Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.NC(N)=S.C[S:15]([C:18]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][N:19]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:23][C:21]1([CH3:24])[O:20][N:19]=[C:18]([S:15][CH2:2][C:3]2[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)[CH2:22]1
Reactant: COc1cc(CBr)on1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(CSC2=NOC(C)(C)C2)on1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
5-Bromomethyl-3-methoxy-isoxazole (1.22 g, 6.35 mmol) was dissolved in ethanol (30 ml) and thiourea (484 mg, 6.4 mmol) was added. The mixture was stirred at room temperature until the solids were dissolved. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (1.08 g, 6.4 mmol) and potassium carbonate (880 mg, 6.4 mmol) were added and the mixture was heated under reflux for 1 hour. The solids were removed by filtration and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as colourless oil (0.69 g, 45% yield over 3 steps).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17]C(=O)OC(C)(C)C)[CH2:11]3)=[CH:6][C:5](=[O:25])[NH:4]1)[CH3:2].F[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH2:17])[CH2:11]3)=[CH:6][C:5]([O:25][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:4]1)[CH3:2]
Reactant: CCn1[nH]c(=O)cc1-c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1ccc2c(c1)CC(N)C2
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 56.7 %

Procedure:
A mixture of tert-butyl [5-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-2-yl]carbamate (28 mg, 0.082 mmol) in DMSO (1 mL) was treated with fluoro-4-(trifluoromethyl)benzene (100 mg, 0.609 mmol) and K2CO3 (20 mg, 0.15 mmol). The suspension was stirred for 40 min at 140° C. until no SM remained. Significant Boc thermolysis was observed under these conditions. The reaction was cooled, diluted with DCM, extracted with 1 N NaOH, water, dried (Na2SO4), concentrated. The residue was dissolved in 0.9 mL of DCM and 0.1 mL of TFA, then stirred for 1 hour, diluted with DCM, extracted with 1 N NaOH, water, dried (Na2SO4), and finally concentrated to give 5-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}-2,3-dihydro-1H-inden-2-amine (18 mg, 57%): MS cal'd for C21H21F3N3O [M+H]+388.2. found 388.1.
Reaction SMILES: [C:1]([C:4](=[O:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:6])([OH:3])=[O:2]>[Pd].CO>[C:1]([C:4](=[O:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:6])([OH:3])=[O:2]
Reactant: O=C(O)C(=O)C(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(NC(=O)C(=O)C(=O)O)c1

Procedure:
A solution of 1.2 g. (0.005 mol) of N-(2-carboxy-2-oxoacetyl)-3-nitroaniline in 60 ml. of methanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. When the theoretical amount of hydrogen had been absorbed the reduction was stopped, 40 ml. of 5% aqueous sodium bicarbonate solution was added and the catalyst filtered. The filtrate was evaporated to approximately 50 ml., acidified with 3N hydrochloric acid to pH 2 and the resulting precipitate filtered, washed with water and dried to give N-(2-carboxy-2-oxoacetyl)-1,3-phenylene diamine, m.p. 246° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:31]C)=[O:30])=[CH:19][CH:18]=3)[C:9]3=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:31])=[O:30])=[CH:19][CH:18]=3)[C:9]3=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 81.4 %

Procedure:
Ethanol (40 ml) and a 10% aqueous solution (20 ml) of sodium hydroxide were added to 1.32 g (3.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine, followed by heating under reflux for 2 hours. After the reaction liquid was cooled, it was concentrated to about one-half the initial volume, and neutralized with 2N hydrochloric acid and acetic acid. The crystal thus precipitated was recovered by filtration and recrystallized from aqueous ethanol to give 1.03 g of the title compound (yield 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C/C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of fumaric acid (0.58 g) in absolute ethanol (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 166.9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCC1Cc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(C[C@@H]2CCCC[C@H]2O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
To a stirring solution of 2-(4'-nitrobenzene)methylcyclohexan-1-one (44) in 5 mL of methanol at 0° C. was added portionwise sodium borohydride, and the reaction mixture was allowed to stir at 0° C. for 1.5 h before quenching with saturated aqueous NH4C1. The methanol was removed under diminished pressure, and the resultant aqueous residue was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated under diminshed pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 4:1) gave 10 mg (20%) of the desired alcohol 45, along with 18 mg (36%) of the diastereoisomeric alcohol 46 as colorless oils. Data for alcohol 45:1H NMR (400MHz, CDCl3) δ0.92 (m, 1H), 1.11 (m, 1H), 1.28 (m, 3H), 1.60 (m, 2H), 1.76 (m, 1H), 2.02 (m, 1H, 2-H), 2.51 and 3.59 (d of ABq, 2H, benzylic-CH2), 3.27 (m, 1H, 1-H), 7.34 (d, 2H, Ar--H), 8.15 ppm (d, 2H, Ar--H). [Compound 45 is hereinafter also referred to as COMPOUND "I" or 120154] ##STR10##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([CH3:18])[CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:9]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][C:11]=3[CH3:18])[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:29]=[CH:30][CH:31]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3c(C)ccnc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3c(C)ccnc3c2=O)cc1C

Procedure:
Experimental conditions analogous to described for Step 3 of Example 1 were used with 93 mg (0.318 mmol) of 3-(3,4-Dimethyl-benzoyl)-8-methyl-1H-[1,5]naphthyridin-4-one, 15 mg (0.382 mmol, 60% dispersion in oil) of sodium hydride, 95.8 mg (0.382 mmol) of 2-bromo-6-bromomethyl-pyridine and 3.0 mL of N,N-dimethylformamide. The crude brown solid was purified by flash column chromatography using 30-100% ethyl acetate in hexane to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-8-methyl-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]: 462.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 3.0 min.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=2)=[O:21])=[N:4][N:3]=[N:2]1.[OH-].[Na+]>C(O)C>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:21])=[N:1][N:2]=[N:3]1
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Yield: 86.9 %

Procedure:
In 10 ml of ethanol was suspended 0.38 g of methyl 4-[2-[2-(1H-tetrazol-5-yl)phenylthio]phenylcarbamoyl]-p-henoxyacetate followed by addition of 1 ml of 10% sodium hydroxide, and the mixture was heated on a water bath for 10 minutes. After cooling, the reaction mixture was acidified with concentrated hydrochloic acid and diluted with water. The precipitate was collected by filtration and washed with water, ethanol and ethyl acetate in the order mentioned to give 0.32 g of the title compound as white crystals, m.p. 252°-253° C.
Reaction SMILES: O[C:2]1[N:3]=[C:4](O)[C:5]2[C:6](=[CH:8][S:9][C:10]=2[CH3:11])[N:7]=1.C([C:18]1[C:22]([NH:23]C(N)=O)=[CH:21]SC=1C)(OCC)=O.Cl>C(O)C>[CH:22]([NH:23][C:4]1[C:5]2[C:6](=[CH:8][S:9][C:10]=2[CH3:11])[N:7]=[C:2]([NH:3][CH2:4][CH2:5][CH3:10])[N:3]=1)([CH3:21])[CH3:18]
Reactant: CCOC(=O)c1c(NC(N)=O)csc1C
Reactant: Cc1scc2nc(O)nc(O)c12
Agent: Cl
Solvent: CCO
Product: CCCNc1nc(NC(C)C)c2c(C)scc2n1

Procedure:
The 2,4-dihydroxy-5-methyl-thieno[3,4-d]pyrimidine used above is also a new compound prepared from 3-carbethoxy-2-methyl-4-ureido-thiophene by heating under reflux with concentrated hydrochloric acid in absolute ethyl alcohol. Yield reaches 70%. M.P. 300°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:21]3[C:20](=[O:22])[NH:19][CH:18](O)[C:17](C)([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[C:27]([O-])(O)=O.[Na+]>OS(O)(=O)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:27])=[C:17]([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: CC1(C)c2ccc3nc(Nc4c(Cl)cccc4Cl)[nH]c3c2C(=O)NC1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)[nH]c32)c1C
Yield: 84 %

Procedure:
2-(2,6-Dichlorophenylamino)-6,6-dimethyl-7-hydroxy-7,8-dihydro-1H,6H-imidazo[4,5-h]isoquinoline-9-one (from Example 2) (45 mg, 0.11 mmol) was suspended in conc. H2SO4 (10 mL) and the resultant mixture was stirred at ambient temperature for 15 min. The solution was poured over ice, neutralized with NaHCO3 and filtered. The filtrate was triturated with water (10 mL) and centrifuged. The liquid was decanted, and the residual solid was triturated with methanol and centrifuged. The supernatant was decanted and the residue dried to give the title compound (35 mg, 84%). Mp>300° C.; MS (ES) 373 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:32])=[O:31]
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (106 mg, 0.222 mmol) was reacted with 3-chloropropane sulfonyl chloride (34 uL, 0.275 mmol) in the presence of triethyl amine (124 uL, 0.888 mmol) in DMF (4 mL) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=[C:25]3[S:21][C:22](=[O:27])[NH:23][C:24]3=[O:26])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(c1)N(Cc1ccccc1)C(=O)CO2
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)N(Cc2ccccc2)C(=O)CO3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (intermediate 66) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 12 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 1.3 l of a 7 N solution of ammonia in methanol is stirred in an autoclave at 125° C. for 4 hours. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography [silica gel, eluent: toluol/dioxane, elution gradient of 7/3 (v/v) to 1/1 (v/v)] to yield the title product.
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:18](O)[CH2:19]CCCC=C>>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:18]=[CH2:19]
Reactant: C=CCCCCCO
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Product: C=CCCCCCOC(=O)N[C@@H](CCCC)C(=O)O

Procedure:
N-[(Hept-6-en-1-yloxy)carbonyl]-L-norleucine was prepared according to the procedure for N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine by using 6-heptenol instead of 4-pentenol. LRMS (ESI) m/z 272 [(M+H)+; calcd for C14H26NO4: 272].
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH—H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [CH:1]1([C:5]([N:7]2[CH2:31][CH2:30][C@:14]34[C:15]5[C:16]6[O:29][CH:13]3[C:12]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:11][CH2:10][C@@:9]4([F:36])[C@H:8]2[CH2:21][C:20]=5[CH:19]=[CH:18][C:17]=6[O:22]C(C2CCC2)=O)=O)[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.C(=O)(O)[O-].[K+]>O1CCCC1.O>[CH:1]1([CH2:5][N:7]2[CH2:31][CH2:30][C@:14]34[C:15]5[C:16]6[O:29][CH:13]3[C:12]3([O:32][CH2:33][CH2:34][O:35]3)[CH2:11][CH2:10][C@@:9]4([F:36])[C@H:8]2[CH2:21][C:20]=5[CH:19]=[CH:18][C:17]=6[OH:22])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Oc1ccc2c3c1OC1C4(CC[C@@]5(F)[C@@H](C2)N(C(=O)C2CCC2)CC[C@]315)OCCO4)C1CCC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2c3c1OC1C4(CC[C@@]5(F)[C@@H](C2)N(CC2CCC2)CC[C@]315)OCCO4

Procedure:
The above obtained amide ester (step b) was heated with lithium aluminum hydride (1 g) in tetrahydrofuran (50 ml) at reflux for 31/2 hours. After cooling the reaction mixture, the excess reducing agent was decomposed by adding ethyl acetate, then water, and then dilute potassium bicarbonate solution until the pH was ca. 8.5. The inorganic salts were filtered off, and the filter cake washed with hot tetrahydrofuran. The filtrate was evaporated to dryness and the residue washed thoroughly with water and air dried. Recrystallization from methanol yielded 700 mg of the title compound whch melted at 173°-174°.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:9])=[N:8][C:4]=2[C:3]=1[CH3:19].C1C=C(O[C:27](OC2N=CC=CC=2)=[S:28])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]([O:12][C:10]([N:6]1[C:5]2[CH:17]=[CH:18][C:2]([N:1]=[C:27]=[S:28])=[C:3]([CH3:19])[C:4]=2[N:8]=[C:7]1[CH3:9])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1c(N)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole (1.1 g, 4.2 mmol) in methylene chloride (60 mL) is added dropwise over 30 minutes to a solution of di-2-pyridyl thionocarbonate (1.9 g, 8.2 mmol) and 4-dimethylaminopyridine (0.1 g) in methylene chloride (150 mL). The mixture is stirred for 2 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-t-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[CH:9]=[C:10]([C:11]#[N:12])[C:3]=12.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:3]=12
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2nccc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2nccc(Cl)c12

Procedure:
4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile was treated with 2M NaOH solution (4 ml) in tetrahydrofuran (8 ml) at ambient temperature for 1 hour. The reaction mixture was cooled and was added water. The aqueous layer was extracted with EtOAc. And the organic layer was washed with brine, dried over MgSO4 and concentrated. Resultings were purified by silica gel column chromatography to give 4-chloro-1H-pyrrolo[2,3-b]-pyridine-3-carbonitrile as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]=[C:22]1[CH:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[CH:24][NH:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:26]3[CH:25]=[CH:24][NH:23][C:22](=[O:21])[CH:27]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc[nH]c(=O)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cc[nH]c(=O)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1,2-dihydro-2-oxo-4-pyridinecarboxylic acid, as starting materials, MS (LC/MS): 424.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][CH:12]=O)[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cl-].[CH3:20][O:21]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O1CCCC1.Cl>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][CH2:12][CH:20]=[O:21])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H](CC=O)CCN1C(=O)OCC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@H](CCC=O)CCN1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.4 g of trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde in 5 ml anhydrous tetrahydrofuran under nitrogen, cooled to -78°, is added dropwise a solution of 1.17 g of methoxymethyl-triphenylphosphonium chloride in 15 ml of anhydrous tetrahydrofuran to which is added 1.55 ml of potassium tert-butoxide/tetrahydrofuran (1.6M). Solution is stirred at room temperature for 4 hours. 2N Hydrochloric acid (11 ml) is added and the mixture is stirred for 45 minutes. The solution is concentrated and then extracted with methylene chloride. The extract is dried over sodium sulfate, filtered, concentrated, and the residue is purified by flash chromatography using ethyl acetate/hexane (1:5 to 3:7) to yield trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Product: O=C(C=Cc1ccccc1)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and cinnamoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.