Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].C(N)(=O)CC.Cl.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45]N>>[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:40]=1[NH:45][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:30])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Reactant: COc1ccccc1NN
Agent: CCC(N)=O
Agent: Cl
Product: COc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl)propanamide and 1-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 510.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[CH:24]=[N:23][N:22]([CH3:25])[C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[OH2:36].C(#N)C>C(#N)C>[C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[CH:24]=[N:23][N:22]([CH3:25])[C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:36])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Solvent: CC#N
Product: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)ethanol from previous reaction (assume 0.024 mmol) in 25% water/acetonitrile (0.70 mL) was added sequentially, a stock solution of CrO3/H5IO6 (296 μL, 0.439 M solution) and CrO3 (3 mg, 0.030 mmol) at room temperature. The reaction was stirred for 1 h, diluted with acetonitrile, filtered and purified by reverse phase HPLC. Fractions containing product were pooled and evaporated to the desired product. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.1 (M+H+); 521.2 (M+H+); 1H NMR (400 MHz, CD3OD): δ 9.26 (d, J=1.9 Hz, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.61-7.59 (m, 3H), 5.26 (s, 1H), 4.15 (s, 3H), 2.61 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([CH2:26][N+:27]([O-])=O)[CH2:21][C:22](OC)=[O:23])[CH:16]=[CH:17][C:18]=1[Cl:19]>O1CCCC1>[NH2:27][CH2:26][CH:20]([C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)[CH2:21][CH2:22][OH:23]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
To a 1M Et2O solution of LiAlH4 (200 mL, 200 mmol) at 0° C., slowly add the product of Step 2 (14.35 g, 49.1 mmol) dissolved in tetrahydrofuran (THF) (100 mL). Allow the reaction mixture to warm to room temperature and stir for 45 min. After recooling to 0° C., quench the excess LiAlH4 by the careful addition of aqueous saturated Na2SO4 (20 mL). Dry the solution with Na2SO4 and filter. Wash the lithium salts with Et2O (3×300 mL). Concentrate the combined filtrates to give 8.65 g of 4-amino-3-(3,4-dichlorophenyl)-butanol as a white solid (36.9 mmol, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[CH2:12](Br)[CH:13]=[CH2:14].CC(C)([O-])C.[K+]>CS(C)=O>[CH2:14]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:11])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1cccc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
Methyl-3-hydroxy-benzoate (1.09 g, 4.9 mmol), allyl bromide (0.73 g, 6.0 mmol) and potassium tert-butoxide (6.5 g, 5.8 mmol) in DMSO (15 mL) was stirred at room temperature for 16 hours. The mixture was poured into ice water, extracted with ether, washed with brine, dried (Na2SO4), and evaporated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.55 (m, 1H), 7.45 (m, 2H), 7.24 (m, 1H), 6.12-5.98 (m, 1H), 5.44-5.26 (m, 2H), 4.64 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:17][CH3:18])([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-:19].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)([CH2:17][CH3:18])[C:9]([NH2:10])=[O:19])=[CH:4][CH:3]=1
Reactant: CCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To a 500 mL flask was charged 100.0 g (0.38 mole) of alpha-(4-chlorophenyl)-alpha-ethyl-1H-1,2,4-triazole-1-propanenitrile and 100 mL of dimethyl sulfoxide. To the stirring solution was added 100 g (1.25 mole) of 50% sodium hydroxide. The reaction mixture was heated at 100° C. for 1 hour after which GLC indicated the starting material was consumed. The reaction was poured into water and extracted with ethyl acetate. After washing with brine, the organic phase was dried over magnesium sulfate and concentrated under vacuum without heating. Removal of the solvent gave a foamy glassy solid which was triturated with hexane, filtered and gave 97 g (91% yield) of a white solid, melting point 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[C:4](=[N+:14]=[N-:15])[C:5](=[O:13])[NH:6]2.[CH2:16]([OH:19])[C:17]#[CH:18]>C(OCC)C.C(O)C>[Cl:1][C:2]1[C:3]2[C:4]3[N:14]([N:15]=[C:17]([CH2:16][OH:19])[CH:18]=3)[C:5](=[O:13])[NH:6][C:7]=2[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(Cl)c2c1NC(=O)C2=[N+]=[N-]
Reactant: C#CCO
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(Cl)c2c1[nH]c(=O)n1nc(CO)cc21
Yield: 63.9 %

Procedure:
2.0 g (0.0089 mole) of the 4-chloro-7-methoxy-3-diazooxindole (prepared in part B) and 10.3 g of 97% propargyl alcohol are refluxed under argon for 4 hours and cooled. The reaction mixture is diluted with 200 ml of ethyl ether and stirred for ~20 minutes and cream-colored precipitates are filtered off. Yield: 2.53 g, m.p. 221°-222°; quantitative crude yield (theor.: 2.49 g). This crude product is taken up in 200 ml absolute ethanol, the clear solution filtered while hot and the filtrate concentrated down to a volume of 50 ml and cooled. The resulting precipitates are filtered off and dried in vacuo at 45° over the weekend to give 1.59 g of title compound, m.p. 230°-232°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[C:7]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:8])([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[C:7]([O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:15]1)=[O:8]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Reaction time: 4 h
Yield: 81.5 %

Procedure:
0.5 g (0.00147 mol) of 1-benzyl-piperidin-4-yl 3-nitro-benzoate was dissolved in 20 ml of ethanol and treated with 0.3 g of Raney-nickel under argon. The mixture was hydrogenated at room temperature under normal pressure for 4 hrs. The catalyst was filtered off, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane 1:1 as the eluent. 0.372 g (82%) of 1-benzyl-piperidin-4-yl 3-amino-benzoate was obtained as white crystals; m.p. 70°-71°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]([OH:15])[C:3]=12
Reactant: Cc1ccnc2c1C(=O)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccnc2c1C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 14 h
Yield: 62 %

Procedure:
A solution of 15 g (0.0769 mol) of 4-methyl-5H-indeno[3,2-b]pyridin-5-one in 150 ml of methanol was treated in portions with 3.8 g (0.1 mol) of NaBH4 at from 0° to -5° C. After stirring at room temperature for 14 hours, the mixture was concentrated under reduced pressure. The residue was treated with 350 ml of methylene chloride and with 150 ml of a 15% strength aqueous potassium hydroxide solution and additionally stirred for 1 hour. The organic phase was separated off, washed with water, dried over Na2SO4 and concentrated to a volume of 50 ml under reduced pressure. The crystal magma was filtered off with suction at 0° C. and washed with a little diethyl ether and pentane. 9.4 g (62% of theory) of 4-methyl-5H-indeno[3,2-b]pyridin-5-ol were obtained as yellowish crystals of m.p. 154°-156° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=2)[C:11]([C:26]#[N:27])=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]=1[C:34]#[N:35]>CN(C=O)C>[C:26]([C:11]1[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=2)=[N:13][C:8]([O:3][CH2:2][CH2:1][OH:4])=[C:9]([C:34]#[N:35])[C:10]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: OCCO
Reactant: CNC(=O)c1cc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(CSc2nc(OCCO)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
22 mg (0.357 mmol) of 1,2-ethanediol are initially charged in 0.5 ml of DMF, and 4.8 mg (0.179 mmol) of sodium hydride are added. After 15 min at RT, 50 mg (0.119 mmol) of the compound from Example 25A are added and the reaction mixture is stirred at 115° C. overnight. After cooling, the reaction solution is purified by prep. HPLC.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>C(#N)C.CCOC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:8]=1)=[O:24])[CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cccc(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-morpholinylphenol (0.34 g; 1.9 mmol) and powdered K2CO3 (0.576 g; 4.2 mmol) in dry acetonitrile (10 mL) was added diethyl carbamylchloride (0.26 mL; 2.0 mmol) via syringe at room temperature under nitrogen atmosphere. The resulting mixture was heated to reflux for 24 hours, then allowed to cool to room temperature. The reaction was diluted with EtOAc (60 mL), washed with water (2×20 mL) and brine, then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via radial chromatography (4 mm chromatotron plate with 2:1 hexanes/EtOAc) to provide the carbamate as a clear, colorless oil (0.39 g; 74%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(#N)C.C(N(CC)CC)C.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:27](=[O:28])[CH2:26][O:25][CH3:24])=[C:7]([CH3:12])[CH:6]=1
Reactant: COCC(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: CC#N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(NC(=O)COC)c(C)c1

Procedure:
3-methyl-4-aminophenyl N-methylcarbamate (3.6g. 0.02 mole) was dissolved in 35 ml. of benzene and 25 ml. of acetonitrile along with triethylamine (2.23g., 0.022 mole). To this stirred solution was added dropwise a solution of methoxyacetyl chloride in benzene. An exotherm to 45° C. was noted as solids began to form. Further heating at reflux for one hour yielded 2.4g. of Et3N.HCl upon filtration. Solvent removal from the filtrate under reduced pressure gave a product which was recrystallized from ethanol-water. The tan solid (2.4g.) melted at 129.5°-132° C. and the infrared spectrum (KBr) displayed the characteristic double carbonyl (5.7 μ and 5.95 μ).
Reaction SMILES: [C:1]1([N:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:21]>CC(C)=O>[Br-:21].[C:8]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N+:14]([CH2:11][C:20]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)N(c1ccccc1)c1ccnc2ccccc12
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(=O)N(c1ccccc1)c1cc[n+](Cc2ccccc2)c2ccccc12
Yield: 121.1 %

Procedure:
A solution of N-phenyl-N-quinolin-4-yl-acetamide (2 g) and benzyle bromide (1.3 g) in acetone was warmed to reflux for 5 days. The solvent was removed to afford an amorphous material, which was crystallized in diethyl ether. 4-[Acetyl-(phenyl)-amino]-1-benzylquinolinium bromide (2 g) was obtained by filtration.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[C:12](Cl)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].CC(C1C=CC=CC=1)=C>CC(CC(C)C)=O>[CH3:13][C:12]([NH:10][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)=[O:9])([CH3:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(NC(N)=O)cc1
Reactant: CC(C)(Cl)c1ccccc1
Agent: C=C(C)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
11.25 parts of p-tolylurea, 7.72 parts of cumyl chloride and 23.64 g of α-methylstyrene were added to 80 parts of methylisobutyl ketone, and the reaction was performed at 60° C. for 5 hours. After the reaction, the solvent was evaporated off at reduced pressure. The residue was washed with n-hexane, and recrystallized from a mixture of water and methanol to afford 5.4 parts of N-(α,α-dimethylbenzyl)-N'-(p-tolyl)urea.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH3:31])[CH3:30])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[C:9]=1[CH3:24])#[N:2].[Cl:32]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:32][C:11]1[C:10]2[C:9]([CH3:24])=[C:8]([O:7][CH2:6][C:5]3[CH:25]=[CH:26][C:27]([O:28][CH:29]([CH3:31])[CH3:30])=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:16]=[CH:15][C:14]=2[N:13]2[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=12
Reactant: Cc1c(OCc2ccc(OC(C)C)c(C#N)c2)ccc2c1cc1n2CCC1CC(=O)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1c(OCc2ccc(OC(C)C)c(C#N)c2)ccc2c1c(Cl)c1n2CCC1CC(=O)O
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
To a solution of 2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acid (30 mg, 0.072 mmol) in DCM (2 mL) was added N-chlorosuccinimide (10.1 mg, 0.075 mmol) at 0° C. The reaction was stirred at that temperature for 40 min, diluted with DCM, washed with aqueous Na2S2O3 solution and water, and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was passed through a silica gel column with 5% MeOH/DCM to give the title compound as beige solid (23 mg). LCMS m/z=453.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.0 Hz, 6H), 2.29-2.38 (m, 1H), 2.58 (dd, J=16.7, 10.5 Hz, 1H), 2.66 (s, 3H), 2.88-2.98 (m, 1H), 3.33 (dd, J=16.7, 3.7 Hz, 1H), 3.76-3.84 (m, 1H), 3.90-3.98 (m, 1H), 4.05-4.13 (m, 1H), 4.62-4.68 (m, 1H), 4.94 (s, 2H), 6.84 (d, J=8.8 Hz, 1H), 6.95-6.98 (m, 2H), 7.56-7.62 (m, 2H).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[CH3:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1I)[C:23]([O:25][CH3:26])=[O:24]>>[CH3:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[C:2]#[C:1][CH:3]([OH:4])[C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)c(C)c1
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(C)c1

Procedure:
Following the basic procedure of Example 11(d), by reacting 2.4 g (10 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 2.7 g (10 mmol) of methyl 3-methyl-4-iodobenzoate, 3.2 g (83%) of the expected ester, with a melting point of 130°-131° C., were obtained.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[CH:2][CH3:3].C1(S([O-])=O)C=CC=CC=1.[Na+].Cl.C1(C)C=CC=CC=1>C1COCC1>[CH:1](/[CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)=[CH:2]\[CH3:3]
Reactant: CC=CC1CCC(c2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Agent: Cl
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C=C/C1CCC(c2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Reaction time: 4 h

Procedure:
26.0 g of 1-propenyl-4-(4-p-tolylethynylphenyl)cyclohexane from Example 9, 10.34 g of sodium benzenesulphinate, 100 ml of 2 N hydrochloric acid solution, 175 ml of toluene and 87 ml of THF were combined and heated to reflux. After 4 hours, the reaction mixture was allowed to cool, and the aqueous phase was removed. A further 10.34 g of sodium benzenesulphinate and 100 ml of 2 N hydrochloric acid solution were then added, and the mixture was refluxed for a further 2 hours, the aqueous phase was again removed after cooling, and a further 10.34 g of sodium benzenesulphinate and 100 ml of 2 N hydrochloric acid solution were added, the mixture was refluxed overnight, and subsequently subjected to conventional work-up, giving 1-E-propenyl-4-(4-p-tolylethynylphenyl)cyclohexane in the form of a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][NH:32][CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C(OCC)C.C(Cl)Cl>[CH2:33]([N:32]([CH3:31])[C:15](=[O:17])[C:14]#[C:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(C#CC(=O)O)cc(OC)c1OC
Reactant: CNCC=Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C#CC(=O)N(C)CC=Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To the solution of 11.8 g of 3,4,5-trimethoxyphenylpropiolic acid in 50 ml of tetrahydrofuran, 7.1 g of triethylamine are added while stirring, followed by 50 ml of diethyl ether. The mixture is cooled with ice and to the resulting suspension the solution of 5.4 g of ethyl chloroformate in 25 ml of diethyl ether is added during 5 minutes. The mixture is stirred for 15 minutes at 0°-5°, whereupon the solution of 7.35 g of N-methylcinnamylamine in 35 ml of diethyl ether is added dropwise, followed by 80 ml of methylene chloride. The mixture is stirred for 30 minutes and allowed to warm to room temperature. It is washed with N hydrochloric acid, N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated under reduced pressure, to yield the N cinnamyl-N-methyl- 3,4,5-trimethoxyphenylpropiolamide.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:15][C@@H:16]1[CH2:24][C@@H:19]2[O:20][C:21](=[O:23])[CH2:22][C@@H:18]2[C@H:17]1[CH2:25][OH:26])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.C1(C)C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[C:7]([O:15][C@@H:16]1[CH2:24][C@@H:19]2[O:20][C:21](=[O:23])[CH2:22][C@@H:18]2[C@H:17]1[CH:25]=[O:26])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of anhydrous chromium trioxide (20.8 g, 208 mmol) in methylene chloride (400 mL) was stirred and cooled in an ice bath as anhydrous pyridine (32.7 mL, 406 mmol) was added. After 15 min at 0° C., the mixture was allowed to warm to ambient temperature for 2 h. The reaction mixture was cooled to 0° C. and treated with a pre-cooled solution of (3aR,4S,5R,6aS)-5-(benzoyloxy)hexahydro-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one (Corey lactone, 9.4 g, 34 mmol) in methylene chloride (400 mL) After 5 min, the reaction was diluted with toluene (240 mL) and filtered. The solid was washed with toluene. The combined filtrate was concentrated to give (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-2-oxo-2H-cyclopenta[b]furan-4-carboxaldehyde. Toluene was added to give about 300 mL of solution.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])([O-])=[O:7].[K+].[CH2:11]([O:13][C:14](=[O:30])[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH3:28])[C:18](=[O:29])[CH2:17]1)[CH3:12]>ClCCl>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([N+:6]([O-:9])=[O:7])[CH:26]=[CH:27][C:20]=2[N:19]([CH3:28])[C:18](=[O:29])[CH2:17]1)[CH3:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
To conc H2SO4 (14 ml), kept in an ice bath, KNO3 (2 g, 20 mmol) was added in portions whereby the temperature rose to 10° C. (see also R. I. Fryer et al., J. Heterocyclic Chem. 1991, 28, 1203-1208). To this mixture was added a solution of (1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (5 g, 18 mmol) in dichloromethane (16 ml) whereby the temperature was kept between 20-25° C. After stirring for 90 min the mixture was carefully poured onto ice water and extracted with dichloromethane. The organic extracts were washed with aqueous sat. NaHCO3 followed by water, dried over Na2SO4 and the solvents evaporated. Upon addition of EtOH to the oily residue a precipitate was formed which was collected by filtration to give (1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (4 g): mp. 129-130° C.; MS (EI): 321 (M)+.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:16]>O>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([Cl:16])[N:7]=1
Reactant: Cl
Reactant: Cc1cc(N)nc(Br)c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)nc(Br)c1
Temperature: -50 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of 56 g 6-amino-2-bromo-4-methylpyridine in 500 ml of concentrated hydrochloric acid was cooled to -50° C. and saturated with gaseous HCl via a gas inlet. Under continuous cooling a solution of 25 g sodium nitrite in 60 ml water was added slowly. The reaction mixture was stirred for a further 2 hours at -50° C. The mixture was allowed to warm up to ambient temperature and set alkaline with a 50% aqueous solution of sodium hydroxide. The aqueous phase was extracted three times each with 200 ml dichloromethane. The combined extracts were dried with calcium chloride, and the solvent removed in vacuo to afford 22.5 g (40%) of 2-bromo-6-chloro-4-methylpyridine as a pale brown solid of melting point 76° C.