Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14].N1C=CC=CC=1.O>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13](=[O:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc2cc[nH]c2c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1c[nH]c2cc(F)ccc12)C(Cl)(Cl)Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 55.2 %

Procedure:
4.37 g (32.32 mmol) of 6-fluoroindole are added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 4 cm3 (35.55 mmol) of trichloroacetyl chloride in 44.5 cm3 of 1,4-dioxane and 2.9 cm3 (35.55 mmol) of pyridine. After stirring at a temperature in the region of 20° C. for 20 hours, the reaction mixture is poured into 125 cm3 of demineralised water. The precipitate which appears is isolated by filtration, washed with 3 times 20 cm3 of water and then dried at 40° C. under reduced pressure to provide 5 g of 6-fluoro-3-trichloroacetyl-1H-indole in the form of a purple powder melting at 244° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].CC(C)([O-])C.[K+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH2:41][C:42](OC)=O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:41][C:42]1[NH:24][C:22](=[O:23])[C:3]2[C:4]([CH2:20][CH3:21])=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CCc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C(N)=O
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1nn(C(CCCc2ccccc2)C(C)O)c2nc(Cc3ccc(OC)c(OC)c3)[nH]c(=O)c12

Procedure:
1.0 g (3.03 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-3-ethyl-1H-pyrazole-4-carboxamide, 1.60 g of potassium tert-butoxide and 1.40 g (19 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed overnight in 20 ml of ethanol. The solvent is removed in vacuo, the residue is taken up in dichloromethane, the mixture is extracted with 1N HCl, the organic phase is dried over Na2SO4 and evaporated on a rotary evaporator. Purification by chromatography (cyclohexane/EA=2:1, 1% formic acid) and separation of the diastereomers by chromatography gives 232 mg (16%) of the diastereomer which elutes more rapidly, Rf=0.2 (cyclohexane/ethyl acetate=2:1) and 150 mg (10%) of the diastereomer which elutes more slowly, Rf=0.15 (cyclohexane/ethyl acetate=2:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:20]([O-])=[O:21].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[N:10]([N:20]=[O:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-6-methyl-1,2,3,4-tetrahydroquinoline (0.28 g, 0.00166 mol) in ethanol (1 mL) was added 1N hydrochloric acid (1 mL), and the reaction mixture was cooled to 0° C. Sodium nitrite (0.160 g, 0.00232 mol) in water (3 mL) was added at 0° C., and the mixture stirred for 1 h at RT. The reaction was monitored by TLC. After completion, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.28 g, 89% yield).
Reaction SMILES: Cl.[NH:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:3]([C:14]([OH:16])=O)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+:10]([O-:12])=[O:11].CN1CCOCC1.OC1C2N=NNC=2C=CC=1.[NH:41](C(OC(C)(C)C)=O)[C@H:42]([C:47]([NH:49][C@H:50]([C:62]([NH:64][C@H:65]([C:76]([NH:78][C@H:79]([C:84]([NH:86][CH2:87][C:88]([O:90][CH3:91])=[O:89])=[O:85])[C@H:80]([CH2:82][CH3:83])[CH3:81])=[O:77])[CH2:66][CH2:67][CH2:68][NH:69][C:70](=[NH:75])[NH:71][N+:72]([O-:74])=[O:73])=[O:63])[CH2:51][C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44]>CN(C=O)C.C(Cl)CCl>[NH:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:3]([C:14]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:62]([NH:64][C@H:65]([C:76]([NH:78][C@H:79]([C:84]([NH:86][CH2:87][C:88]([O:90][CH3:91])=[O:89])=[O:85])[C@H:80]([CH2:82][CH3:83])[CH3:81])=[O:77])[CH2:66][CH2:67][CH2:68][NH:69][C:70](=[NH:75])[NH:71][N+:72]([O-:74])=[O:73])=[O:63])[CH2:51][C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44])=[O:16])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N[C@H](C(=O)NCC(=O)OC)[C@@H](C)CC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)NCC(=O)OC

Procedure:
A sample HCl salt 13 and about 1.2 molar equivalents of Boc-Arg(NO2)-OH are mixed in DMF with N-methylmorpholine and hydroxybenztriazole; the solution is then treated with EDC and, after 3 h, the reaction is worked up exactly as described for pentapeptide (12) to give the compound (14) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>O.ClCCCl>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=Cc1cccc(C2CCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: c1ccc(Oc2cccc(NCc3cccc(C4CCCC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a 1,2-dichloroethane (12 mL) solution of 3-cyclopentylbenzaldehyde (0.69 g, 4.0 mmol; P. L. Ornstein et al., J. Med. Chem. 1998, 41, 358-378) was added 3-phenoxyaniline (0.73 g, 4.0 mmol), NaB(OAc)3H (1.08 g, 5.1 mmol) and acetic acid (0.24 mL, 4.2 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0.30 g (22%) of the desired N-(3-phenoxyphenyl)-[[3-cyclopentylphenyl]methyl]amine product as a colorless oil. 1H NMR (CDCl3) δ1.55 (m, 2H), 1.63 (m, 2H), 1.78 (m, 2H), 2.02 (m, 2H), 2.94 (m, 1H), 4.10 (m, 1H), 4.22 (m, 2H), 6.35 (m, 3H), 7.0-7.2 (m, 10H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ4.22) in the 1H NMR spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C@H:26]3[CH2:28][C@H:27]3[CH2:29][CH2:30]O)[CH2:22][CH2:21]2)=[N:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:13][C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C@H:26]3[CH2:28][C@H:27]3[CH2:29][CH2:30][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=3)[CH2:22][CH2:21]2)=[N:18][CH:19]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (4-hydroxyphenyl)acetate (106 mg, 0.639 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (150 mg, 0.532 mmol) in 5 ml anhydrous dichloromethane, triphenylphosphine (polymer-bound, 419 mg, 1.21 mmol), and di-test-butyl azodicarboxylate (245 mg, 1.07 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite® and concentrated. The residue was purified by column chromatography on silica gel (50 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 430.3 (M+H)+.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:42][O:43][CH3:44])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][CH:34]=[C:35]3[C:39]([O-:41])=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].C(O)=O>O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:42][O:43][CH3:44])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][CH:34]=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CSCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CSCC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The 297 mg of the product of Step A were suspended in 1.5 ml of aqueous 66% formic acid solution and the mixture was stirred at 50° C. for 15 minutes and was then cooled to room temperature. 0.66 ml of water were added to the mixture which was then filtered and the filter was rinsed with water. A little ethanol was added to the filtrate which was then evaporated to dryness under reduced pressure. The oil residue was taken up in water and ethanol and the mixture was again evaporated to dryness. The residue was added to 2 ml of a 1 M solution of sodium bicarbonate solution and 1.65 ml of water to form a solution which was then filtered. 2 N hydrochloric acid was added to the mixture to adjust the pH to 3 and a little ethanol was added thereto. After crystallization, the mixture was filtered and the product was rinsed with water and then with ether and dried to obtain 102 mg of syn isomer of (6RS, 7RS) 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]([C@H:13]([CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH2:14][C:15]3([C:20]([NH:22][C@@H:23]4[CH2:28][CH2:27][C@H:26]([C:29]([O:31]CC5C=CC=CC=5)=[O:30])[CH2:25][CH2:24]4)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]([C@H:13]([CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH2:14][C:15]3([C:20]([NH:22][C@@H:23]4[CH2:24][CH2:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]4)=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COCCOC[C@H](CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)Oc1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: CCO
Product: COCCOC[C@H](CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)Oc1ccc2c(c1)CCC2
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
A solution of (S)-benzyl cis-4-{1-[2-(5-indanyloxycarbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarboxamido}-1-cyclohexanecarboxylate (597 mg, 0.986 mmole) in 5% aqueous ethanol (10 ml) was hydrogenated over 10% palladium on charcoal catalyst (60 mg) at 60 p.s.i. (4.1 bar) and room temperature for 3.5 hours. The catalyst was removed by filtration and the filtrate evaporated under vacuum. The residue was dissolved in diethyl ether (50 ml) and the solution was clarified by filtration, and concentrated to low volume (about 5 ml) when crystallisation occurred. After granulation, filtration and drying gave the title ester (390 mg, 77%) as white crystals m.p. 107°-9° C., [α]D -5.8° (c=1, MeOH), Rf. 0.40 (silica; toluene, dioxane, acetic acid 90:24:5). Found: C,67.45; H,8.18; N,2.63. C29H41NO7 requires C,67.55; H,8.01; N,2.72%.
Reaction SMILES: OCC[C:4](=[O:32])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([O:25]C4CCCCO4)[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1.[C:33]([O:36][C:37](=[O:39])[CH3:38])(=O)[CH3:34]>N1C=CC=CC=1>[C:37]([O:36][CH2:33][CH2:34][C:4](=[O:32])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@@H](OC3CCCCO3)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCO)[C@@]3(C)CC(=O)[C@@H]12
Solvent: c1ccncc1
Product: CC(=O)OCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
21Hydroxymethyl-3α-tetrahydropyranyloxy-5α-pregnane-11,20- dione (600 mg) in anhydrous pyridine (12 ml) was treated with acetic anhydride (1.0 ml), and the solution was stirred at room temperature for 21/2 hours. The solution was partitioned between hydrochloric acid (2N, 100 ml) and ether/ethyl acetate 1/1, and the organic phase was washed with water, dried over sodium sulphate and evaporated to an oil (640 mg). The crude product (630 mg) was dissolved in I.M.S. (25 ml) and dilute hydrochloric acid (2N; 2.5 ml) was added. The solution was stirred at room temperature for 2 hours. The solution was neutralised with 10% potassium bicarbonate solution (5 ml) and concentrated by evaporation until an oily solid began to separate. The mixture was then diluted with water and extracted twice with ether/ethyl acetate 1/1. The combined organic extract was washed with water, dried over sodium sulphate and evaporated to a pale yellow oil (500 mg) which as purified by preparative t.l.c. in ethyl acetate/petrol 1/1. The main band, Rf 0.3 was separated to give 242 mg of solid which was recrystallized from ethyl acetate/petrol to give title compound (187 mg) as colourless plates, m.p. 113°-115°, [α]D + 103° (c 1.32).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[CH2:20]=O>C(O)C>[ClH:10].[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][CH2:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: C=O
Reactant: CC(=O)c1ccccc1
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(CCC(=O)c1ccccc1)Cc1ccccc1
Temperature: 24 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a five liter, 3-necked, round bottom flask equipped with two condensers were added 558.0 g (4.6 mol) methylbenzylamine and 500 ml of ethanol. The solution was stirred while an ethanolic solution of hydrochloric acid (170.0 g of acid dissolved in 2500 ml of ethanol) was added over a one hour period. After hydrochloric acid addition was complete, acetophenone (552.5 g; 4.6 mol) and paraformaldehyde (207.0 g; 6.9 mol) were added. The solution was heated until the liquid began to reflux and then stirred at that temperature overnight. The next morning an additional 137.0 g (4.6 mol) of paraformaldehyde were added and the reaction solution was stirred for an additional five hours at the reflux temperature. The solution was then cooled to room temperature (24° C.) and the solids which precipitated were collected by filtration, washed with ethanol and dried in a vacuum oven at 40° C. to provide 1090.0 g (82.0% yield) of 3-[methyl(phenylmethyl)amino]-1-phenyl-1-propanone hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13](Br)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH:26]=[O:27])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cccc2c(Br)cccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc2c(C=O)cccc12
Temperature: -95 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-bromo-1-naphtoic acid tert-butyl ester (Example 9.2) (6.1 g) in dry tetrahydrofuran (54 ml) cooled to −100° C. was added a solution of butyl lithium (1.6M in hexane) (12.5 ml) dropwise at −100° C., followed by addition of dimethyl-formamide (“DMF”) (2.77 ml) at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured onto a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated to give 5-formyl-1-naphtoic acid tert-butyl ester (3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.35 (s, 1H), 9.50 (s, 1H), 9.18 (d, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.65-7.75 (m, 2H), 1.65 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10](=O)[NH:9]1.[CH3:19][N:20](C)[C:21](Cl)=O>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]([N:20]([CH3:21])[CH3:19])=[N:9]1
Reactant: CN(C)C(=O)Cl
Reactant: O=C1Cc2ccccc2C(c2ccccc2Cl)N1
Product: CN(C)C1=NC(c2ccccc2Cl)c2ccccc2C1
Product: Cl

Procedure:
1-(2-Chlorophenyl)-1,4-dihydroisoquinol-3-one (11.0 g, 43 mmol) was dissolved in dimethylcarbamyl chloride (50 g) on an oil bath (bath temperature 160°-170° C.) for 1 and three quarter hours. The mixture was cooled, evaporated under reduced pressure and partitioned between water (150 ml), 5M hydrochloric acid, ethyl acetate (100 ml) and chloroform (100 ml). The organic layer was separated and extracted with a portion of water (50 ml). The combined aqueous extracts were washed with ethyl acetate (3×25 ml) and basified (10% sodium hydroxide) to pH 14. The oil so formed was extracted with ethyl acetate (2×100 ml) and the combined ethyl acetate layers were washed with brine (50 ml) and dried over sodium sulphate. The solution was filtered and reduced to 100 ml under reduced pressure. Ethereal hydrogen chloride was added to precipitate the salt. After trituration, the solid was filtered off and dried in the vacuum over (90° C., 1 mm). This gave 1-(2-chlorophenyl)-3-dimethylamino-1,4-dihydroisoquinoline hydrochloride (5.7 g, 42%) m.p. 162°-6° C. (soften then hardened and remelted 252°-5° C.). I.R. νmax (Nujol) 1650 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH2:13][OH:14])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH:13]=[O:14])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: C=CCC(C=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 79.3 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-hydroxymethyl-3-butenyl]methylcarbamate (45 g) was dissolved in anhydrous dimethyl sulfoxide (320 mL), and triethylamine (87 mL) was added thereto. Under cooling with ice, sulfur trioxide-pyridine (31.7 g) was added, and the resultant mixture was stirred for 1 hour at room temperature. Ice-water (650 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (500 mL). The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby give the title compound (35.5 g, 77%).
Reaction SMILES: [Cl:1]C1C=C2C(C(=O)C(C(O)=O)=CN2C2C=CC=C(F)C=2)=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37](C4C=CN=CC=4)[CH:38]=3)[C:33](=[O:46])[C:32]([C:47]([NH2:49])=[O:48])=[CH:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:37]1[CH:38]=[C:39]2[C:34]([C:33](=[O:46])[C:32]([C:47]([NH2:49])=[O:48])=[CH:31][N:30]2[C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:35][CH:36]=1
Reactant: O=C(O)c1cn(-c2cccc(F)c2)c2cc(Cl)ccc2c1=O
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O

Procedure:
7-Chloro-1,4-dihydro-1-(3-fluorophenyl)-4-oxo-3-quinolinecarboxamide [IV; R=H, R1 =3-FC6H4, R2 =H, R6H, X=Cl]was prepared from 7.36 g 7-chloro-1,4-dihydro1-(3-fluorophenyl)-4-oxo-3-quinolinecarboxylic acid by the procedure of Example 1, part (h), and was obtained (7.14 g) as a colorless solid, m.p. 294-296° C. when recrystallized from DMF. e) 1,4-Dihydro-1-(3-fluorophenyl)-4-oxo-7-(4-pyridinyl)3-quinolinecarboxamide [I; R=H, R1 =3-FC6H4, R2 =H, R6H, R7 4 -pyridinyl]was prepared from 4.13 g 7-chloro-1,4-dihydro-1-(3-fluorophenyl)-4-oxo-3-quinolinecarboxamide, 3.78 g 4-trimethylstannylpyridine and 0.46 g dichloro-bis-triphenylphosphine palladium according to the procedure of Example 37, part (c), and was obtained (2.4 g) in the form of its methanesulfonate salt, m.p. above 320° C. when recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[C:18]1([CH3:40])[CH:23]=[CH:22][C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.CN(C)C=O.C(O[K])(C)(C)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([N:24]([C:25]3[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=3)[C:21]3[CH:22]=[CH:23][C:18]([CH3:40])=[CH:19][CH:20]=3)=[CH:38][CH:37]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Reactant: CCOP(=O)(Cc1ccc(OC)cc1)OCC
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)cc1
Reaction time: 5 h

Procedure:
Equal molar amounts of diethyl 4-methoxybenzylphosphonate and 4-(di-p-tolylamino)benzaldehyde were dissolved into N,N-dimethylformamide, and with agitation under water cooling, t-butoxy potassium was added little by little. After agitation for 5 hours at room temperature, water was added, and the solution was rendered acidic so that crude target product precipitates. The crude target product was purified by column chromatography on silica gel to give 4-methoxy-4′-(di-p-tolylamino)stilbene.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[C:13]([C:34]#[N:35])=[C:14]([C:28]2[CH:33]=[CH:32][N:31]=[N:30][CH:29]=2)[S:15][C:16]=1[C:17]1[N:21]=[CH:20][N:19](C2CCCCO2)[N:18]=1.CO.Cl.O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[C:13]([C:34]#[N:35])=[C:14]([C:28]2[CH:33]=[CH:32][N:31]=[N:30][CH:29]=2)[S:15][C:16]=1[C:17]1[NH:21][CH:20]=[N:19][N:18]=1
Reactant: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Cc1ccc2ccccc2c1
Agent: Cl
Solvent: O
Solvent: CO
Product: N#Cc1c(-c2ccnnc2)sc(-c2nnc[nH]2)c1Cc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
4-(2-Naphthylmethyl)-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (0.03178 g, 0.06641 mmol) was dissolved in methanol (3.00 mL, 74.0 mmol). HCl in water (12 M, 3.00 mL, 36.0 mmol) was added. The solution was heated at 50° C. for 60 min then cooled to rt. The mixture was evaporated in vacuo to remove the most of methanol. To the residue was added 30 mL saturated sodium bicarbonate solution, extracted with 40 mL ethyl acetate twice. The combined EtOAc layers were washed with 20 mL water then concentrated in vacuo. The resulting crystalline solid was collected by filtration to afford a pure product (0.0158 g, yield 60.3%). LCMS: (AA) ES+ 395. 1H NMR (300 MHz, d4-methanol) δ: 9.60 (s, 1H), 9.27-9.29 (m, 1H), 8.47 (s, 1H), 8.09-8.11 (m, 1H), 7.69-7.77 (m, 4H), 7.37-7.47 (m, 3H), 3.30 (s, 2H).