Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:33]([O:32][C:30]([NH:29][CH:20]([C:21]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=2)=[CH:18][CH:17]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCOCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
The amide 13 (2.2 g, 4.3 mmol) was dissolved in THF (25 mL) and diluted with water (25 mL). Lithium hydroxide (0.41 g, 17.0 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×50 mL). The organic layer was washed with water (1×50 mL) and brine (1×50 mL), dried and concentrated to yield the desired acid compound 14 (2.0 g, 93.5%). 1H NMR (400 MHz, DMSO-d6): 12.1 (br, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.52 (m, 1H), 3.22-3.47 (m, 8H), 2.72-2.80 (m, 4H), 1.28 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[CH:7]=[C:6]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)Cl.B(Br)(Br)Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-n2cc(-c3ccccc3)c3cc(OC)ccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1c2ccc(O)cc2c(-c2ccccc2)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-4-phenylisoquinolin-1(2H)-one (0.36 g, 1.01 mmol) was placed in a dry 150 mL single-necked flask fitted with a stirring bar and septa. Methylene chloride (30 mL) was added via a syringe. Boron tribromide (5.0 mL of 1.0 M methylene chloride solution) was added dropwise with stirring under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 16 hours. Then, 20 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.29 g, 87.9% yield. MS: 330.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 10.31 (s, 1H), 9.69 (s, 1H), 8.19 (d, 1H, J=8.7 Hz), 7.52-7.39 (m, 5H), 7.28 (d, 2H, J=8.7 Hz), 7.18 (s. 1H), 7.00 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.87-6.82 (m, 3H).
Reaction SMILES: C([Mg]Br)C.O1CCCCC1[O:11][CH2:12][C:13]#[C:14][CH2:15][C:16]#[CH:17].I[CH2:19][C:20]#[C:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[O:23]([CH2:22][C:21]#[C:20][CH2:19][C:17]#[C:16][CH2:15][C:14]#[C:13][CH2:12][OH:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#CCC#CCOC1CCCCO1
Reactant: ICC#CCOc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC#CCC#CCC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
3.99 ml (2.15 g, 0.016 mol) of a 4.05N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2.879 (0.0161 mol) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 30 ml of tetrahydrofuran maintained at -20° C. After the addition was finished, the reactionmixture was stirred for 2 hours further at -20° C. Then, 52.8 mg (0.53 mmol) of cuprous chloride was added. The mixture was stirred for 20 additional minutes, warmed to room temperature and 2.2 g (0.008 mol) of 1-iodo-4-phenoxybut-2-yne was added. The reaction mixture was then stirredat room temperature for 3 hours, poured into 50 ml of saturated ammonium chloride solution and extracted with ether (3×50 ml). The combined extracts were dried over sodium sulfate and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography on80 g of silica gel, using hexane:ether (90:10) as eluant thus obtaining thetetrahydropyranyl ether of 10-phenoxydeca-2,5,8-triyn-1-ol, as an oil. Thisproduct was stored in dry ice.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([F:24])([F:23])[F:22])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:28][NH2:29]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:28][NH:29]3)=[CH:6][CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([F:24])([F:22])[F:23])[N:13]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
2-Fluoro-4-{2-(methylamino)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (166 mg, 0.454 mmol) was dissolved in ethanol (3 mL) in a 5 mL sealable vial. Hydrazine monohydrate (0.668 mL, 13.63 mmol) was added, the vial was capped, and the reaction was heated at 100° C. overnight. The reaction was concentrated, dissolved in 2 mL of DMSO and purified in HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 1% CH3CN/H2O, 0.1% TFA to 42% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3, then extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (91 mg) as a light yellow solid. LC-MS (ES) m/z=377 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.01-2.22 (m, 4H), 2.85 (d, J=4.3 Hz, 3H), 3.48-3.61 (m, 1H), 3.68 (dt, J=10.1, 5.1 Hz, 1H), 5.14 (t, 1H), 5.40 (bs, 2H), 6.50 (bs, 1H), 6.68 (bs, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (bs, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([N+:22]([O-:24])=[O:23])=[CH:6][CH:5]=2.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1.C(OC(=O)C)(=O)C>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:17])[O:16]1
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C(=O)c1ccccc1C(=O)O
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
Following a procedure similar to that described in part B of Example 18 for interacting 3.24 g (0.01 mole) of 2-[(2-methyl-5-nitro-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, and 1.6 g (0.01 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in the presence of 5.0 ml of acetic anhydride, there is obtained 3-[2,4-bis(dimethylamino)phenyl]-3-(2-methyl-5-nitro-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =NO2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:18]([F:27])[C:17]=3[F:28])[CH2:12][CH2:11]2)=[C:6]([F:30])[C:5]=1[F:31])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:18]([F:27])[C:17]=3[F:28])[CH2:12][CH:11]=2)=[C:6]([F:30])[C:5]=1[F:31])[CH3:2]
Reactant: CCCCOc1ccc(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CC=C(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Yield: 56.5 %

Procedure:
The compound (29) (19.0 g), p-toluenesulfonic acid (0.57 g) and toluene (200 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The obtained reaction mixture was cooled to 30° C., and water (200 ml) and toluene (200 ml) were added thereto, and mixed. The mixture was then allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solution obtained was purified by means of column chromatography (silica gel; toluene), and further purified by means of recrystallization (Solmix A-11: ethyl acetate=2:1 by volume), giving 10.3 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexene (No. 77). The yield based on the compound (27) was 55.0%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([O:12]C)=[O:11])=[N:6][C:7]=1[O:8]C.Br[C:15]1[CH:16]=[CH:17][C:18]([C:23](=N)OC)=[N:19][C:20]=1OC.[ClH:27]>CO>[ClH:27].[CH3:23][C:18]1[CH:17]=[C:16]([C:2]2[C:7](=[O:8])[NH:6][C:5]([C:10]([OH:12])=[O:11])=[CH:4][CH:3]=2)[CH:15]=[CH:20][N:19]=1
Reactant: COC(=O)c1ccc(Br)c(OC)n1
Reactant: COC(=N)c1ccc(Br)c(OC)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2ccc(C(=O)O)[nH]c2=O)ccn1

Procedure:
Synthesis of methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30). A stirred solution of methyl 5-bromo-6-methoxypyridine-2-carboximidoate (C29) (9.42 g, 38.4 mmol) in methanol (66 mL) and concentrated hydrochloric acid (6.6 mL) was heated under reflux for 18 hours. The reaction was concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (500 mL) and washed with saturated aqueous sodium bicarbonate solution (250 mL). The aqueous phase was extracted with dichloromethane (200 mL), and the combined organics were washed with water (250 mL), with saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound. The reaction was repeated on additional material (1.65 g, 6.73 mmol), worked up in a similar manner, combined with the first reaction, and purified by silica gel chromatography (Eluant: 10% ethyl acetate in heptane) to provide the title compound as a yellow solid. Yield: 4.48 g, 18.2 mmol, 40%. LCMS m/z 246.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 4.11 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.[C:21]1([CH2:27][C:28](Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:28][CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1

Procedure:
The title compound was prepared as described in General Method 5 using 2.0 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 2.1 mmol of phenylacetyl chloride, 2.1 mmol of triethylamine, and 10 mL of THF, followed by 10 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.5 mmol of the intermediate 3-acyl compound. Reduction of this acyl derivative was accomplished with 3 mmol of sodium cyanoborohydride. The product was triturated from ether (m.p. 158°-159° C.). 1H NMR (DMSO-d6) 2.31 (m, 4 H), 3.37 (m, 2 H), 6.93 (d, 1 H), 7.07-7.17 (m, 3 H), 7.24-7.28 (m, 2 H), 7.35 (m, 8 H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([N+:17]([O-:19])=[O:18])=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1CC(=O)O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A solution of 2-o-tolylacetic acid (3.54 g, 23.6 mmol) in DCM (12 mL) was added to a pre-cooled mixture of concentrated sulfuric acid (10 mL, 188 mmol) and 90% nitric acid (1 mL, 22.4 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 30 minutes, then slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into ice-water. The white solid was collected by filtration, rinsed with water, and concentrated. The solid was triturated with ether and filtered to obtain Intermediate 80A (2.4 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.62 (1H, br. s.), 8.13 (1H, d, J=2.51 Hz), 8.04 (1H, dd, J=8.28, 2.51 Hz), 7.47 (1H, d, J=8.53 Hz), 3.80 (2H, s), 2.34 (3H, s).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([CH2:13][S:14][C:15](=[O:17])[CH3:16])[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C1COCC1.C(Cl)Cl>[C:27]([O:26][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:10](=[O:12])[CH:9]([CH2:13][S:14][C:15](=[O:17])[CH3:16])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(=O)SCC(CCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-phenyl-2-[acetylthio-methyl]butyric acid (3.57 g. 14.2 mmole) in 66 mL of THF at 0° C. was added (S)-leucine, t-butyl ester (2.91 g 15.6 mmole) and 1-hydroxybenzotriazole hydrate (HOBT·H2O, 2.86 g, 21.2 mmole) and N-methylmorpholine (4.29 g, 42.4 mmole). The mixture was stirred at 0° C. for 15 minutes, then 5.42 g of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC·HCl, 28.3 mmole) was added and the mixture stirred overnight. The solution was worked up by adding 100 mL methylene chloride and the mixture extracted with 3×50 ml of 5% sodium bicarbonate and washed with 2×50 mL of brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with methylene chloride/ethyl acetate (95/5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]([F:35])([F:34])[F:23])[CH:3]=2)[N:10]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ccccc4C(F)(F)F)c3)n2)c(F)c1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 2-trifluoromethylphenylboronic acid by the method of Example 12 to give 3-(2,4-difluorophenyl)-5-(2-fluoro-2′-trifluoromethylbiphenyl-5-yl)-[1,2,4]triazine as a pale yellow solid: δH (400 MHz, CDCl3) 6.98-7.09 (2H, m), 7.35-7.42 (2H, m), 7.65 (2H, dd, J 7.4, 17.6 Hz), 7.84 (1H, d, J 7.8 Hz), 8.21 (1H, dd, J 2.2, 6.8 Hz), 8.28-8.36 (2H, m), 9.61 (1H, s); m/z (ES+) 432.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH3:12])=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9].[H-].[Na+].[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16].O>O1CCCC1>[CH2:15]([O:17][C:18](=[O:28])[C:19]([C:8]([C:7]1[CH:6]=[N:5][C:4]([CH3:12])=[C:3]([CH3:2])[CH:11]=1)=[O:9])=[CH:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16]
Reactant: CCOC(=O)C=CNc1ccccc1
Reactant: Cc1cc(C(=O)Cl)cnc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)c1cnc(C)c(C)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 7.7 %

Procedure:
3.31 g (16.0 mmol) of 5,6-dimethyl-nicotinoyl chloride hydrochloride 6a (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) was dissolved in 35 mL of dry tetrahydrofuran and cooled down to −10° C. under nitrogen atmosphere. To the resultant solution was added 1.60 g (40.0 mmol) of 60% sodium hydride and the mixture was stirred for 15 minutes, followed by the addition of 3.06 g (16.0 mmol) of 3-phenylamino-acrylic acid ethyl ester 5a. The mixture was stirred at −10° C. for 2 hours, followed by the addition of 100 mL of water to the reaction mixture. The product was extracted twice with 100 mL dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated in vacuo. Purification of the crude product using flash chromatography (10-75% ethyl acetate in hexane) yielded 400 mg of 2-(5,6-dimethyl-pyridine-3-carbonyl)-3-phenylamino-acrylic acid ethyl ester 2d as a yellow solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([Cl:21])=[CH:11][C:12]([O:18][CH2:19][CH3:20])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:24])=[N-]>O1CCCC1>[CH3:24][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([Cl:21])=[CH:11][C:12]=1[O:18][CH2:19][CH3:20]
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C(=O)OC
Reaction time: 0.5 h

Procedure:
5-tert-Butylsulfamoyl-4-chloro-2-ethoxybenzoic acid (0.8 g, 24 mmol) in 10 mL of tetrahydrofuran was treated with diazomethane (15 mL, ˜2-3 M in ether, prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) at room temperature and stirred for 0.5 h. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel, eluting with 20% ethyl acetate in hexane) to give 0.45 g of 5-tert-butylsulfamoyl-4-chloro-2-ethoxybenzoic acid methyl ester as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:19]1
Reactant: O=C(O)c1ccsc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccsc4)cc23)CC1
Yield: 92.3 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.5 mg (0.09 mMol) 3-thienoic acid, 9.4 mg (92%) of the title compound were recovered.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>O>[C:24]([O:23][C:21]([NH:20][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:10][CH:11]=1)[C:3]([OH:28])=[O:2])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1-c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
A solution of (S)-N-t-butoxycarbonylamino-3-(2'-methoxybiphenyl-4-yl)-propionic acid methyl ester (4.1 g in methanolic 1N sodium hydroxide (60 mL) is stirred at room temperature for 3 hours. Ether (30 mL) and water (30 mL) are added. The aqueous layer is separated and acidified with concentrated HCl, then extracted with ether (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives (S)-N-t-butoxycarbonylamino-3-(2'-methoxybiphenyl-4-yl)-propionic acid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:16]1[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH2:13][CH2:14][CH3:15]>C(Cl)(Cl)Cl>[CH2:12]([C:16]1[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:6])=[CH:20][C:19]=2[N:28]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid 3-chloroperoxybenzoic acid (2.1 g of ˜60%) was added in portions over a period of 3 minutes to a solution of 2-butyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline (2.7 g, 7.2 mmol) in chloroform (72 μL). The reaction mixture was stirred at ambient temperature for 30 minutes then additional 3-chloroperoxybenzoic acid (0.4 g) was added. The reaction mixture was stirred at ambient temperature for 15 minutes and then partitioned between dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL). The organic layer was washed sequentially with saturated aqueous sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to provide 2-butyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline 5-oxide as an orange foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CN(CCCCN)CC2
Yield: 62.5 %

Procedure:
A solution of 7-methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (17.4 g 0.0478 mol) and hydrazine monohydrate (4.6 ml, 0.095 mol) in ethanol (300 ml) were stirred at room temperature for 18 h and at reflux for 1 h. The cooled reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in 2.5N hydrochloric acid, filtered through Kieselguhr and the filtrate basified with 0.880 ammonia. The product was extracted into dichloromethane (4×200 ml), the combined extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a brown oil (7 g, 63%).