Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:15](O)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)C1C=CC=CC=1>C(O)C.C1(C)C=CC=CC=1>[CH2:15]([O:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([Cl:12])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(O)c1c(Cl)ccc(O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCc1ccccc1
Product: O=C(O)c1c(Cl)ccc(OCc2ccccc2)c1Cl
Reaction time: 1 h

Procedure:
271.6 g of 2,6-dichloro-3-hydroxybenzoic acid are dissolved in ethanol (2 1). Aqueous sodium hydroxide (242 g of 50% aqueous NaOH solution in 550 ml H2O) is added to the benzoic acid solution, followed by the addition of benzyl chloride (368 g). The reaction mixture is heated to reflux with stirring, and after one hour, additional sodium hydroxide solution (45 g of a 50% aqueous NaOH) and benzyl chloride (30 g) are added. After one hour twenty-five minutes, another 20 g of 50% sodium hydroxide solution are added. After twenty minutes, the reaction mixture is cooled and evaporated to remove ethanol. The mixture is then partitioned between diethylether (2 1) and 5% aqueous sodium hydroxide (2 1). The layers are separated and the aqueous solution washed with diethylether. The aqueous extract is cooled in an ice bath and acidified just short of neutral with conc. HCl. Diethylether (2 1) is added and the solution made strongly acidic. The two layers are stirred for fifteen minutes and separated. The aqueous layer is washed with diethylether and the combined ether layers washed with H2O, saturated sodium chloride solution, and dried over Na2SO4. The ether is filtered and the filtrate evaporated in vacuo to a light yellow oil (338.2 g). 500 ml of toluene are added to the oil and partially evaporated, resulting in a precipitate. The suspension is allowed to stand and used without further treatment for the further reactions. The toluene suspension contains a large amount of heavy crystalline precipitate.
Reaction SMILES: [C:1]([P:7](=[O:10])([O-:9])[O-:8])([P:3](=[O:6])([O-:5])[O-:4])=[CH2:2].[Na+:11].[Na+].[Na+].[Na+].[S:15]1C=C[CH:17]=[C:16]1CC(O)=O.[OH2:24]>>[Na+:11].[Na+:11].[C:16]([S:15][CH2:2][CH:1]([P:7](=[O:9])([O-:8])[O-:10])[P:3](=[O:5])([OH:4])[OH:6])(=[O:24])[CH3:17]
Reactant: O
Reactant: C=C(P(=O)([O-])[O-])P(=O)([O-])[O-]
Reactant: O=C(O)Cc1cccs1
Agent: [Na+]
Product: CC(=O)SCC(P(=O)([O-])[O-])P(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Tetrasodium ethenylidenebis(phosphonate) (2.76 g, 10 mmol) [prepared as described in R. L. Carroll, U.S. Pat. No. 3,686,290 (1972) and in R. L. Carroll and M. M. Crutchfield, Canadian Patent 811,736 (1969)] and thiolacetic acid (3.81 g, 50 mmol) are dissolved in water (20 ml) and stirred at room temperature under an atmosphere of nitrogen for 20 hours. The reaction mixture is then concentrated under reduced pressure and further dried under vacuum overnight. The solid product is triturated in warm ethanol, cooled and filtered while washing with diethyl ether to yield pure product as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)CCc1ccccc1Br
Product: COC(=O)CCc1ccccc1Br

Procedure:
Prepared according to the procedure described in Example 34, Step 1, using 3-(2-bromo-phenyl)-propionic acid and methanol.
Reaction SMILES: [H-].[Na+].CO.[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[CH:21]N(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(Cl)cc2Cl)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a dried round bottom flask was added NaH (3.73 g in 60% disp.; 93.3 mmol), DMF (100 mL), and methanol (3.78 mL; 93.3 mmol) under a nitrogen atmosphere. To this suspension was added a solution of 2-cyanoacetamide (3.92 g; 46.6 mmol) in DMF (30 mL) via syringe. Then a solution of the crude product of Step B (42.4 mmol) in DMF (30 mL) was added via syringe. The resulting reaction mixture was heated to 95° C. and stirred for 3 hours. The reaction was quenched with saturated aq. NaHSO4 solution and extracted with methylene chloride (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by trituration in ethanol. The precipitate was collected and washed with cold ethanol to afford the desired product: m/e=355 (M+1) Rt=3.3 min on LCMS.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]([O:18][CH2:19][C@:20]12[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:23]([O:24][CH2:25]1)[C@H:22]([N:35]1[CH:43]=[N:42][C:41]3[C:40](=O)[NH:39][CH:38]=[N:37][C:36]1=3)[O:21]2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(OCC)(=O)C>[C:10]([O:18][CH2:19][C@:20]12[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:23]([O:24][CH2:25]1)[C@H:22]([N:35]1[CH:43]=[N:42][C:41]3[C:36]1=[N:37][CH:38]=[N:39][C:40]=3[Cl:3])[O:21]2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OC[C@]12CO[C@@H]([C@H](n3cnc4c(=O)[nH]cnc43)O1)[C@@H]2OCc1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OC[C@]12CO[C@@H]([C@H](n3cnc4c(Cl)ncnc43)O1)[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (2.1 mL, 29 mmol) and DMF (1 mL) were added to a solution of compound 22 (1.24 g, 2.62 mmol) in dichloromethane. The mixture was stirred at 30° C. (oil bath) overnight, diluted with ethyl acetate (50 mL), washed with NaHCO3 (sat. aq., 100 mL) and water (2×50 mL), dried (Na2SO4), and concentrated under reduced pressure. A white solid residue was purified by column silica gel chromatography using 0 to 2% of methanol/dichloromethane as eluent. Yield: 1.2 g (93%) of compound 26 as a white solid material.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16]2)=[CH:12][C:11]=1[N+:22]([O-])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:20][C:14]1([CH3:21])[C:13]2[C:17](=[CH:18][C:10]3[NH:9][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:22][C:11]=3[CH:12]=2)[NH:16][C:15]1=[O:19]
Reactant: [H][H]
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccccc3)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccccc4)nc3cc21

Procedure:
1.0 g. palladium/charcoal (10%) were introduced into 10.0 g. (30.7 mmol) 6-benzoylamino-5-nitro-3,3-dimethylindolin-2-one in 250 ml. glacial acetic acid. This mixture was hydrogenated in a shaking bomb at ambient temperature and normal pressure. After the take up of hydrogen had ceased, the solution was separated from the catalyst, slowly evaporated at 60° C. and the residue taken up in water and neutralised with 2N aqueous ammonia solution. The precipitate was filtered off with suction and recrystallised from methylene chloride. There were obtained 6.9 g. (81% of theory) of the title compound; m.p. 195°-220° C.
Reaction SMILES: C([O:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[Cl:31])C1C=CC=CC=1>[Pd].CO.C1COCC1.CCOC(C)=O>[Cl:31][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([Cl:30])[C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:27]=[N:26][N:25]=[CH:24]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N(Cc2cc(Cl)c(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2cc(Cl)c(O)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (100 mg, 10% Pd) was added to a solution of 4-[(4-benzyloxy-3,5-dichloro-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02119, 1.13 g, 2.50 mmol) in MeOH/THF/EtOAc (30 mL/30 mL/40 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 h at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 306 mg (34%). 1H-NMR (400 MHz, d6-DMSO) δ 4.97 (s, 2H, —CH2Ar), 6.76 (d, J=9.0 Hz, 2H), 7.31 (s, 2H), 7.77 (d, J=9.0 Hz, 2H), 8.85 (s, 2H), 10.29 (s, 1H, —OH). 13C-NMR (100 MHz, CDCl3) δ=56.57, 103.76, 114.55, 119.69, 122.89, 128.14, 129.46, 134.58, 144.03, 149.46, 151.85. LRMS (FAB+): 360.0 (100,
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.[H-].[Na+]>CN(C=O)C>[C:1]1([C:7]2([C:8]#[N:9])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#CCC1=CCCCC1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(C2=CCCCC2)CCCC1

Procedure:
Cyclohex-1-en-1-ylacetonitrile and 1,4-dibromobutane were reacted in DMF at room temperature in the presence of sodium hydride to obtain 1-cyclohex-1-en-1-ylcyclopentanecarbonitrile.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].Cl>CN(C=O)C.CO>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:13]=1
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a slurry of NaH (1.38 g, 60% in mineral oil, 34.41 mmol) in DMF (20 mL) at 0° C. was added a solution of 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (2-2; 4.15 g, 15.64 mmol) and 2-cyanoacetamide (1.45 g, 17.2 mmol) in MeOH (1.5 mL) and DMF (40 mL) dropwise over 40 min. The resulting mixture was stirred at 90° C. for 4 h and cooled to rt. The mixture was poured into dilute HCl aqueous solution (240 mL, 0.25 M) and filtered, washed with water (40 mL) and dried in vacuo to afford 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2-3). 1H-NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.15-7.28 (m, 7H), 7.05-7.07 (m, 2H), 2.36 (s, 3H). LRMS m/z (M+H) Calcd: 287.3, found: 287.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]([OH:32])[CH2:12][CH:13]([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:14]([O:16]C(C)(C)C)=[O:15])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([N:8]([CH2:10][C:11](=[O:32])[CH2:12][CH:13]([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:14]([OH:16])=[O:15])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)CC(O)CC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CC(=O)CC(Cc1cccc2ccccc12)C(=O)O)Cc1ccccc1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
5.64 g of a sulfur trioxide/pyridine complex were added to a solution of 3.13 g (7.22 mmole) of t-butyl 5-(N-benzyl-N-methylamino)-4-hydroxy-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 29) and 5 ml of triethylamine dissolved in 20 ml of dimethyl sulfoxide at room temperature, and the mixture was stirred for 2 hours. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. 20 ml of a 4N solution of hydrogen chloride in dioxane were added to the residue, and the mixture was stirred for 2 hours; it was then concentrated by evaporation under reduced pressure. The residue was dissolved in water, and the resulting solution was neutralized by adding a 1N aqueous solution of sodium hydroxide. It was then concentrated by evaporation under reduced pressure. The residue was dissolved in methylene chloride and the resulting insoluble materials were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure to afford 1.94 g of the title compound as a colorless amorphous substance.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[P:18](=[S:26])(Cl)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].[H][H]>C(#N)C>[P:18](=[S:26])([O:11][C:8]1[CH:7]=[N:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:10][CH:9]=1)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=S)(Cl)OCC
Reactant: [H][H]
Reactant: CC(C)(C)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1cnc(C(C)(C)C)nc1
Reaction time: 1 h

Procedure:
To a mixture of 98 grams of 2-(1,1-dimethylethyl)-5-pyrimidinol, 130 grams of finely powdered potassium carbonate and 800 ml of acetonitrile was added 121 grams of O,O-diethyl phosphorochloridothioate. The temperature of the reaction mixture rose to 55° C. Stirring was continued until no more starting O,O-diethyl phosphorochloridothioate could be detected by gas-liquid chromatography. The reaction appeared to be complete in about 1 hour. The salts present were then removed by filtration, the filtrate concentrated in a rotary evaporator, the residue taken up in ether, the ether solution washed twice with 2 percent aqueous sodium hydroxide, and once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The ether was then removed under vacuum leaving a pale yellow colored oil with a refractive index at 25° of 1.4913. On elemental analysis the product was found to contain by weight 47.38% carbon; 6.67% hydrogen and 9.19% nitrogen. Theoretical analysis is 47.35% carbon; 6.96% hydrogen and 9.21% nitrogen.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]=[O:20]>>[CH2:1]([N:8]1[C:9](=[O:12])[S:10][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:19]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: S=C=NCc1ccccc1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cn1sc(=O)n(Cc2ccccc2)c1=O

Procedure:
Reagents: Benzyl isothiocyanate (0.86 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), Ethyl isocyanatoacetate (0.73 ml, 6.5 mmol).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:24]([NH2:29])[CH:25]=[N:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:1]([CH2:2][CH2:3][CH3:4])=[N:29][C:24]=3[CH:25]=[N:26][C:27]=2[CH:28]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 105 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Trimethyl orthobutyrate (29.75 mL, 0.1859 mol) was added in three portions to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (54.6 g, 0.170 mol) in toluene (795 mL). Pyridine hydrochloride (1.96 g) was then added, and the reaction was heated at 105° C. and stirred for four hours. Additional trimethyl orthobutyrate (7 mL, 40 mmol) was then added, and the reaction was stirred for three hours. The reaction was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The oily residue was treated with chloroform, which was removed under reduced pressure to remove residual toluene, and then again diluted with chloroform (1.2 L). The resulting solution was washed sequentially with 5% aqueous sodium bicarbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to yield 60.3 g of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an oily brown solid, containing a small amount of toluene (0.93 equivalents).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(NCc3ccccc3)ccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a stirred solution of 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (350 mg, 1.41 mmol) in dichloromethane (15 ml) was added benzaldehyde (143 μl, 1.41 mmol), acetic acid (81 μl, 1.41 mmol) followed by sodium triacetoxyborohydride (418 mg, 1.97 mmol) and the reaction was stirred at room temperature for 16 hrs. The reaction mixture was quenched by cooling in ice batch and neutralising with aqueous sodium hydroxide 2M. The aqueous mixture was extracted using dichloromethane (3×50 ml) and the organics were combined, dried over sodium sulfate and then concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as cream solid (320 mg, 67% yield). HPLC retention time 4.98 min. Mass spectrum (ES+) m/z 339 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]([CH3:24])[C:21](=[O:23])[CH3:22].[C:25](OCC)(=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH3:19][N:20]([CH3:24])[C:21](=[O:23])[CH2:22][C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
10.2 g of diisopropylamine (0.1 mol) were dissolved in 100 ml of dry THF under nitrogen and cooled in a freezing mixture. 40 ml n-butyllithium in hexane (2.5 M, 0.1 mol) were slowly added dropwise. When the addition was completed it was allowed to stir for 60 minutes and then 8.7 g N,N-dimethylacetamide (0.1 mol) were added dropwise. The reaction mixture was stirred for another 20 min in the freezing mixture. In a second flask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THF were cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 150 ml ethyl acetate, the combined organic phases dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.) and 17 g of crude product were obtained. 5.5 g product was obtained as white crystals with a melting point of 28° C. after crystallization from n-hexane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:13]([CH3:15])[CH3:14])=[C:4]([CH:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[C:8]=1[OH:9])[OH:5].[Cl:16][CH2:17]OC>C(=S)=S>[Br:1][C:2]1[C:8]([OH:9])=[C:7]([CH:10]([CH3:11])[CH3:12])[C:6]([CH2:17][Cl:16])=[C:4]([C:3]=1[CH:13]([CH3:15])[CH3:14])[OH:5]
Reactant: CC(C)c1cc(O)c(C(C)C)c(Br)c1O
Reactant: COCCl
Solvent: S=C=S
Product: CC(C)c1c(O)c(CCl)c(C(C)C)c(O)c1Br

Procedure:
Two hundred seventy-three parts of 3-bromo-2,5-diisopropylhydroquinone is allowed to react with 130 parts of chloromethylmethyl ether and 80 parts of stannic chloride in 400 parts of carbon disulfide under general conditions set forth in "Organic Reactions", Vol. 1, p. 68 and 69. The reaction mixture is poured on ice, and the organic layer is separated and dried over anhydrous calcium sulfate. The solvent is allowed to evaporate and the residue is crystallized to give a pure sample of the title compound. Chloromethylation of the following monohalo- or dihalodialkylhydroquinones or resorcinols gives the corresponding chloromethyl derivatives.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:19][C:20]1[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>O>[F:19][C:20]1[CH:25]=[C:24]([C:13]2[CH:12]=[CH:11][C:10]([CH:7]3[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH:23]=[CH:22][C:21]=1[OH:27]
Reactant: Oc1ccc(Br)cc1F
Reactant: CCCC1CCC(c2ccc(B(O)O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CCCC1CCC(c2ccc(-c3ccc(O)c(F)c3)cc2)CC1
Temperature: 70 °C
Yield: 55.2 %

Procedure:
Dichlorobistriphenylphosphinepalladium (0.143 g) was added to a mixture of 4-(4-propylcyclohexyl)phenylboronic acid (10.0 g), 2-fluoro-4-bromophenol (7.76 g), potassium carbonate (11.2 g) and isopropyl alcohol (90 ml) under a stream of nitrogen, and the mixture was heated to reflux at 70° C. for 4 hours. The reaction mixture was poured into water, which was extracted with diethyl ether. The extract was washed with water three times and the solvent was distilled off. The residue was purified by silica gel-column chromatography (solvent: toluene/ethyl acetate=10/1 by volume), and then by recrystallization-filtration (solvent: toluene/heptane=0.5/2 by volume) to give colorless crystals of 3-fluoro-4′-(4-propylcyclohexyl)biphenyl-4-ol (7.0 g, GC purity: 95%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([N:15]=[C:16]=[O:17])[S:13][CH:14]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])[S:13][CH:14]=1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1cc(Cl)cs1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1cc(Cl)cs1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To 3.0 g (26.5 mM) of creatinine in 50 ml of anhydrous DMF was added with stirring a solution of 4-chloro-2-thienyl isocyanate in 25 ml of toluene. After stirring at 65° C. for 5 hrs., the mixture was cooled, added to 200 ml of water and filtered to separate a precipitate, which was recrystallized from ethanol and then ethyl acetate to give 1.0 g of the above urea as a light tan solid, m.p. 203°-204° C. (dec.) containing 1/8 mole of ethyl acetate of recrystallization.