Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O.[NH2:25][NH2:26]>CCO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:25][NH2:26])=[O:19])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
To a suspension of methyl 4-{[3-(3,4-dihydroxyphenyl)propanoyl]amino}benzoate (227 mg, 0.72 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.55 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave 117 mg of the title compound (52%) as a white solid in 99.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl>O1CCCC1>[OH:15][C@@H:14]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COP([O-])OC
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)[C@H](O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Dimethyl phosphite (37 μl, 0.40 mmol) was added to the solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -78° C., and it was maintained at this temperature for 15 minutes. Then p-nitrobenzaldehyde (0.40 mmol) was added thereto. After the temperature was raised to room temperature, the stirring was continued for 12 hours. Hydrochloric acid (1N) was added thereto to stop the reaction, and the mixture was extracted with ethyl acetate (10 ml×three times). The combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-nitrophenyl)methylphosphonate as a final product in a yield of 81%. The chemical reaction in this Example is shown in chemical formula 31.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:30]([OH:32])=[O:31])[C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:15](C4CCCCO4)[C:13]=3[N:14]=2)=[CH:5][C:4]=1[C:33]([O:35][CH3:36])=[O:34].O>O1CCOCC1.C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:30]([OH:32])=[O:31])[C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][NH:15][C:13]=3[N:14]=2)=[CH:5][C:4]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccccc4)nn(C4CCCCO4)c3n2)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccccc4)n[nH]c3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
10 mL of a solution of anhydrous hydrogen chloride in dioxane (4 M) are added to a solution of 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2.0 g/4.20 mmol) in 35 mL of DCM. The solution is stirred at ambient temperature for 15 minutes and then run into water and extracted with EtOAc. The organic phase is washed with water and then with a saturated aqueous solution of NaCl, dried over sodium sulphate and concentrated to dryness to give 1.4 g of a pale yellow powder (yield: 86%).
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].C(N(CC)CC)C.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:5][CH:3]([CH2:4][S:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[O:1]
Reactant: Sc1ccccc1
Reactant: C=C(C)C=O
Solvent: CCN(CC)CC
Product: CC(C=O)CSc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 51.4 g (0.733 mole) of methacrolein and 2 g (0.018 mole) of triethylamine at 0-5° C. is added 80.8 g (0.733 mole) of benzenethiol slowly. The addition rate is such that the temperature was under 10° C. The reaction mixture is stirred at 0-5° C. for one hour. The mixture is placed on a rotary evaporator to remove triethylamine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1ccccc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 78.4 %

Procedure:
To a stirred solution of 4-fluoroaniline (2.4 mL, 25 mmol) and pyridine (6.1 mL, 75 mmol) in dichloromethane (30 mL) was added 2-nitrobenzoyl chloride (3.6 mL, 28 mmol). After 12 h, the mixture was diluted with dichloromethane and washed with 1 N aqueous citric acid, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The resulting solid was suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 5.1 g (79%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[S:8](Cl)([OH:11])(=O)=[O:9].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: c1ccccc1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(CNS(=O)(=O)c1ccccc1)OC
Reaction time: 2 h
Yield: 101 %

Procedure:
56 g 2-aminoacetaldehyde dimethyl acetal are dissolved in 200 ml of a 14 wt. % aqueous sodium carbonate solution at 20° C. in a three-necked flask, equipped with a thermometer, reflux condenser, tap funnel and magnetic stirrer. Subsequently, 88 g benzene sulfochloride are added drop-wise within 1 hour at this temperature under intensive stirring followed by another 2 hours of heating the reaction to 40° to 50° C. mixture under vigorous stirring. After that the intensive smell of benzene sulfochloride has disappeared and a second phase has formed. This heavy oily phase is separated in the separatory funnel, imbibed using diethyl ether and dried over water-free sodium sulfate. Once the drying agent has been removed and the ether has been distilled off, 112 g of the product are obtained (yield: 88% based on the amino acetal used).
Reaction SMILES: [OH-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH:7]=1>C(O)C>[N:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-n2cnnc2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
5.5 ml of a 5 N aqueous sodium hydroxide solution was added to a solution of 1.2 g of ethyl 4-(1,2,4-triazol-4-yl)benzoate in 15 ml of ethanol. The mixture was stirred at 50-60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added ice water. The mixture was made acidic with acetic acid. The resulting crystals were collected by filtration, water-washed, and dried to obtain 0.95 g of 4-(1,2,4-triazol-4-yl)benzoic acid as a white powder. Melting point: 300° C. or above.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:1][NH:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(C=O)c1
Reactant: NC1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cccc(CNC2CCCCC2)c1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of m-anisaldeyde (500 mg, 3.67 mmol) and cyclohexylamine (420 μL, 3.67 mmol) in acetonitrile (30 mL) was stirred for 4 h and slowly treated with sodium cyanoborohydride (227 mg, 4.4 mmol). Glacial acetic acid was added until pH˜6 (pH paper), and the solution was stirred for 16 h. Conc. HCl (0.5 mL) was added and acetonitrile was evaporated under reduced pressure. The crude residue was quenched with water (100 mL) and extracted with ethyl acetate. The aqueous phase was basified with 10% aqueous NaOH until pH>7 and extracted with dichloromethane (3×50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure without heating to provide 670 mg of N-(3-methoxybenzyl)-cyclohexylamine (83% yield) as a light oil. 1H NMR (300 MHz, acetone-d6) δ 1.05-1.30 (m, 5H), 1.58 (m, 1H), 1.72 (m, 2H), 1.89 (m, 2H), 2.45 (m, 1H), 3.77 (s, 2H), 3.79 (s, 3H), 6.77 (dd, J=2.1 and 8.2 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 7.21 (t, J=7.8 Hz, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[C:25]([O:31][CH3:32])(=[O:30])[CH2:26][C:27]([CH3:29])=O>C1COCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:26]([C:25]([O:31][CH3:32])=[O:30])=[C:27]([CH3:29])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[C:10](=[S:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde (238.2 mg, 1.82 mmol) and methyl acetoacetate (211 mg, 1.82 mmol) are dissolved in 5 ml THF. Ethyl polyphosphate (0.30 g) is added and the reaction mixture is stirred at reflux temperature overnight. After cooling to room temperature, the reaction is quenched with 10 ml of water and extracted with 10 ml ethyl acetate (2×). The combined organic layers are dried with sodium sulfate and the solvent is removed in vacuo. The product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6])#[N:2]
Reactant: N#Cc1ccccc1C(=O)O
Reactant: Oc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
2-Cyanobenzoic acid (1.00 g, 6.80 mmol), phenol (576 mg, 6.12 mmol) and PyBOP (3.90 g, 7.48 mmol) were dissolved in DMF (12 mL), and triethylamine (2.10 mL, 15.0 mmol) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:2) to afford phenyl 2-cyanobenzoate (1.24 g, 82%).
Reaction SMILES: O[CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:3](O)=[O:4].Cl.[NH2:17][NH2:18].N>O.C(O)(=O)C.C(N(CC)CC)C>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:2][C:3](=[O:4])[NH:17][N:18]=1
Reactant: O=C(CC(O)C(=O)O)c1ccccc1O
Reactant: NN
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=c1ccc(-c2ccccc2O)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a stirred suspension of 2-hydroxy-4-oxo-4-(2-hydroxyphenyl)butyric acid (0.025M) in water (20 ml) was added triethylamine (3.3 ml), taking the pH to 9.5, followed by concentrated hydrochloric acid (2.5 ml) to take the pH to 4. Hydrazine (0.05M) was added slowly with the concurrent addition of sufficient glacial acetic acid to maintain a pH of 7.0. Steam heating was applied for 2 hours and during this time the pH of 7.0 was maintained by the addition of ammonia as necessary. The reaction mixture was allowed to cool to room temperature. The solid was filtered off, washed with water, 2-propanol and dried to afford 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (78.3%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([Br:27])=[CH:21][N:20]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([Br:27])=[CH:21][N:20]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1nc(Br)cnc1N
Solvent: c1ccncc1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
5-Dimethylamino-1-naphthalenesulphonyl chloride (15.2 g) and 2-amino-5-bromo-3-methoxypyrazine (obtained as described in Gazz. Chim. Ital. 1960, 90, 1807) (9.5 g) were mixed intimately in a mortar and pestle and added to pyridine (150 ml) at 0° C. The solution was kept at 0° C. for 1 hour and then heated at 80° C. for 18 hours. Volatile material was removed by evaporation and dichloromethane (250 ml) was added to the residue. Insoluble material was removed by filtration and the filtrate was washed with water (100 ml) and saturated sodium chloride solution (100 ml). The solution was treated with charcoal and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v). The resulting solid was triturated with ether and recrystallised from ethanol to give 5-dimethylamino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (4.7 g), m.p. 166°-167° C.; 1H NMR (d6 -DMSO): 2.8 (s,6H), 3.9 (s,3H), 7.2 (d,1H), 7.55-7.7 (d,2H), 7.8 (s,1H), 8.3 (d,1H), 8.4-8.5 (m,2H), 11.5 (s,1H); mass spectrum (+ve CI): 437 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:35]1([NH2:42])[C:36]([NH2:41])=[CH:37][CH:38]=[CH:39][CH:40]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[NH:42][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:41]=2)[N:8]([C:6](=[O:7])[CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:12]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1N
Product: CON=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 1,2-benzenediamine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=425.4.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]([N:15]([CH3:17])[CH3:16])=O.[CH3:18][C:19]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[C:33]([CH3:39])[C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1>O1CCCC1.C(O)(=O)C>[CH3:39][C:33]1[CH:34]=[C:35]([C:37]2[N:38]=[N:13][N:15]([CH3:17])[CH:16]=2)[CH:36]=[C:19]([CH3:18])[C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1
Reactant: CN(C)N=O
Reactant: Cc1cc(CCCCCOc2c(C)cc(C#N)cc2C)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: Cc1cc(CCCCCOc2c(C)cc(-c3cn(C)nn3)cc2C)on1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6.6 ml diisopropylamine in 150 dry tetrahydrofuran at 0° C. under nitrogen was slowly added 18.4 ml (2.5 m) n-butyllithium. The mixture was cooled to -78° C., and 3.2 ml N-nitrosodimethylamine was then slowly added. The latter mixture was stirred for 30 min, and 6.0 g 5-[5-(2,6-dimethyl-4-cyanophenoxy)pentyl]-3-methylisoxazole in 33 ml dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -73° C. for 8.5 hours, and 3 ml glacial acetic acid in 10 ml tetrahydrofuran was then added. The reaction mixture was stirred overnight, then concentrated, and the residue dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride, dried over magnesium sulfate and concentrated to an oily residue. The latter was chromatographed on silica gel and eluted with ethyl acetate/hexane 60:40. The product was recrystallized from ethyl acetate/hexane to give 2.69 g 4-[3,5-dimethyl-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}phenyl]-1-methyl-1H-1,2,3-triazole, m.p. 117-118° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[C:13]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[CH3:14].[H-].[Na+].Cl>C1COCC1>[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6])(=[O:15])[CH3:14]
Reactant: CC(=O)OCCO
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCCOCc1cc(Cl)cc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a soln. of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.3 mmol) (A.2.2.1.) and 2-hydroxyethyl acetate (1.43 mmol) in 7 mL THF was added NaH (1.95 mmol, 60% suspension in oil). The reaction mixture was stirred at RT overnight and then poured into a 1M HCl soln. The mixture was extracted twice with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4 and conc. in vacuo. Purification with CC (0-25% EtOAc/Hept) gives the desired compound as orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.C(O)C.Cl>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1O)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1O)C2

Procedure:
To 7-(5-chloro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one were added aminoguanidine hydrochloride (0.53 g), ethanol (30 ml), concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make the solution alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-hydroxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 167) (1.1 g) as colorless crystals.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]=1[OH:28])[CH:23]=O>>[C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:23][C:22]1[CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]([OH:28])=[C:20]([Br:19])[CH:21]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Product: CCOc1cc(C=C2C(=O)Nc3ccc(C(=O)c4ccccc4)cc32)cc(Br)c1O

Procedure:
The title compound was synthesized in an identical manner to example 2 except 5-benzoyl oxindole was used in place of 5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride and 3-bromo-5-ethoxy4-hydroxy-benzaldehyde was used in place of 3,5-dibromo-4-hydroxy-benzaldehyde. 1H NMR (DMSO-d6) δ1.38 (t, J=7 Hz, 3H), 4.14 (q, J=7 Hz, 2H), 6.94 (d, J=8.2 Hz, 1H), 7.50-7.68 (m, 4H), 7.69-7.72 (m, 2H), 7.90 (s, 1H), 8.14 (s, 1H), 8.34 (d, J=1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H), 10.15 (s, 1H), 11.02 (s, 1H); APCI-MS: m/z 464 (m−H)−. Anal. Calcd for C24H18NO4Br: C, 62.08; H, 3.91; N, 3.02; Br, 17.21. Found: C, 61.98; H, 3.88; N, 3.08; Br, 17.28.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:21]1[CH:22]=[CH:23][S:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc2c(cc(-c3ccsc3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 3-thienylboronic acid (0.044 g, 0.34 mmol, Aldrich) and Na2CO3 (0.16 g, 1.6 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.6 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.031 mmol) was added and the reaction was stirred at reflux for 15 minutes. Upon cooling to room temperature, the reaction was diluted with water. The product was extracted with EtOAc, and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a light yellow solid (47 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.36-7.27 (m, 4H), 7.20 (dd, J=5.0, 1.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.02-6.96 (m, 2H), 6.80 (d, J=0.8 Hz, 1H), 5.43 (s, 2H). LCMS (M+H)+: 324.9.