Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.CO.C([O:10][C:11]([CH:13]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[N:18]=[C:17]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:12])C.[OH-].[Li+]>C1(C)C=CC=CC=1.C(O)CCC.O>[C:36]1([CH2:35][CH:13]([C:11]([OH:12])=[O:10])[CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=3[N:18]=[C:17]2[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.1 %

Procedure:
To a mixture of tetrahydrofuran (84 ml), methanol (28 ml), and water (28 ml), were added 1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (3.05 g, 6.4 mmol) and lithium hydroxide (788 mg, 3 eq.). The resulting mixture was stirred overnight at room temperature and was then concentrated in vacuo to yield a white solid. This residue was taken into 250 ml of a 3:1 butanol:toluene solution. The organic fraction was washed once with 200 ml of water and then dried over magnesium sulfate. The solvents were removed in vacuo to yield 4.17 grams of tan solid, which was further purified by flash chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated under reduced pressure to yield 2.71 grams (94%) of the desired title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:14][CH2:15][CH3:16])[C:9]2=[O:13])=[CH:4][C:3]=1[O:17][CH3:18]>CC(O)C.[Pd]>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:14][CH2:15][CH3:16])[C:9]2=[O:13])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CCC=C1CCc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [Pd]
Solvent: CC(C)O
Product: CCCC1CCc2cc(OC)c(Cl)c(Cl)c2C1=O
Yield: 61.4 %

Procedure:
7,8-Dichloro-6-methoxy-2-propylidene-1-tetralone (1.1 g) in 50 ml of 2-propanol and 150 mg of 5% Pd/C catalyst, were placed in a Parr apparatus and hydrogenated at 30 psi for 20 minutes. The reaction mixture was warmed slightly, the catalyst filtered, rinsed with 2-propanol, evaporated to dryness and chromatographed on 40 g SiO2 (ethyl acetae-hexane, 1:3) to yield 680 mg of 7,8-dichloro-6-methoxy-2-propyl-1-tetralone which melted at 127°-9° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[N:7][NH2:8])[CH3:6].[O:15]1[CH2:20][CH2:19][O:18][C:17]([C:21](=[N:30][O:31][CH3:32])[C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=O)=[N:16]1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[N:7][N:8]=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[C:21]([C:17]1[O:18][CH2:19][CH2:20][O:15][N:16]=1)=[N:30][O:31][CH3:32])[CH3:6]
Reactant: CON=C(C(C)=NN)c1ccccc1
Reactant: CON=C(C1=NOCCO1)c1ccccc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CON=C(C(C)=NN=Cc1ccccc1C(=NOC)C1=NOCCO1)c1ccccc1
Yield: 41.1 %

Procedure:
1 g (0.0052 mol) of 2-hydrazono-1-phenylpropan-1-one O-methyl oxime is heated under reflux at the boiling point in 5 ml of ethanol with 1.3 g (0.0052 mol) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde and 5 g of anhydrous magnesium sulphate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with diethyl ether and the crystals formed are filtered off. The solid is chromatographed over silica gel with diethylether/petroleum ether/methylene chloride (2:1:1). 0.9 g (40.8% of theory) of crystalline 2-({2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzylidene}-hydrazono)-1-phenylpropan-1-one O-methyl oxime of melting point 136° C. is obtained.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:43])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:42])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:42])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:43])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Lithium hydroxide monohydrate (0.011 g, 0.26 mmol) was added to a stirred solution of {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-chloro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.038 g, 0.063 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-chloro-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s, 1 H) 8.71 (s, 2 H) 8.59 (s, 1 H) 8.35 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.40 Hz, 1 H) 7.91 (s, 1 H) 7.58 (d, J=7.82 Hz, 2 H) 7.48 (d, J=8.60 Hz, 1 H) 6.95 (s, 1 H) 3.84 (s, 2 H) 2.03 (s, 3 H). MS calcd. for C27H16ClF6O4S [(M−H)−] 585, obsd. 585.3.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1.COC1C=CC(C[NH:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=CC=1.CN1C=CN=C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:34][C:35]4[N:36]=[CH:37][S:38][CH:39]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COc1ccc(CNc2cscn2)cc1
Reactant: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Nc3cscn3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
A solution of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride (0.300 g, 0.745 mmol) and N-(4-methoxybenzyl)thiazol-4-amine (Intermediate PPPPP; 0.492 g, 2.234 mmol) in 6 mL MeCN was placed under argon and was treated with 1-methylimidazole (0.073 ml, 0.745 mmol). After stirring for 3 hours at room temperature, LC/MS showed mostly product, so the reaction mixture was concentrated. The crude residue was dissolved in TFA (2.295 ml, 29.8 mmol) and was heated to 100° C. for 2 hours. LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-N-(thiazol-4-yl)quinazoline-7-sulfonamide (0.141 g, 0.302 mmol, 40.6% yield). 1H NMR (MeCN-d3) δ: 9.43 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.79-7.86 (m, 1H), 7.37 (d, J=5.4 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 6.92-7.25 (m, 2H), 3.71 (s, 3H). (M+H)+=467.0.
Reaction SMILES: NC[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:32])=[N:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=4)[N:19]=3)=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]([CH:44]=O)[CH3:43]>C(OCC)(=O)C>[CH3:43][N:42]([CH2:44][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:32])=[N:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:30])[CH3:31])(=[O:27])=[O:28])=[CH:22][CH:21]=4)[N:19]=3)=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:41]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN)c4)o3)n2)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN(C)C)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
3-[5-[3-(aminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (12 mg, 0.02108 mmol) was added to a solution of MeI (8.976 mg, 3.937 μL, 0.06324 mmol) and potassium carbonate (8.740 mg, 0.06324 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (3 mL) and washed successively with water (1×5 mL) and brine (1×5 mL). The organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (3.0 mg, 24% yield); 1H NMR (400 MHz, MeOD) d 1.35-1.4 (m, 6H), 2.95 (s, 6H), 4.65 (s, 2H), 7.8-7.85 (m, 2H), 8.05-8.1 (m, 2H), 8.4-8.5 (m, 4H) and 9.95 (s, 1H) ppm; MS (ES+) 479.3
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[OH:36][C:32]1[CH:31]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CNc1cccc(O)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (30.7 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 61% (75 mg, 0.156 mmol) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]([OH:23])=O)=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:23])=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cnc(C3CCCCC3)n12
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c(=O)c2cnc(C4CCCCC4)n23)CC1
Reaction time: 8 h

Procedure:
1-Cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxyic acid as synthesized in above Example 58, 218 mg, N-methylpiperazine 85 μL, 1-hydroxybenzotriazole monohydrate 161 mg, 4-dimethylaminopyridine 17 mg, pyridine 4.8 mL and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 202 mg were mixed and stirred overnight under nitrogen atmosphere. After distilling the solvent off, ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added, and the organic layer was separated. The organic layer was washed with water and dried over magnesium sulfate. After distilling the solvent off, 67 mg of the title compound was obtained upon recrystallization from diethyl ether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([C:19]([OH:21])=O)[CH:16]=[N:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][C:23]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH3:41])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(OCC)(=O)C>O1CCCC1.CN(C)C=O.N1C=CC=CC=1.O>[C:45]([O:44][C:42]([N:39]([CH2:40][CH3:41])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([NH:22][C:19]([C:15]2[CH:16]=[N:17][CH:18]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:14]=2)=[O:21])[CH:32]=1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: O=C(O)c1cncc(-c2ccccc2)c1
Reactant: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.2 %

Procedure:
Under ice-cooling, oxalyl chloride (0.23 mL) was added to a solution mixture of 5-phenylpyridine-3-carboxylic acid (0.48 g) in tetrahydrofuran (4.8 mL) and N,N-dimethylformamide (0.010 mL), followed by stirring at room temperature for 40 minutes. The reaction mixture was added to a solution mixture of methyl 2-amino-4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)benzoate (0.80 g) in tetrahydrofuran (8.0 mL) and pyridine (0.44 mL) under ice-cooling, followed by stirring at room temperature for 1 hour and 10 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-70% hexane/ethyl acetate] to obtain 0.86 g of methyl 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCC(CN)NC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Palladium catalyst (10% on carbon, 10.0 mg) was added in one portion to a solution of tert-butyl N-[1-(azidomethyl)undecyl]-carbamate 63 (100 mg, 0.282 mmol) in abs. methanol (5 ml) under a hydrogen atmosphere. The solution was allowed to stir for 12 hours. The catalyst was subsequently filtered off, and the solvent evaporated to give 64 (78 mg, 84%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])C(=O)[NH:7]2)[CH3:2].C(C1C=CC(C(O)=[O:21])=C(N)C=1)C>>[CH2:1]([C:3]1[C:4]([C:5]([OH:13])=[O:21])=[C:8]([NH2:7])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Reactant: CCc1ccc(C(=O)O)c(N)c1
Product: CCc1cccc(N)c1C(=O)O

Procedure:
Oxidation of 9.6 gm of 4-ethyl isatin according to the method described in (iii), above, gave 7.3 gm of the title compound: mp. 99°-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].CC(C)([O-])C.[K+].Cl[C:18]1[C:23]([CH3:24])=[C:22]([Cl:25])[CH:21]=[C:20]([CH3:26])[N:19]=1.[Cl-].[NH4+]>[Cu]I.CO.N1C=CC=CC=1>[Cl:25][C:22]1[CH:21]=[C:20]([CH3:26])[N:19]=[C:18]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:23]=1[CH3:24]
Reactant: Cc1cc(Cl)c(C)c(Cl)n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
Pyridine (250 mL) was added to a 2 liter flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen inlet. The flask was cooled in an ice bath and 2,4,6-trimethylphenol (42.5 g, 0.312 mol) and potassium t-butoxide (35.1 g, 0.313 mol) were added. The flask was warmed to room temperature and 2,4-dichloro-3,6-dimethylpyridine (50.0 g, 0.284 mol) and copper (I) iodide (13.5 g, 0.071 mol) were added. The reaction mixture was heated under reflux for two hours and then cooled to 0° C. The reaction mixture was diluted with hexanes (500 mL) and mixed with saturated ammonium chloride (NH4Cl, 1000 mL). After warming to room temperature, the mixture was stirred overnight. The layers were separated and the organic layer was washed with 3×125 mL of 1N hydrochloric acid (HCl) and 1×250 mL of water. After drying over sodium sulfate (Na2SO4), the solids were removed by filtration and washed with hexanes. The filtrate was concentrated under vacuum to afford a brown oil. The residue was mixed with methanol (250 mL) and was stirred overnight. The resulting slurry was filtered under vacuum. The off-white solids were washed with methanol then dried to afford 31.6 g (40.4%) of the title compound of Preparation F. 1HNMR (CDCl3): δ 6.88 (s, 2H), 6.78 (s, 1H), 2.40 (s, 3H), 2.30 (s, 3H), 2.20 (s, 3H), 2.04 (s, 6H).
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][C:15]#[N:16])=[C:11]([Cl:19])[C:10]=1[Cl:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Al+3].[Cl-].[Cl-].[Cl-].C1COCC1>Cl>[C:1]([C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][C:15]2[NH:23][N:22]=[N:21][N:16]=2)=[C:11]([Cl:19])[C:10]=1[Cl:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCOc1ccc(C(=O)c2ccccc2)c(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(OCc2nnn[nH]2)c(Cl)c1Cl

Procedure:
A mixture of 30.60 g. (0.1 mole) of 4-benzoyl-2,3-dichlorophenoxyacetonitrile, 7.80 g. (0.12 mole) of NaN3 and 15.96 g. (0.12 mole) of AlCl3 in 100 ml. of THF was refluxed for 24 hours. The reaction mixture was cooled and poured in dilute HCl. The solid obtained was filtered and recrystallized from benzene. Yield 26.80 g. (75%); m.p. 184°-186°.
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:22][CH2:21][C:20](=O)[CH:19]=[CH:18]2)=[CH:13][CH:12]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC>O1CCCC1.CCCCCC.C(NC(C)C)(C)C.C(OCC)C.C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]2([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=3)[CH2:18][C:19]3[NH:2][N:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:20]=3[CH:21]=[CH:22]2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: COc1ccc(C2(c3ccc(OC)cc3)C=CC(=O)CC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1n[nH]c2c1C=CC(c1ccc(OC)cc1)(c1ccc(OC)cc1)C2
Temperature: -70 °C
Reaction time: 3 h

Procedure:
0.9 cm3 of ethyl diazoacetate is added, dropwise, to a solution, cooled to −78° C., of 2 g of 4,4-bis(4-methoxyphenyl)cyclohex-2-enone in 50 cm3 of tetrahydrofuran, followed by slow addition of 13 cm3 of a lithium diisopropylamide solution prepared beforehand from 6.5 cm3 of 1.6 M n-butyllithium in hexane and 1.46 cm3 of diisopropylamine in solution in 15 cm3 of tetrahydrofuran. After stirring the reaction mixture at a temperature in the region of −70° C. for 3 hours, 1.2 cm3 of glacial acetic acid are added and the temperature is allowed to rise to the region of 20° C. 250 cm3 of ethyl ether are then added and the resultant mixture is then washed with twice 200 cm3 of distilled water and then dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue is dissolved in 65 cm3 of toluene and then heated at a temperature in the region of 110° C. for 1.5 hours, followed by concentrating to dryness under reduced pressure. The residue obtained is purified by flash chromatography on a silica gel (35–70 μm), eluting with a cyclohexane/ethyl acetate (70/30) mixture to give 0.48 g of ethyl 6,6-bis(4-methoxyphenyl)-6,7-dihydro-1H-indazole-3-carboxylate in the form of a yellow foam, the characteristics of which are as follows:
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15]C(C)(C)C)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(=O)N2CCC2)o1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(C(=O)N2CCC2)o1

Procedure:
A solution of 5-(azetidin-1-ylcarbonyl)-N-(tert-butyl)furan-2-sulfonamide (the product of step ii) (3 g) in trifluoroacetic acid (90 mL) was stirred at room temperature. After 18 h the mixture was evaporated to dryness in vacuo. The resulting oil was triturated with Et2O and filtered to give the subtitle compound as a white solid. Yield: 1.75 g.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:14]([O:21][C:22](=[O:41])[C@H:23]([CH3:40])[CH2:24][C@H:25]([NH2:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([O:21][C:22](=[O:41])[C@H:23]([CH3:40])[CH2:24][C@H:25]([N:39]=[C:2]=[O:4])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:31][CH:32]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (6 mL) at 0° C. is added triphosgene (18 mg, 0.061 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (75 mg, 0.183 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4]CC.[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=[O:9])[CH3:8]>>[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[CH3:8]
Reactant: C=CCCCCCCCOC(C)=O
Reactant: C=CCCCC
Product: CCCC/C=C\CCCCCCCOC(C)=O

Procedure:
Reactions between 1-hexene and 8-nonenyl acetate were conducted using methods analogous to those described above using to form the pheromone derivative 17. When catalyzed by Ruthenium complex 1, the reaction proceeded in good yield (67%) with high Z-selectivity (91%) at a low catalyst loading (0.5 mol %).