Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31][CH2:32][OH:33]>>[Br:1][C:2]1[C:3]([O:33][CH2:32][CH2:31][O:30][CH3:29])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: COCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 250 mg, 0.632 mmol) and K2CO3 (131 mg, 0.948 mmol) in 2-methoxyethanol (997 μl, 12.64 mmol) was stirred at 110° C. for 4 h. The solvent was evaporated off under reduced pressure to afford the title compound which was used directly. UPLC-MS (Condition 2) tR=1.18 min, m/z=435.2/437.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.32 (s, 3H) 3.64-3.76 (m, 2H) 4.48-4.59 (m, 2H) 7.38 (d, J=8.66 Hz, 2H) 7.85 (d, J=9.03 Hz, 2H) 8.55 (d, J=2.07 Hz, 1H) 8.72 (d, J=2.07 Hz, 1H) 10.47 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]2[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH2:5][CH2:4]1.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][C:34]([F:37])([F:36])[F:35])[CH:26]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]3[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH2:5][CH2:4]2)=[C:27]([O:33][C:34]([F:35])([F:36])[F:37])[CH:26]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CN)CC2)nc2ccccc12
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-N2-(4-aminomethyl-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (500 mg, 1.59 mmol) in CH2Cl2 (5 mL) were added 4-bromo-2-trifluoromethoxy-benzaldehyde obtained in step A of example 13 (428 mg, 1.59 mmol), acetic acid (95 mg, 1.59 mmol), and NaBH(OAc)3 (505 mg, 2.38 mmol). The reaction mixture was stirred at ambient temperature for 4 hr. The reaction was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine (783 mg, 89%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH3:32])[N:25]([CH3:33])[CH:24]=2)[C:10]1=[O:34])[CH2:5][CH2:6][CH2:7][CH3:8]>O1CCOCC1.O>[CH3:33][N:25]1[C:26]2[C:31](=[C:30]([CH3:32])[CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[C:18](=[O:19])[N:9]([C@@H:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([OH:35])=[O:2])[C:10]2=[O:34])=[CH:24]1
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)c2ccc(OC)cc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC[C@@H](C(=O)O)n1c(=O)c2ccc(OC)cc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (145 mg, 0.30 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (50 mg, 1.19 mmol) in H2O (2.5 mL). The resulting mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is triturated with H2O and MeOH to afford (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid. LCMS (ESMS): m/z 464.22 (M+H+).
Reaction SMILES: [CH2:1]([CH:11]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:12]([OH:14])=[O:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C(OCC)(=O)C>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:13][C:12](=[O:14])[CH:11]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)=CCC/C(C)=C/CC(C/C=C(\C)CCC=C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)=CCC/C(C)=C/CC(C/C=C(\C)CCC=C(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Digeranylacetic acid (300 mg, 0.9 m mol) and p-nitrophenol (139 mg, 1 m mol) were dissolved in acetonitrile-ethyl acetate (1:1) (10 ml), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (227 mg, 1.1 m mols) was added. The mixture was stirred at 0° C. for 3 hours and at room temperature for 15 hours. The crystalline precipitate was removed and the solvent was distilled off under reduced pressure, whereby digeranyl acetic acid p-nitrophenyl ester was obtained.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:16])C.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]2[CH2:11][O:16]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)Oc1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-tert-butoxystyrene (17.6 g, 100 mmol) in methylene chloride (200 mL) cooled in an ice bath is added a solution of 32% peracetic acid in acetic acid (31.5 mL, 150 mmol). The mixture is stirred at rt overnight and quenched by addition of saturated sodium bicarbonate solution. The organic phase is separated, washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. Chromatography on silica gel provides 2-(4-tert-butoxyphenyl)oxirane.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.O[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:29]([O:28][C:27]([NH:26][CH2:25][CH2:24][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:18]=1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(Cl)cc1
Yield: 78 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)propionate (1.01 g), which is the product of Reference example 38(b), t-butyl 2-hydroxyethylcarbamate (1.27 g), triphenylphosphine (2.06 g) and diethylazodicarboxylate (1.37 g) and the reaction mixture was treated to afford the title compound (1.14 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:14][CH2:15][CH3:16])(OCC)[CH2:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH3:10])[C:24](=[O:23])[C:26]([F:29])([F:28])[F:27])=[CH:6][CH:7]=1
Reactant: CCOC(CC)(OCC)c1ccc(Cl)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 2.0 g of 1-chloro-4-(1,1-diethoxypropyl)benzene and 2.5 mL of CH2Cl2 was treated with 1.45 mL of pyridine. The solution was cooled to 0° C. and treated with 5.5 mL of (CF3CO)2O in 2.5 mL of CH2Cl2. After heating overnight at reflux, the reaction mixture was cooled, diluted with CH2Cl2 and 12 mL of ice cold water was added. The organic layer was seperated and washed with 20 mL of 1N HCl, followed by a washing with 20 mL, of 10% Na2 CO3 and two washings with 20 mL of water. The organic layer was dried over Na2SO4 and concd in vacuo to yield 1.69 g of a dark brown oil. Chromatographic purification (silica, 10% ethyl acetate in hexanes) yielded 1.0 g of a yellow oil. Bulb to bulb distillation gave 0.45 g of a very pure light yellow oil: μ (23,D) 1.5137; major geometric isomer: 1HNMR (CDCl3) δ1.22 (t, 3H, 7.0Hz), 1.70 (s, 3H), 3.64 (q, 2H, 7.0 Hz), 7.30 (d, 2H, 8.3 Hz), 7.46 (d, 2H, 8.4 Hz). 19FNMR (CDCl3) δ-74.68 (CF3). Anal. Calcd for C13H12 O2F3Cl: C, 53.35; H, 4.13. Found: C, 53.44; H, 4.10.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=[O:16])=[N:6][CH:7]=1.CO.[BH4-].[Na+]>C1COCC1>[OH:16][CH:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=2)[C:12](=[O:13])[CH2:11][C:10]1([CH3:15])[CH3:14]
Reactant: CC1(C)CC(=O)N(c2ccc(I)cn2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(I)cn2)C1O
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
(800 mg, 2.42 mmol) 145-Iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (Example 13, step 1) was dissolved in THF (6 ml) and MeOH (2 ml) and the solution was cooled to 0-5° C. NaBH4 (101 mg, 2.67 mmol, 1.1 equiv.) was added at 0-5° C. and the mixture was stirred for 1 hr at 0-5° C. The reaction mixture was extracted with sat. NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a amino-silica gel column and eluting with a ethyl acetate/heptane gradient, 0:100 to 100:0. The desired (5-RS)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (370 mg, 46% yield) was obtained as a white solid, MS: m/e=333.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:27][CH2:28][C@@H:29]1[CH2:33][C@@H:32]([OH:34])[CH2:31][N:30]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C(=O)C>[CH2:38]([O:37][C:35]([N:30]1[CH2:31][C@H:32]([OH:34])[CH2:33][C@H:29]1[CH2:28][CH2:27][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Reactant: COc1cc(CCc2cc(F)ccc2O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(OC)c1
Yield: 52.2 %

Procedure:
622 mg of 4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 5) were dissolved in 7 ml of N,N-dimethylacetamide. The resulting solution was allowed to react with 343 mg of potassium t-butoxide and 678 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 1. The resulting oily substance was purified by silica gel column chromatography, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 552 mg (yield 52%) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccccc1-n1cccn1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccccc4-n4cccn4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 45.5 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Pyrazol-1-yl-benzaldehyde (28 mg, 0.163 mmol) were reacted to produce 33 mg (45%) of the title compound. mp: 120° C., 1H NMR (300 MHz, DMSO-d6): 12.88 (s, 1H), 8.00 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 3H), 7.60 (m, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.37 (s, 1H), 6.22 (s, 1H), 6.10 (s, 1H), 4.87 (t, J=8 Hz, 1H), 3.32 (s, 1H), 2.80 (s, 1H), 2.16 (d, J=8 Hz, 1H), 1.31 (d, J=8 Hz, 1H). MS: 490, 492 (M+H), HPLC: 2.28 min (G method).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([S:26](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:28])=[O:27])=[CH:23][CH:24]=4)[CH:19]=[C:18]([O:41][CH3:42])[C:17]3=[O:43])=[CH:10][C:9]=2[F:44])=[CH:4][C:3]=1[CH3:45].[O:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([S:26]([NH:51][C:48]5[CH:49]=[CH:50][O:46][N:47]=5)(=[O:27])=[O:28])=[CH:23][CH:24]=4)[CH:19]=[C:18]([O:41][CH3:42])[C:17]3=[O:43])=[CH:10][C:9]=2[F:44])=[CH:4][C:3]=1[CH3:45]
Reactant: Nc1ccon1
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1-n1c(=O)c(OC)cc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1-n1c(=O)c(OC)cc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A flask was charged with perfluorophenyl 1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.2262 g, 0.338 mmol) and isoxazol-3-amine (0.034 g, 0.405 mmol). A septum was attached and THF (3.4 ml) was added under N2 flow. The solution was cooled to 0° C. and LHMDS (0.709 ml, 0.709 mmol) was added to give a bright yellow solution. After 10 min, 5 mL of 1 N HCl was added and the mixture was partitioned between 1 N HCL (10 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×10 mL). The combined organic layers were dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal DCM and absorbed onto a 5 g loading cartridge and passed through a Interchim 25 g spherical silical gel column using a gradient of 5% EtOH and 15% EtOAc in heptane to 25% EtOH in EtOAc with 10% DCM constant additive to afford 1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.187 g, 0.328 mmol, 97% yield) as a colorless foam. The racemic product was subjected to chiral separation by SFC on a Chiralcel OJ column (45% MeOH/80% CO2) to give (M)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (P)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 2. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.59 (br.s, 1H), 8.66 (d, J=1.62 Hz, 1H), 8.20 (d, J=1.88 Hz, 1H), 7.60-7.70 (m, 2H), 7.40-7.58 (m, 4H), 7.25-7.38 (m, 1H), 6.74 (d, J=8.89 Hz, 1H), 6.38 (d, J=1.56 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.37 (s, 3H). m/z (ESI) 568.2 (M+H)+. Data for peak 2: 1H NMR (500 MHz, DMSO-d6) δ 11.56 (br. s, 1H), 8.65 (d, J=1.56 Hz, 1H), 8.19 (d, J=1.95 Hz, 1H), 7.60-7.71 (m, 2H), 7.40-7.57 (m, 4H), 7.32 (d, J=6.88 Hz, 1H), 6.73 (d, J=8.89 Hz, 1H), 6.37 (d, J=1.62 Hz, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 237 (s, 3H). m/z (ESI) 568.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1OC
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Trifluoromethylbenzoyl chloride (200 grams), 1,2-dimethoxybenzene (128 mL), and dichloromethane (1800 mL) were combined in a reaction flask under a nitrogen atmosphere. Tin (IV) chloride (168 mL) was added to the reaction mixture slowly drop-wise over 45 minutes. The reaction mixture was heated to reflux for 11 hours. It was subsequently cooled to room temperature and slowly poured into a mixture of 200 mL of hydrochloric acid and 1800 mL of ice water. The layers were phase separated. The organic layer was washed with 4 portions of water (1 L each) and then with 1.5 L of 20% saturated aqueous sodium hydroxide (w/v). The organic layer was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation. The residue was recrystallized in 1 L of 15% ethyl acetate/85% hexanes. The crystalline solid was collected by vacuum filtration yielding 132 grams of 3,4-dimethoxy-4′-trifluoromethylbenzophenone. This material was not purified further but was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(F)c(C(=O)Nc2ccccc2)c1
Product: O=C(Nc1ccccc1)c1cc(NC(=S)Nc2cc(Cl)cc(Cl)c2)ccc1F
Yield: 87.5 %

Procedure:
Prepared according to the procedure described for Example 60 using 5-amino-2-fluoro-N-phenyl-benzamide (0.920 g, 4.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.817 g, 4.00 mmol) to afford the product (1.52 g); m.p. 195-196° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccccn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-pyridyl)pentanoate (1.5 eq., prepared in Synthetic Example 21) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 201 to 202° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:21]2[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=O)(C)(C)C>ClCCl>[NH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:21]2[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCNC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCN)ccc21
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a stirred solution of methyl 5-(2-t-butoxycarbonylaminoethyl)-3-(3-pyridylmethyl)-1H-indole -1-propanoate (5.0 g) in dry dichloromethane (50 ml) and the solution was stirred for 3 hours. An additional 5 ml of trifluoroacetic acid was then added and stirring was continued for a further 2 hours. The solution was evaporated and the residue was partitioned between dichloromethane and dilute aqueous ammonia. The aqueous layer was separated and extracted withdichloromethane. The organic layers were combined and evaporated. Water (ca50 ml) was added followed by sufficient acetic acid to adjust the pH to ca4. The solution was washed twice with ethyl acetate and then made basic with concentrated aqueous ammonia solution. The mixture was extracted twice with dichloromethane and the combined extracts were dried (MgSO4) and evaporated to give the title compound as a gum (2.51 g), Rf. 0.15(SS3).
Reaction SMILES: [CH2:1]([NH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:9]=[O:10]>O>[CH2:1]([N:3]([CH2:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCNC(=O)OCC
Solvent: O
Product: CCOC(=O)N(CC)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[C:33]([O:32][C:30]([CH2:29][N:6]1[CH2:5][CH2:4][N:3]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:2](=[O:1])[C:7]1=[O:8])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCCN1CCNC(=O)C1=O)OC(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)CN1CCN(CCCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O

Procedure:
With 1.30 g of diphenylmethyl 4-(2,3-dioxopiperazin-1-yl)butyrate was reacted 0.63 ml of tert-butyl bromoacetate by the same method as in Reference Example 12 to obtain 1.48 g of diphenylmethyl 4-(4-tert-butoxycarbonylmethyl-2,3-dioxopiperazin-1-yl)butyrate as a yellow oil.