Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C@@H:5]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)[C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[C:36]([NH:35][C@@H:5]([C:6]1[CH:7]=[CH:8][C:9]([N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)[C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=1)[CH2:4][C:3]([OH:44])=[O:2])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(N(C(C)=O)c2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N(C(C)=O)c2ccc([C@@H](CC(=O)O)NC(=O)c3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 80.3 %

Procedure:
A mixture of (R)-3-benzoylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid methyl ester [4.08 g, Reference Example 12(a)], and methanol (40 ml) was heated to 40° C. and then treated with 10% aqueous sodium hydroxide solution (34 ml). After stirring at 40° C. for 2.5 hours, the reaction mixture was cooled and then acidified to pH 1.0 by addition of hydrochloric acid (1M). The resultant white solid was collected, washed with water and then dried in vacuo. Recrystallisation from acetic acid gave the title compound as a white crystalline solid (3.2 g), m.p. 220-222° C. MS: MH+ 581. [Elemental analysis:—C, 68.0; H, 5.4; N, 9.5%. Calculated for C33H32N4O6:—C, 68.3; H, 5.6; N, 9.65%]. 99% ee by HPLC analysis on a CHIRALPAK AD F294 column eluting with heptane:isopropanol:ethanol:trifluoroacetic acid (200:25:25:1) at a rate of 0.7 ml/min.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@@:10]23[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][C@H:15]2[CH2:14][NH:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:1].[CH:21]1([CH2:24][N:13]2[CH2:12][CH2:11][C@@:10]3([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=4)[C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH2:19]3)[CH2:14]2)[CH2:23][CH2:22]1
Reactant: COc1cccc([C@]23CCNC[C@@H]2CCC(=O)C3)c1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cccc([C@]23CCN(CC4CC4)C[C@@H]2CCC(=O)C3)c1
Yield: 26 %

Procedure:
0.88 g (3.08 mmol) of (±)-trans-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.44 g (3,23 mmol) of cyclopropylmethyl bromide, 0.64 g of potassium carbonate and a catalytical amount of potassium iodide in 15.4 ml of DMF were stirred at 60° C. for 2 h. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (EtOAc/MeOH/conc. NH4OH 90:10:0.8). The solid product was dissolved in acetone and the solution brought to acidic pH with HCl/Et2O. The precipitate was filtered, yielding 0.28 g of the title compound. M.p.=78° C. dec.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[N+:13]([O-])=O.[Sn].Cl.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[NH2:13]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(F)c(F)c(N)c(F)c1F
Yield: 27.7 %

Procedure:
Then, 25 g of the 2,3,5,6-tetrafluoro-4-methoxynitrobenzene was added to a dispersion of 30.3 g of tin dispersed in 230 ml of 95% ethanol. Thereto was dropwise added 70 ml of concentrated hydrochloric acid with ice-cooling. The mixture was refluxed for 2 hours with heating. Then, the reaction mixture was poured into 1,000 ml of water. Thereto was added an aqueous sodium hydroxide solution until the water layer became alkaline. The organic layer was extracted with 500 ml of ether. The ether layer was washed with an aqueous sodium chloride solution and dried over MgSO4. The resulting solution was subjected to vacuum distillation to remove the ether. The residue was subjected to recrystallization from ligroin to obtain 6 g of 2,3,5,6-tetrafluoro-4-methoxyaniline (yield: 28%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].Cl.CCCCCC.CCCCCCC.[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(C1C=CC=CC=1)C>O1CCCC1>[C:9]([NH:13][S:14]([CH2:17][CH:33]([OH:32])[CH2:34][CH2:35][CH3:36])(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NS(C)(=O)=O
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: CCCC(O)CS(=O)(=O)NC(C)(C)C
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A 2.0 M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (400 ml) was cooled to −45 to −50° C. under nitrogen atmosphere. A solution (100 ml) of N-t-butylmethanesulfonamide (55.0 g) in tetrahydrofuran was added dropwise thereto for 20 minutes. After raising the temperature to 5° C. taking 1 hour, the solution was cooled again to −65° C. To the resulting solution was added dropwise a solution of n-butyl aldehyde (28.8 g) in tetrahydrofuran (100 ml) for 30 minutes. The solution was stirred for 18 hours while raising the temperature gradually to room temperature. The resulting reaction solution was poured into an excess amount of dilute hydrochloric acid under cooling with ice to make it acidic and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain a solid crude product. Hexane (300 ml) was added thereto with stirring. Crystals thus obtained were collected by filtration, washed with hexane, and dried under reduced pressure to obtain N-t-butyl-2-hydroxy-1-pentane-sulfonamide (46.2 g) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C(O)C>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:27][CH:28]=1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc([N+](=O)[O-])cc1)c1ccc(C(C)C)cc1)CCC2
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 89.2 %

Procedure:
N-(4-Isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.2 g) was dissolved in ethanol (8.1 mL), and stannic chloride (1.5 g) and conc. hydrochloric acid (2.7 mL) were added. The mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from a mixed solvent of chloroform and diisopropyl ether to give N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.0 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:25])=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:25][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:24]
Reactant: CS(=O)c1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CS(=O)c1ccccc1C1CCNCC1
Yield: 96 %

Procedure:
The product of Step 4 (0.5 g) was treated with trifluoroacetic acid (10 mL) and heated at reflux temperature for 45 minutes. The reaction mixture was cooled, diluted with toluene (40 mL) and evaporated. This procedure was repeated two more times. The residue was treated with CH2Cl2 (70 mL) and adjusted to alkaline pH via addition of NH4OH solution. The organic layer was separated, dried over MgSO4, filtered and evaporated to give 4-(2-methylsulfinylphenyl)piperidine (0.3 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of quinolin-6-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl[C:10]1[CH:16]=[C:15]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([Br:21])([F:20])[F:19])[CH:14]=[CH:13][C:11]=1[NH2:12]>C(#N)C>[Br:1][C:10]1[CH:16]=[C:15]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([Br:21])([F:20])[F:19])[CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1Br

Procedure:
22.11 g (0.12 mol) of N-bromosuccinimide were added at 60° C. to a mixture of 40.0 g (0.12 mol) of 4-(1-bromo-1,1,2,3,3,3-hexafluoro-2-propyl)aniline from Example 6 and 125 ml of acetonitrile, and the resulting mixture was heated to reflux for 3 hours. Subsequently, the solvent was for the most part distilled off, the residue was washed with 100 ml of 1N NaOH solution, the organic phase was dried over sodium sulphate and finally the remaining solvent was removed under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:38]1([NH2:45])[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[CH:39]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[NH2:44][C:40]1[CH:39]=[C:38]([NH:45][C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[CH3:13])[CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Nc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)isobutyric acid (203 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg) and 1-hydroxybenzotriazole monohydrate (149 mg) in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (510 μL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, a solution of 1,3-phenylenediamine (260 mg) in N,N-dimethylformamide (2 mL) was added at room temperature, and the mixture was stirred at 80° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (1-((3-aminophenyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate (B8, 195 mg) as white solid.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[O:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[CH:1](=[N:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: NCc1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C=NCc1cccc(Oc2ccccc2)c1
Reaction time: 0.33 h
Yield: 98 %

Procedure:
38 g (0.528 mol) of isobutyraldehyde is added dropwise within 30 minutes, with stirring, to a solution of 99.5 g (0.5 mol) of 3-phenoxybenzylamine in 100 ml of toluene. After completion of the dropwise addition, stirring is continued for 20 minutes at room temperature, and the water which has formed (about 8.5 g) is separated in a separating funnel. The toluene with the unreacted isobutyraldehyde and residual water is then removed by rotation in a water-jet vacuum, and the residue is distilled in an oil-pump vacuum to yield 124 g (0.49 mol) of N-isobutylidene-(3-phenoxybenzylamine) as a colourless, mobile liquid, corresponding to a yield of 97.8% of theory; b.p. 85° C./4 Pa; nD20 =1.5666.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]([C:16]#[N:17])[C:7]2=O)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:16]#[N:17]
Reactant: CCOc1cc2c(=O)c(C#N)c[nH]c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC

Procedure:
A mixture of 7.95 g (32.6 mmol) of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 50 mL of phosphorous oxychloride was refluxed for 3 h 40 min. The phosphorous oxychloride was removed in vacuo and the residue was slurried with ice water. Solid NaHCO3 was added (pH8) and the product was collected by filtration, washed well with water and dried in vacuo (40° C.). The yield was 7.75 g of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 262.8, 264.8.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH:6]1[CH2:8][CH2:7]1)[CH3:5].C(OC)(=O)C1C=CC=CC=1.CO.[OH-].[K+]>O>[Br:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]([CH:6]2[CH2:7][CH2:8]2)([CH3:5])[C:3]([OH:16])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(c1ccc(Br)cc1)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: COC(=O)c1ccccc1
Product: CC(C(=O)O)(c1ccc(Br)cc1)C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 115.6 %

Procedure:
A 250 mL reaction vessel equipped with a condenser is charged with a mixture (9.18 g) of 2-(4-Bromo-phenyl)-2-cyclopropyl-propionic acid methyl ester (47.2 wt %, 15.3 mmoles, 1 equiv.) and methyl benzoate (19.3 wt %, 13 mmoles). The vessel is then charged with methanol (42 mL, ACS grade), water (8 mL, DI) and finally potassium hydroxide (KOH) (13.0 g, 12.7 equiv). The solution is then heated to 60±5° C. and allowed to stir for about 1.5 to 2.5 h. The colorless solution is cooled to 25±5° C. Methanol is distilled off to a minimum volume. The resulting heterogeneous mixture is acidified (pH=1) with concentrated HCl (16 mL, 37%), then extracted with methyl tert-butyl ether twice (35 mL). To the combined organic layer is added half saturated brine (40 mL). 4 N sodium hydroxide (NaOH) aqueous is added (1.6-2.3 equiv., 6-8.8 mL). The mixture is stirred for 5 min. Then the layers are separated. The organic layer is washed with brine 20 mL once and 1 N HCl 20 mL once and separated. It is concentrated to an oil to give 2-(4-Bromo-phenyl)-2-cyclopropyl-propionic acid (4.76 g). NMR assay showed 70.48 wt %; 81.4% yield.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Yield: 51.1 %

Procedure:
A solution of 2-bromo-4-(3-methoxyphenyl)-1,3-thiazole (3.70 g, 13.7 mmol), tert-butyl piperazine-1-carboxylate (3.83 g, 20.5 mmol) and potassium carbonate (1.89 g, 13.7 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 7 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.63 g (51.2%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](OC)=[O:23])=[CH:18][CH:17]=1.O>CN(C)C=O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][N:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Sodium hydride (60%, oily, 1.58 g) was added to a solution of 2-quinolylmethanol (6.29 g) and methyl 6-chloro-3-pyridinecarboxylate (6.78 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.50 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (12.7 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(2-quinolylmethoxy)-5-pyridylmethanol (5.31 g, yield 50%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 124–125° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][NH:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10].[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[CH2:8][CH:7]([NH:6][CH3:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO
Reactant: CNC(CC(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (30 ml) was added at 0°-5° C. to a stirred solution of 3-methylamino-3-phenylpropionic acid (39 g) in anhydrous methanol and the mixture stirred at ambient temperature for 5 hours. The solution was evaporated under reduced pressure and the residue treated with 2N sodium carbonate (350 ml). The solution was extracted with dichloromethane (2×100 ml). The combined extracts were washed with water (250 ml) dried over magnesium sulphate and evaporated under reduced pressure to give methyl-3-methylamino-3-phenylpropionate (36.9 g) as a clear orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)[CH3:2].C(OC(=O)C)(=O)C>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:12](=[O:13])[O:14][C:9](=[O:11])[C:6]2=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Product: CCc1cnc2c(c1)C(=O)OC2=O

Procedure:
A mixture of the above carboxylic acid (3.0 g, 15.37 mmol) and acetic anhydride (15 ml) is heated until the acid is dissolved. The mixture is then concentrated under vacuum, and the residue is dissolved in ether, stirred, filtered, concentrated and dried to give 5-ethyl-2,3-pyridinedicarboxylic anhydride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:15][NH:14][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:11])(=[O:10])[NH2:12])=[CH:5][CH:4]=1
Reactant: NO
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C

Procedure:
1 mmol of 4-Cyano-benzenesulfonamide are dissolved in a mixture of ethanol/water (7:3) and 5 eq of hydroxylamine hydrochloride and 2.5 eq. Na2CO3 added. The suspension is heated to 80° C. for 2 h. After evaporation of the solvent mixture the resulting material is extracted from ethylacetate/water. The product was not further characterized.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:36][S:37]([O:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:51](=[NH:53])[NH2:52])[CH:47]=2)[CH:42]=1)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:36][S:37]([OH:40])(=[O:39])=[O:38].[NH:6]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([O:18][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:51](=[NH:52])[NH2:53])[CH:47]=3)[CH:42]=2)=[O:17])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)Nc1ccc(C=CC(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(C=CC(=O)Oc2ccc3cc(C(=N)N)ccc3c2)cc1
Yield: 42.6 %

Procedure:
To a solution of 3.0 g of 4-guanidinocinnamic acid methanesulfonate in 30 ml of anhydrous pyridine, was added 2.4 g of DCC. To the mixture, while being cooled in ice and stirred, was added 2.8 g of 6-amidino-2-naphthol methanesulfonate. After having been stirred for 24 hours, the reaction mixture was filtered to remove insolubles and the filtrate was mixed with ethyl ether to separate an only substance which was left standing at room temperature to crystallize. Upon recrystallization from a methanol-ethyl ether mixture, there was obtained 2.4 g of 6-amidino-2-naphthyl 4-guanidinocinnamate dimethanesulfonate.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O(C(OC)=O)[Na]>CO>[C:2]1([C:1](=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: COC(=O)O[Na]
Solvent: CO
Product: N#CC(=Cc1ccccc1)c1ccccc1

Procedure:
12 Grams of benzyl cyanide and 11 grams of benzaldehyde with 10 grams of NaOCOOCH3 are dissolved in 100 mls methanol and refluxed during two hours. The sodium carbonate is collected, hot, on a filter and the solvent is evaporated in a vacuo. There are obtained 22 grams of phenylcinnamonitrile, having Na2CO3 as an impurity. The pure product is obtained by washing with water.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][CH:4]([OH:8])[CH:5]=[CH:6][CH3:7].CC(=CCCC(=CC=O)C)C.C#CC.CC1C=CCC(C)(C)C=1C(O)C#CC.CC1C=CCC(C)(C)C=1C(=O)C#CC.CC(CCC=C(C)C)=CC(=O)C=CC>O=[Mn]=O>[CH3:1][C:2]1[CH:9]=[CH:10][CH2:11][C:12]([CH3:13])([CH3:14])[C:3]=1[C:4](=[O:8])/[CH:5]=[CH:6]\[CH3:7]
Reactant: CC=CC(O)C=C(C)CCC=C(C)C
Agent: O=[Mn]=O
Agent: C#CC
Agent: CC#CC(=O)C1=C(C)C=CCC1(C)C
Product: C/C=C\C(=O)C1=C(C)C=CCC1(C)C

Procedure:
Safranal, prepared according to Compt. rend. 262, 1725 (1966), was reacted with propyne to give 2,6,6-trimethyl-1-[1-hydroxy-2-butynyl]-1,3-cyclohexadiene, following the procedure outlined in Example 18, paragraph (b), for the reaction of citral with propyne. The above carbinol was oxidised with MnO2 to 2,6,6-trimethyl-1-tetrolyl-1,3-cyclohexadiene, following the procedure described in Example 18, paragraph (c), for the oxidation of the dihydro analogue. The above acetylenic ketone was then partially reduced to the title compound folowing the method described in Example 18, paragraph (a). Cis-2,6,6-trimethyl-1-crotonoyl-1,3-cyclohexadiene gave the following NMR data (CCl4): 1.06 (6 H, s) 1.69 (3 H, s), 2.09 (2 H, d, J=2.3 cps.), 2.14 (3 H, d, J=5.5 cps), 5.81 (2 H, t+s, J=2.3 cps), 6.2 (2 H, complex band) ppm (δ).