Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]([OH:25])=[O:24])=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27].[C:32](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]([O:25][CH3:32])=[O:24])=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (5 drops) was added to a suspension of 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (12.5 g, 27.6 mmol) in dichloromethane (120 mL). Oxalyl chloride (3.62 mL, 41.4 mmol) was added slowly. The mixture was stirred at room temperature for 1 h. Methanol (30 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to provide methyl 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 468.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:23]=[N:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:56]([O:58][C:59](=[O:63])[CH2:60][CH2:61][NH2:62])[CH3:57].C(N(CC)CC)C>ClCCl>[CH2:56]([O:58][C:59](=[O:63])[CH2:60][CH2:61][NH:62][C:28]([C:25]1[N:26]=[CH:27][C:22]([NH:21][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:23][N:24]=1)=[O:29])[CH3:57]
Reactant: CCOC(=O)CCN
Reactant: CC(C)CC(Nc1cnc(C(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.5 %

Procedure:
(+/−)-5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid (636 mg, theoretical 596 mg, 1.39 mmol) was combined with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (399 mg, 2.08 mmol), 1-hydroxybenzotriazole hydrate (319 mg, 2.08 mmol), and anhydrous dichloromethane (10 mL). Beta-alanine ethyl ester hydrochloride (256 mg, 1.67 mmol) was added followed by triethylamine (0.386 mL, 2.78 mmol). This was stirred at room temperature as a solution for 17 h before the reaction was partitioned between ethyl acetate and sat. NH4Cl. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptanes followed by methanol/ethyl acetate) gave impure material. The residue was partitioned between ethyl acetate and sat. NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4 and concentrated in vacuo to give (+/−)-3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester (0.687 g, 94%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 8.17 (t, J=6.2 Hz, 1H) 8.09 (s, 2H) 7.62-7.73 (m, 4H) 7.56 (d, J=8.2 Hz, 2H) 7.40 (d, J=8.2 Hz, 2H) 4.53-4.58 (m, 1H) 4.44-4.52 (m, 1H) 4.11-4.19 (m, 2H) 3.72 (q, J=6.2 Hz, 2H) 2.61 (t, J=6.0 Hz, 2H) 1.66-1.87 (m, 3H) 1.21-1.29 (m, 3H) 1.04 (d, J=6.0 Hz, 3H) 0.99 (d, J=5.9 Hz, 3H); MS (M+1): 529.7.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[O:5].[CH2:13]([Mg]Br)[CH3:14].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:11][C:7]1[N:8]=[CH:9][O:10][C:6]=1[C:4](=[O:5])[CH2:13][CH3:14]
Reactant: CON(C)C(=O)c1ocnc1C
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1ocnc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (5 g) in dry tetrahydrofuran at -40° C. was stirred under a nitrogen atmosphere and ethylmagnesium bromide (1M solution in tetrahydrofuran, 35 ml) was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature and then stirred for a further 1 hour. Aqueous sodium hydrogen carbonate was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The material thus obtained was purified by flash chromatography to yield a pale yellow liquid which solidified on cooling.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:24]([CH2:23][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: ICOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1nonc1-c1nc2ccccc2n1COc1ccccc1

Procedure:
To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g, 0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) and iodomethoxy benzene (0.128 g, 0.546 mmol). The mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue between water and ethyl acetate followed by drying of the organic solution over sodium sulphate and chromatography of the residue gives the title compound as a colorless solid, m.p. 171-173° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](Br)[CH3:32])[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH:31]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:10])=[CH:12]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(Br)c1cccc(Br)n1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(C(C)c3cccc(Br)n3)c3ccccc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 55 mg (0.20 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 10 mg (0.26 mmol) of 60% sodium hydride, 68 mg (0.26 mmol) of 2-bromo-6-(1-bromo-ethyl)-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 24 mg of a white solid: LC-MSD, m/z for C24H20BrN3O2 [M+H]+=462.0, 464.0; HPLC retention time: 1.4 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[N:4]=1)=[O:20])(=[O:17])=[O:16]
Reactant: Cc1cn(C)cn1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cn(C)c(C(=O)NS(=O)(=O)c2ccccc2Cl)n1
Yield: 37.1 %

Procedure:
2.0 g of 1,4-dimethylimidazole and 4.3 g of 2-chlorophenylsulfonyl isocyanate in 200 ml of toluene are refluxed for 6 h. The precipitate which forms on cooling is filtered off with suction and washed with acetone. The residue is suspended in acetonitrile/methanol and refluxed for 0.5 h. After cooling, the solid is filtered off with suction and dried under reduced pressure. 2.3 g of N-(2-chlorophenylsulfonyl)-1,4-dimethylimidazole-2-carboxamide with a melting point of 230°-231° C. are obtained. (Active ingredient Example No. 113).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:17][CH:16]([CH2:18][NH:19][C:20](=O)[CH3:21])[O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:17][CH:16]([CH2:18][NH:19][C:20](=[S:32])[CH3:21])[O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: CC(=O)NCC1CC(c2ccc(-n3cccc3)c(F)c2)=NO1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NCC1CC(c2ccc(-n3cccc3)c(F)c2)=NO1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(pyrrol-1-yl)phenyll)isoxazoline (Example 12) (452 mg) is combined with Lawesson's Reagent (655 mg) in 5 ml dioxane in a 25 ml one neck round bottom flask under nitrogen. The reaction is warmed to reflux for 30 minutes and is cooled to room temperature. The insoluble material is removed by filtration and the filtrate is concentrated in vacuo to an amber syrup. The crude material is chromatographed two times over 25 g silica gel (230-400 mesh), eluting with 3% methanol/dichloromethane while collecting 5 ml fractions. Fractions 10-30 are combined and concentrated to provide 345 mg of the title compound as an off-white solid, mp 152-153° C., [α]25D -27 (c 0.60, ethanol).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:11](=[O:12])[C:10]([CH:13](O)[C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]([CH3:19])[C:7]=1[CH3:20].C(#N)C.CO>ClCCl>[ClH:3].[Cl:3][CH:13]([C:10]1[C:11](=[O:12])[C:6]([OH:5])=[C:7]([CH3:20])[N:8]([CH3:19])[CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1c(O)c(=O)c(C(O)C(F)(F)F)cn1C
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(O)c(=O)c(C(Cl)C(F)(F)F)cn1C
Product: Cl
Yield: 78 %

Procedure:
Thionyl chloride (7.5 mL, 102.7 mmol) was added dropwise to a suspension of 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (3.00 g, 12.7 mmol) and acetonitrile (110 mL) with external cooling using a tap water bath under a blanket of nitrogen. The progress of the reaction was monitored by TLC (eluant: methanol:dichloromethane, 1:10, v:v). After the addition of SOCl2, a clear solution resulted, and white solid gradually formed upon further stirring. The reaction mixture was concentrated repeatedly in acetonitrile to give a solid, which was then collected and washed with acetonitrile (15 mL×2). Thus, 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride, was obtained as a white solid (2.89 g). Yield=78%; 1H NMR (DMSO-D6) δ (ppm): 8.17 (s, 1H), 6.19 (q, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.35 (s, 3H). (c) A mixture of 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (395 mg, 1.4 mmol) and acetonitrile (30 mL) was added to a 40 wt % dimethylamine in water (3.5 mL, 27.7 mmol). The resulting yellowish solution was stirred vigorously, and the progress of the reaction was monitored by TLC (eluant: methanol/dichloromethane, 1/10, v/v). The starting material was completely consumed within 5 min. The reaction mixture was concentrated to give a solid. The solid was dissolved in dichloromethane (30 mL), which was then washed with a 10% ammonium chloride solution (15 mL×2). The organic phase was dried over sodium sulfate, filtered, and concentrated to give 5-[1-(dimethylamino)-2,2,2-trifluoroethyl]-3-hydroxy-1,2-dimethylpyridin-4(1H)-one (Apo7053) as a solid product (200 mg). Yield=56%; HPLC Method 1, RT=10.2 min, HPLC purity (AUC): 98.3% at 280 nm); 1H NMR (DMSO-D6) δ (ppm): 7.68 (s, 1H), 4.86 (q, J=10.1 Hz, 1H), 3.73 (s, 3H), 2.29 (s, 3H), 2.23 (s, 6H). MS-ESI m/z 265 [M+1]+, 220 (100%), 192.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)CCO2
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)CCO2
Yield: 64.9 %

Procedure:
Similarly, (2-fluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))-pyrazin-2-yl]carboxamide (167) (6.8 mg, yield: 64.9%, purity>95%) was prepared from 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (165) (7.5 mg, 0.03 mmol) and 2-fluorobenzoyl chloride (11 μl).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[C:30](O)[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][O:24][C:30]3[CH:29]=[CH:28][C:27]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:26]([F:25])[CH:31]=3)=[CH:21][CH:22]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3-c3ccccc3)cc2)cc1F
Temperature: 25 °C

Procedure:
To a mixture of {4-[(3-tert-butyl-5-phenyl-1H-pyrazol-1-yl)methyl]phenyl}methanol (320 mg, 1.0 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (212 mg, 1.0 mmol), triphenylphosphine (262 mg, 1.0 mmol) and dichloromethane (5 mL) added dropwise diethyl azodicarboxylate (40% toluene solution, 435 mg, 1.0 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 1.37 (9H, s), 2.58 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=7.6 Hz), 4.12 (2H, q, J=7.2 Hz), 4.97 (2H, s), 5.32 (2H, s), 6.20 (1H, s), 6.60-6.70 (2H, m), 7.02 (2H, d, J=8.1 Hz), 7.09 (1H, t, J=8.8 Hz), 7.25-7.40 (7H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[Li]CCCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1c(F)cccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(Cl)ccc(C=O)c1F
Temperature: -49 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a solution of 2-chloro-6-fluoroanisole (321.2 g) in 2 L of dry tetrahydrofuran (THF), cooled to −70° C., was added 890 mL of 2.5 M n-BuLi in hexane over 30 min with good mechanical stirring. During the addition the reaction warmed to −48 to −50° C. and was held there for 15 min after addition was complete. The solution was cooled to −75° C. before a solution of 177 g of dimethylformamide (DMF) in 100 mL of THF was added keeping the temperature below −50° C. The reaction was warmed to room temperature and 260 g of 37% aqueous HCl was slowly added and stirring was continued for 2 hours. The phases were separated and the organic phase concentrated and taken into 2 L of ether. The solution was washed twice with 500 mL of aqueous 10% HCl. The organic phase was dried over MgSO4, filtered and concentrated to 372 g of a light gold oil (93% pure by GC). This oil was distilled bulb to bulb to give 282 g (75% yield) of a light gold oil that solidified upon standing. A small sample was crystallized from pentane to give fine white needles; MP 44-45° C.; 1H NMR (CDCl3, 300 MHz) δ 10.3 (s, 1H); 7.5 (dd, 1H, J=6.6, 8.5 Hz); 7.3 (m, 1H); 4.0 (s, 3H).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[OH:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:34])[CH:29]=[CH:28]2>CC#N.O.C(Cl)Cl>[O:4]=[C:26]1[CH:25]=[CH:24][C:23](=[O:22])[C:32]2[N:31]=[C:30]([C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:34])[CH:29]=[CH:28][C:27]1=2
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCCCCCCCOC(=O)c1ccc2cccc(O)c2n1
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1ccc2c(n1)C(=O)C=CC2=O
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a stirred solution of [bis(trifluoroacetoxy)iodo]benzene (PIFA) (258 mg, 0.6 mmol) in MeCN/water 2:1 (3 ml) at 0° C. was added octyl 8-hydroxyquinoline-2-carboxylate (71 mg, 0.24 mmol) in CH2Cl2 (1 ml). The solution was stirred for 20 min, poured into CH2Cl2 (20 mL), washed with water and dried in vacuo to give octyl 5,8-dioxo-5,8-dihydroquinoline-2-carboxylate (69 mg, 90%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41](=[O:50])[CH2:42][N:43]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:39]>>[CH2:38]([O:40][C:41](=[O:50])[CH2:42][N:43]1[CH2:49][CH2:48][CH2:47][N:46]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:45][CH2:44]1)[CH3:39]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCOC(=O)CN1CCCNCC1
Product: CCOC(=O)CN1CCCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with homopiperazine-acetic acid ethyl ester to give 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-1-yl}-acetic acid ethyl ester. The ester was hydrolyzed, then the corresponding acid was treated with amonium chloride to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2927.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH:14]([OH:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
A mixture of N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.2 g, 2.81 mmol), pyridium chlorochromate (1.21 g, 5.63 mmol) and celite (0.6 g) in methylene chloride (35 mL) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the celite washed with methylene chloride. The filtrate was washed with water, brine, dried, and concentrated. The residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 9:1) to yield N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (0.9 g, 76%); mp 128-129° C.; 1H NMR (CDCl3) δ9.52 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.06-7.03 (m, 2H), 6.82 (d, J=8.9 Hz, 1H), 5.73-5.07 (dd, J=5.2 and 10.0 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 4.04-3.93 (dd, J=10.0 and 18.0 Hz, 1H), 3.83 (s, 3H), 3.28-3.19 (dd, J=5.2 and 18.0 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.46 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) δ205.18, 170.62, 169.17, 167.10, 149.21, 148.40, 137.38, 135.81, 131.34, 131.24, 124.69, 120.02, 117.91, 115.30, 112.57, 111.37, 64.44, 55.93, 49.96, 44.82, 30.14, 24.93, 14.73; Anal. Calcd. For C23H24N2O6: C, 65.08; H, 5.70; N, 6.60. Found: C, 65.11; H, 5.64; N, 6.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31]CCC.N1CCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]2[CH2:31][CH2:30][CH2:20]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCCCS(=O)(=O)Cl
Agent: C1CNC1
Product: C[C@H](CCCS(=O)(=O)N1CCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 24 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(1-azetidinyl)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with azetidine. Yield=24%; MS (ESI+), 526 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CS(C)=O.CCOC(C)=O>[C:10]([C:9]1[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)#[N:11]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(F)(F)F)cc1N1CCNCC1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of piperazine (13.7 g, 159 mmol) in 20 mL DMSO was added 2-fluoro-4-trifluoromethylbenzonitrile (10 g, 52.9 mmol). After stirring overnight, the solution was diluted with 200 mL of EtOAc, washed with water and brine, and then dried (Na2SO4), filtered and concentrated to afford about 13.0 g (51.1 mmol, 96%) of 4-(2-cyano-5-trifluoromethyl-phenyl)piperazine. LRMS (ESI+): 256.1 [M+1]. The tide compound was prepared from 4-(2-cyano-5-trifluoromethyl-phenyl)piperazine in the same manner as described in Preparation 67A except that dimethyl amine was used to displace the mesylate. LRMS (ESI+): 388.1 [M+1]
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH:47]12[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:55][CH:49]([CH2:50]3)[CH:48]1[CH2:57][OH:58])[CH2:54]2>>[CH:47]12[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:55][CH:49]([CH2:50]3)[CH:48]1[CH2:57][O:58][C:19]1[C:18]([Cl:17])=[CH:32][C:22]([C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24])=[C:21]([F:33])[CH:20]=1)[CH2:54]2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1C2CC3CC(C2)CC1C3
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with adamantan-2-ylmethanol (J. Am. Chem. Soc. 2012, 134(2), 675), the title compound was obtained as a colorless solid (0.14 g, 27%): 1H NMR (300 MHz, CDCl3) δ 8.75-8.57 (m, 1H), 8.13-8.03 (m, 1H), 6.82-6.67 (m, 1H), 4.23-4.03 (m, 2H), 3.03 (s, 6H), 2.37-2.27 (m, 1H), 2.04-1.73 (m, 11H), 1.69-1.54 (m, 3H); MS (ES−) m/z 443.2 (M−1), 445.2 (M−1);