S
Reactant: NCCOCc1ccccn1
Solvent: CC(C)O
Product: CNC(=S)NCCOCc1ccccn1

Procedure:
2-(2-Aminoethoxymethyl)pyridine is caused to react with methyl isothiocyanate (1.21 g.) in isopropyl alcohol (25 ml.) by the procedure of Example 1 to give N-methyl-N'-[2-(2-pyridylmethoxy)ethyl]-thiourea.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1ccc(C(=O)O)cn1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Intermediate example I-94 in 58% yield starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 3-methylbutan-1-amine; MS (APPI/APCI) m/z 237[M+H+].
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH3:14].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:12][O:13][CH3:14])=[CH:6][N:7]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromopyridin-3-ol (25 g, 144 mmol) in DMF (300 mL) at 0° C. under N2 is added portionwise NaH (5.7 g, 144 mmol) over 5 min. The reaction was stirred 1 h, then chloro(methoxy)methane (12 g, 144 mmol) was added and the reaction stirred an additional 1 h at 0° C. Saturated sodium bicarbonate (500 mL) was added slowly and the suspension stirred 30 min and warmed to rt. The solution was extracted with EtOAc (3×400 mL), the combined organic layers washed with H2O (500 mL), saturated NaCl (500 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[O:23][CH3:24].[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:36][C:34]2[CH:33]=[CH:32][C:29]3[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=3[N:35]=2)[C@H:3]([O:23][CH3:24])[CH2:4]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1NCc1ccc2c(n1)NC(=O)CO2
Yield: 57.2 %

Procedure:
Cis(±)1-[2-(4-amino-3-methoxypiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 167, 140 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg, 0.42 mmol) and sodium triacetoxy borohydride (250 mg, 1.20 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.50% ammonium hydroxide gave 120 mg (57%) of the free base of the product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1(P(O[NH2:36])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:36][N:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:20]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Product: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1

Procedure:
4-(4-Isopropylphenyl)phthalazin-1(2H)-one was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give the title compound. MS (APCI+) M/Z 279 (M+H)+.
Reaction SMILES: CC([O:4][CH2:5][C:6]1[C@H:10]2[C@H:11]([O:18][C@@H:19]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]3[OH:29])[O:12][CH:13]=[C:14]3[C:15]([O:17][C@H:8]([C@@H:9]23)[CH:7]=1)=[O:16])=O.[CH3:30][OH:31]>O>[CH3:30][O:31][C:15]([C:14]1[C@H:9]2[C@@H:8]([OH:17])[CH:7]=[C:6]([CH2:5][OH:4])[C@H:10]2[C@H:11]([O:18][C@@H:19]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]2[OH:29])[O:12][CH:13]=1)=[O:16]
Reactant: CO
Reactant: CC(=O)OCC1=C[C@@H]2OC(=O)C3=CO[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H]1[C@@H]32
Solvent: O
Product: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2C(CO)=C[C@H](O)[C@H]12

Procedure:
Asperuloside (1.0 g) was dissolved in distilled water (10 ml) and adjusted to pH=10 by adding a small amount of a saturated solution of BaO in methanol. This solution was allowed to stand for a few minutes to become cloudy white, which, after neutralization and concentration, was treated by silica gel column chromatography (Waco Gel C-300, 50 g, solvent: chloroform-methanol system). Silica gel column chromatography gave deacetyl asperulosidic acid methyl ester having Rf value=0.79 (chloroform-methanol-water=6:6:1, visualized with 50(%)-sulfuric acid) on TLC, as white needles (1.80 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C3CCCCO3)=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.O>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:30][CH:31]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)N(Cc1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide in methanol (20 mL) was added 1N HCl (5 mL). After stirring for 2 hr., water was added and the aqueous solution was washed with methylene chloride (3×). The combined organic solutions were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated. The residue was purified via radial chromatography using a solvent gradient (methylene chloride to 10% methanol/methylene chloride) to provide the title compound. 1H NMR (CD3OD) δ 7.44 (d, 2H, J=8.0 Hz), 6.96 (d, 2H, J=8.0 Hz), 6.85–6.74 (m, 4H), 6.73 (d, 2H, J=8.0 Hz), 6.58 (d, 2H, J=8.0 Hz), 4.55 (s, 2H), 4.02 (t, 2H, J=5.6 Hz), 2.89 (t, 2H, J=5.6 Hz), 2.67 (bs, 4H), 1.81 (bs, 4H).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)(C)C>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C#Cc2ccc(C3CCC(CO)CC3)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1ccc(C#Cc2ccc(C3CCC(C=O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36.6 g of [4-(4-p-tolylethynylphenyl)cyclohexyl]methanol were mixed with 300 ml of dichloromethane, and a mixture of 21 g of Celite and 28.5 g of pyridinium chlorochromate (PCC) were added under a nitrogen atmosphere. The reaction mixture was stirred overnight at RT. 100 ml of isopropanol were then added to the black suspension, and the mixture was stirred at RT for 1½ hours in order to destroy the excess PCC. This suspension was then filtered, and the filtrate was subjected to conventional work-up, giving 4-(4-p-tolylethynylphenyl)cyclohexanecarbaldehyde in the form of a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][CH2:15][CH2:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14]2
Reactant: Cc1cc2c(cc1Cl)CCN2
Reactant: O=C=Nc1cccnc1
Product: Cc1cc2c(cc1Cl)CCN2C(=O)Nc1cccnc1

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5-chloro-6-methylindoline (D45) to give (E23) (0.76 g, 73%) m.p. 217°-218° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:11]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: BrC1CCCC1
Reactant: CCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Product: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrite was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((1E)-2-ethoxycarbonylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:44]([NH:47][NH2:48])(=[O:46])[CH3:45]>O.CN(C)C=O>[C:44]([NH:47][NH:48][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])(=[O:46])[CH3:45]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 1H-1,2,3-benzotriazol-1-ol (0.36 g) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.51 g) at room temperature. The mixture was stirred for 10 min and acetohydrazide (0.33 g) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.65 g, yield 77%) as colorless crystals. melting point 254-256° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][O:8][CH3:9])=[CH:5][CH:6]=1.C([Li])CCC.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:8][CH2:7][C:4]1[S:3][C:2]([CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: COCc1ccc(Br)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 31.1 %

Procedure:
To a solution of 2-bromo-5-(methoxymethyl)thiophene (439 mg, 2.12 mmol) in 6 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.93 mL, 2.5 M in hexanes) dropwise. After stirring for 2 minutes at −78° C., dimethylformamide (0.82 mL, 10.6 mmol) was added in a single portion and the reaction mixture was allowed to warm to room temperature before being poured into 30 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (3×30 mL), washed with water (2×30 mL, brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-20% ethyl acetate in hexanes) to give 5-(methoxymethyl)thiophene-2-carbaldehyde (103 mg, 31%) as an oil. Used without further characterization.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10].[OH-].[NH4+]>C1COCC1.[Pd]>[N:4]1[CH:3]=[CH:2][C:7]([NH:8][C:9]([C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:28][CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccncc2)c2c1oc1ccc(NC(C)=O)cc12

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide (60 mg) (Example 4) and 25-28% aqueous ammonium hydroxide (3 ml) in THF (35 ml) was hydrogenated at 50 psi using 10% Pd/C (60 mg) for 24 h at room temperature. The reaction was filtered through celite and the filtrate was concentrated. The residue was dissolved in DCM, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography using 2-10% methanol in DCM as eluent to obtain