Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H](OC1C(N)=CC(O)=C([N+]([O-])=O)C=1)CCCCCC.N([O-])=O.[Na+].Cl.C(O)C.[CH3:29][C@H:30]([O:37][C:38]1[C:43]([N:44]=[N:45][C:46]2[CH:51]=[C:50]([O:52][C@@H:53](C)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:49]([N:61]([CH3:63])[CH3:62])=[CH:48][C:47]=2[OH:64])=[CH:42][C:41]([OH:65])=[C:40]([N+:66]([O-:68])=[O:67])[CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>N1C=CC=CC=1>[CH3:29][C@H:30]([O:37][C:38]1[C:43]([N:44]=[N:45][C:46]2[CH:51]=[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:49]([N:61]([CH3:62])[CH3:63])=[CH:48][C:47]=2[OH:64])=[CH:42][C:41]([OH:65])=[C:40]([N+:66]([O-:68])=[O:67])[CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(O)cc1N=Nc1cc(O[C@@H](C)CCCCCC)c(N(C)C)cc1O
Agent: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(O)cc1N
Agent: Cl
Agent: O=N[O-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCCOc1cc(N=Nc2cc(O)c([N+](=O)[O-])cc2O[C@@H](C)CCCCCC)c(O)cc1N(C)C
Yield: 64 %

Procedure:
Compound 43b (143 mg, 0.57 mol), compound 51a (161 mg, 0.57 mmol), 0.1M aqueous sodium nitrite (5.6 ml), and pyridine (1.8 ml) in 15 ml of a 15% HCl/ethanol solution were reacted according to the procedure for compound 52a. The crude product was adsorbed onto silica gel and purified via flash chromatography with gradual elutions from 85/10/5 to 75/20/5 (Hex/EtOAc/dichloromethane). Evaporation of solvent yielded 199 mg (64%) of a metallic green solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:11](=[O:16])[CH2:12][S:13]([CH3:15])=[O:14])[NH:8]2)=[CH:4][C:3]=1[Cl:23].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:7]([C:11](=[O:16])[CH2:12][S:13]([CH3:15])(=[O:32])=[O:14])[NH:8]2)=[CH:4][C:3]=1[Cl:23]
Reactant: CS(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1

Procedure:
Stir a mixture of 6.0 g of 6-bromo-5-chloro-2-[(methyl-sulfinyl)acetyl]-3-phenylindole and 6.0 g of m-chloroperbenzoic acid in 150 ml of chloroform at room temperature for 2 hours. Concentrate the mixture to about 50 ml, in vacuo, and filter and wash the product with 20 ml of cold chloroform to obtain 6-bromo-5-chloro-2[(methylsulfonyl)acetyl]-3-phenylindole, m.p. 224°-225°.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:34])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A 200 ml. four-necked flask equipped with a condenser tube and a thermometer was charged with 36 g of p-acetoxybenzoic acid and 71.4 g of thionyl chloride, and they were reacted at 50° C. for 4 hours. The excess of thionyl chloride was evaporated under reduced pressure to give p-acetoxybenzoyl chloride. Then, a 300 ml four-necked flask equipped with a condenser tube, a thermometer and a dropping funnel was charged with 45.7 g of benzyl p-hydroxybenzoate, 20.2 g of triethylamine and 100 ml of toluene. The temperature of the flask was raised to 30° C., and a solution of 39.7 g of p-acetoxybenzoyl chloride in 50 g of toluene was added dropwise over 1 hour, and the reaction was carried out at 50° C. for 30 minutes. After cooling, the reaction mixture was washed with three 50 ml portions of water, and the solvent was evaporated under reduced pressure. Recrystallization of the residue from methanol gave benzyl p-(p-acetoxybenzoyloxy)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]([CH2:29][CH2:30][C:31](Cl)=[O:32])([O:27][CH3:28])=[O:26].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31](=[O:32])[CH2:30][CH2:29][C:25]([O:27][CH3:28])=[O:26])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 24 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 2.1 eq of 3-carbomethoxypropionyl chloride in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica gel, 1:4 ethyl acetate:methylene chloride). The resulting product is slurried in ethyl acetate and filtered to give pure 4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoic acid, methyl ester (24%); mp 157.5°-158° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-(4-nitrophenyl)-4-oxobutyric acid (0.50 g, 2.2 mmol), 1-dodecanol (5.0 ml, 22 mmol), and p-toluenesulfonic acid (50 mg) in tetrahydrofuran (2.5 ml) was stirred 60 hours at room temperature then heated under reflux for 1.5 hours. Concentration of the reaction mixture in vacuo and purification by chromatography or silica gel (200 g) eluting with methylene chloride:hexane (1.1 to 2:1) followed by filtration of the solid product from a small volume of hexane gave, after drying under high vacuum, dodecyl 4-(4-nitrophenyl)-4-oxobytyrate (0.43 g) as a white solid. 1H NMR (DMSO-66, 300 MHz) δ: 0.86 (t, J=6.5 Hz, 3H, ester CH3), 1.07-1.35 (m, 18H, ester CH2 's), 1.47-1.60 (m, 2H, ester CH2), 2.69 (t, J=6 HZ, 2H, CH2), 3.39 (t, J=6 HZ, 2H, CH2), 4.00 (t, J=6.5 Hz, 2H, ester CH2), 8.22 (d, J=9 Hz, 2H, Ar), 8.36 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C22H33NO5 : C, 67.49; H, 8.50; N, 3.58. Found: C, 67.36; H, 8.54; N, 3.55.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][NH:3][CH:2]2[C:7]([NH:9][C:10]1[C:11]([F:24])=[CH:12][C:13]([Cl:23])=[C:14]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)=[O:8].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[Cl:23][C:13]1[CH:12]=[C:11]([F:24])[C:10]([N:9]2[C:7](=[O:8])[CH:2]3[CH:1]4[CH2:6][CH:5]4[CH2:4][N:3]3[C:33]2=[O:35])=[CH:15][C:14]=1[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C=Cc1cc(NC(=O)C2NCC3CC32)c(F)cc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C=Cc1cc(N2C(=O)C3C4CC4CN3C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of the compound of Step G, Example 2, (300.0 mg, 0.85 mmol) and triethylamine (1.18 mL, 8.5 mmol) in CH2Cl2 (50 mL), under N2, at room temperature, was added dropwise a solution of triphosgene (84.0 mg, 0.28 mmol) in CH2Cl2 (10 mL) over a period of 15 minutes. The solution was stirred at room temperature for 10 minutes. A mixture of CH2Cl2 (100 mL) and H2O (50 mL) was added. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to dryness. The residue was chromatographed on silica gel using 25% ethyl acetate in hexane as eluent. Fractions containing the title compound were combined and evaporated under reduce pressure to yield the title compound, a compound of the invention, as a white solid (84.0 mg), 26%; m.p. 154°-156° C., IR (nujol, cm-1): 1720.4 (C=O); 1H NMR δ: 0.61-0.63 (q,1H), 1.32-1.36 (m,4H), 2.01-2.03 (m,1H), 2.11-2.18 (m,1H), 3.12-3.18 (d,1H), 4.18-4.28 (m,4H), 6.37-6.41 (d,1H), 7.32-7.35 (d,1H), 7.59-7.62 (d,1H), 7.94-7.99 (d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][N:41]2C(OC(C)(C)C)=O)=[O:39])[C:10](=[O:36])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])(=[O:26])=[O:25])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][NH:41]2)=[O:39])[C:10](=[O:36])[N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])(=[O:26])=[O:25])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3)CC2)c(C)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-(N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}phenyl) piperidyl]ethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (146 mg, 0.18 mmol) and 50% TFA in CH2Cl2 (10 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min) provided the title compound (TFA salt) as a white foam (81 mg). MS (ESI, pos. ion) m/z: 699 (M+1); (ESI, neg. ion) m/z: 697 (M−1). Calc'd for C30H43ClN4O4S: 698.27.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1ccccc1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ccccc2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using Aniline instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=308.3, 309.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=[O:14])[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1.C(=O)=O.CC(C)=O>[OH:13][C:11]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([CH3:12])[C:10]([N:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc(N(C(=O)C(C)=O)c2ccc(OC)cc2)cc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(N(C(=O)C(C)(O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
N,N-bis(4-methoxyphenyl)-2-oxopropanamide (0.53 g, 1.77 mmol) was placed in a 250 mL three-necked round-bottomed flask fitted with a stiffing bar, a rubber stopper and a nitrogen inlet, and dissolved in 30 mL anhydrous THF. The solution was cooled to −78° C. in dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (3.89 mL of 0.5 M THF solution, 7.25 mmol) was added dropwise with stiffing at −78° C. under nitrogen atmosphere. The resulted solution was stirred at −78° C. for one hour and then at room temperature for one hour. The reaction was quenched by adding 20 mL of saturated NH4Cl solution. EtOAc (3×30 mL) was added to extract the solution. The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, 2-hydroxy-N,N,2-tris(4-methoxyphenyl)propanamide, 0.61 g, 84.7% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13](Br)=[CH:14][CH:15]=2)[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:8]1[C:9]([C:11]2[S:12][C:13]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:14][CH:15]=2)=[CH:10][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:24])=[N:7]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)COc1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)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: O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 70 °C
Yield: 44.5 %

Procedure:
To a solution of [5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-1H-pyrazol-3-yloxy]-acetic acid methyl ester (1.43 g, 3.33 mmol) in anhydrous THF (13.0 mL) was added sequentially 3-methylsulfonylphenylboronic acid (0.80 g, 4.0 mmol), Pd(PPh3)4 (192 mg, 0.17 mmol), Na2CO3 (1.06 g, 10.0 mmol) and water (1.0 mL). The reaction mixture was heated to reflux at 70° C. for overnight. The solvent was evaporated and the crude residue was purified by flash column chromatography with 50% ethyl acetate in hexane, resulting the product methyl {1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazol-3-yloxy}acetate (0.746 g, 45% yield). 1H-NMR (CDCl3): δ 8.17 (m, 1H), 7.83 (m, 2H), 7.55 (m, 3H), 7.40 (m, 3H), 7.33 (m, 1H), 5.91 (s, 1H), 4.70 (s, 2H), 3.81 (s, 3H), 3.09 (s, 3H). MS (ES): 503 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][N:31]=[C:23]([N:22]([CH3:21])[CH3:32])[CH:24]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: CN(C)c1cc(C(=O)O)ccn1
Product: CN(C)c1cc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)ccn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-dimethylamino-iso-nicotinamide was prepared starting from intermediate D and 2-dimethylamino-isonicotinic acid. MS calcd. for C24H22ClN4O2 [(M+H)+] 433.1, obsd. 432.9.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:25]>>[Cl:25][C:1]1[NH:2][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2F)[nH]c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate (19.3 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=10:1→3:1) to give the title compound as a brown solid (yield 8.76 g, 53%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[CH3:15][N:16](C)C=O>>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:15]#[N:16])([O-:13])=[O:12]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: O
Product: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
1-Chloro-2,6-dinitrobenzene (40.4 grams) is dissolved in anhydrous dimethylformamide (200 ml.). Cuprous cyanide (72 grams) is added and the stirred reaction mixture is heated to reflux for six hours. The dark brown reaction mixture is cooled and poured into water (1.5 l.) with stirring. The tan precipitate is collected by filtration and then extracted three times with hot ethanol (300 ml.). Removal of two-thirds of the solvent from combined ethanol extracts under reduced pressure gives a tan precipitate. The precipitate is collected by filtration and recrystallized from ethanol to give a tan product (7.2 grams) melting at 143°-146.5°.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:34]([C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:35]([NH:34][C:37]3[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1NC(=O)N1CCC(c2ccccc2)C(CN[C@H](C)c2cccc3ccccc23)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a solution of 158 mg of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.100 mL of triethylamine in 3.0 mL of toluene was added 83 mg of methyl 2-isocyanatobenzoate at room temperature. It was stirred at 90° C. overnight, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 27.3 mg of methyl 2-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a colorless foamy substance.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27](O)=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[NH4+]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]([NH2:31])=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A solution of compound 21a (100 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), DIPEA (77 mg, 0.6 mmol) in DCM (5 mL) was stirred at it for 0.5 hr. Ammonium hydroxide (12 mg, 0.36 mmol) was added and the mixture was stirred at it for 2 hr. The reaction mixture was quenched with water and extracted with DCM. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give the desired compound 23 (32 mg, 32% yield). LCMS (m/z): 412.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:15][CH:14]=1)[CH3:11]
Reactant: Cc1ccc(C)c(Cl)c1
Reactant: CCOc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCOc1ccc(Nc2cc(C)ccc2C)cc1
Temperature: 110 °C
Yield: 97.4 %

Procedure:
Following general procedure E, a mixture of 2-chloro-p-xylene (134 μL, 1.0 mmol), 4-ethoxyaniline (154 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (235 mg, 98%), mp 56-58° C. 1H NMR (300 MHz, CDCl3) δ: 7.10 (m, 3H), 6.95 (m, 3H), 6.72 (d, J=7.5 Hz, 1H), 5.26 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.29 (s, 3H), 1.51 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 154.7, 143.5, 136.8, 136.5, 130.9, 122.5, 121.0, 116.1, 116.1, 115.6, 64.1, 21.6, 17.7, 15.3 ppm. IR (neat, cm−1): 3402, 2978, 2923, 1511, 1478, 1292, 1238, 1117, 1049, 798. Anal. Calcd. for C16H19NO: C, 79.63; H, 7.94. Found: C, 79.70; H, 8.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1([C:18](=O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:18]([CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccccc2)CC(=O)c2cc(Br)ccc2O1
Yield: 24.9 %

Procedure:
A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (64.2 g, 0.3 mol), 1-phenyl-ethanone (46.8 g, 0.39 mol) and pyrrolidine (6 g, 0.084 mol) in toluene (125 mL) was stirred vigorously at room temperature overnight. Then the mixture was refluxed for 6 h. After cooling, the mixture was treated with water (100 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were concentrated and the residue was purified by column to give 6-bromo-2-methyl-2-phenyl-chroman-4-one (23.7 g, 25%). 1H-NMR (CDCl3): 1.74 (s, 3H), 3.06 (d, 1H), 3.31 (d, 1H), 6.95 (d, 1H), 7.20-7.37 (m, 5H), 7.52 (d, 1H), 7.84 (s, 1H).