Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]#[N:32])[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]S(C)(=O)=O.[H-].[Na+].[C:35]([O:38][CH2:39]C)(=O)[CH3:36]>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][O:23][CH2:36][CH2:35][O:38][CH3:39])[CH:28]=[CH:29][C:30]=1[C:31]#[N:32]
Reactant: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Product: COCCOCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
120 mg Methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester were dissolved in 5 ml 2-methoxyethanol. 10.0 mg sodium hydride were added and the mixture stirred at 50° C. for one hour. The reaction mixture was diluted by addition of 50 ml ethyl acetate, washed with brine then dried over MgSO4. The solvent was removed in vacuo and the residue purified by RP-HPLC to provide 30 mg of 2-Chloro-4-[4-(2-methoxy-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as lyophilisate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[CH2:18]OS(C(F)(F)F)(=O)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:18][C:17]([F:28])([F:27])[F:16]
Reactant: Oc1ccc(F)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To 2-chloro-4-fluorophenol (52, 1.58 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL), cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (124, 2.10 g, 85.3%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([O:9][C:10]([NH:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:11])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[CH:6]([O:9][C:10]([NH:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3](=[O:4])[CH2:2][Br:1])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:11])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Nc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1

Procedure:
Bromoacetyl bromide (18.6 g) was added dropwise with stirring to a solution of 4-isopropoxycarbonylamino-2-nitroaniline (22g) in toluene (300 ml). The solution was refluxed for 1 hour, cooled, and the solid filtered off and recrystallised from benzene to give N-(4-isopropoxycarbonylamino-2-nitrophenyl)-2-bromoacetamide (20 g), m.p. 195°-197° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].N1CC[CH2:22][CH2:21]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]1[CH2:18][CH2:22][CH2:21][CH2:19]1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CN(C)C)C2=O
Reactant: C1CCNC1
Product: CC(=O)Nc1ccc2c(c1)CCC(=CN1CCCC1)C2=O

Procedure:
6-Acetylamino-2-[(dimethylamino)methylidene]-1-tetralone (4.90 g, 0.017 mol) obtained in Example 41-1) was suspended in pyrrolidine (25 ml), which was refluxed with heating for 2 hours. The crystallized product was collected by filtration, washed with a mixed solution of ethyl acetate and n-hexane (1:1), to give 6-acetylamino-2-(1-pyrrolidinylmethylidene)-1-tetralone (5.03 g) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])=[CH:3][C:4]=1[CH3:12]
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a mixture of methyl 4-amino-2-methylbenzoate (208.9 mg, 1.230 mmol) in N,N-dimethyl formamide (5 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 215 mg, 1.29 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-[(Imidazole-1-carbonyl)-amino]-2-methyl-benzoic acid methyl ester (342.0 mg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][N:16]([C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](O)=O)=[CH:20][CH:19]=1)[CH3:17]>>[CH3:15][N:16]([C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: CN(C)c1ccc(C=CC(=O)O)cc1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(N(C)C)cc3)nc2n(CC)c1=O
Yield: 52.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.30 g (17.3 mmol) of 4-(N,N-dimethylamino)cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.78 g (yield 52%) of Compound 162 as yellow needles.
Reaction SMILES: [N+](=[CH2:3])=[N-].C(OCC)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][C@H:21]([CH2:23][C@H:24]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH2:25][CH3:26])[NH:20][CH2:19][C@@H:18]2[O:32][CH:33]([C:44]2[CH:45]=[CH:46][C:47]3[O:52][CH2:51][CH2:50][N:49]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:48]=3[CH:58]=2)[S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Mg+2].[N+](=C)=[N-]>CO>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][C@H:21]([CH2:23][C@H:24]([C:27]3[N:28]([CH3:3])[N:29]=[N:30][N:31]=3)[CH2:25][CH3:26])[NH:20][CH2:19][C@@H:18]2[O:32][CH:33]([C:44]2[CH:45]=[CH:46][C:47]3[O:52][CH2:51][CH2:50][N:49]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:48]=3[CH:58]=2)[S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])=[CH:13][CH:12]=1
Reactant: C=[N+]=[N-]
Reactant: CC[C@H](C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OC(c2ccc3c(c2)N(CCCOC)CCO3)S(=O)(=O)c2ccc(C)cc2)CN1)c1nnn[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CO
Product: CC[C@H](C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OC(c2ccc3c(c2)N(CCCOC)CCO3)S(=O)(=O)c2ccc(C)cc2)CN1)c1nnnn1C
Reaction time: 2.5 h

Procedure:
A freshly prepared solution of diazomethane/diethylether (from Diazald®) is added dropwise to a solution of 0.201 g of 6-[(3R,4R,6S)-4-(4-methoxy-phenyl)-6-[(R)-2-(1H-tetrazol-5-yl)-butyl]-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine (from example 64a) in 8 ml of methanol at 0° C. After 2.5 hours, solid magnesium sulfate is added to decompose any excess diazomethane and then the reaction mixture is concentrated. The resulting residue is suspended in dichloromethane, filtered and re-concentrated. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound together with its N-methylated regioisomer.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH2:14][CH3:15])[CH2:12]O>>[CH3:10][CH:11]([CH2:14][CH3:15])[CH2:12][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH:11]([CH3:12])[CH2:14][CH3:15])=[O:6])[OH:3]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CCC(C)CO
Product: CCC(C)COC(=O)CC(O)C(=O)OCC(C)CC
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Di(2-methylbutyl)-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (100.56 g), 2-methyl-1-butanol (325 mL) and Amberlyst®15 ion exchange resin (15.1 g) were added. The mixture was placed under nitrogen and heated to reflux. At 108° C., two phases started to collect in the Dean-Stark trap. After 1.5 hr, the reaction temperature was increased to 115° C. for 20 minutes and 120° C. for 20 minutes. Once water ceased to collect in the Dean-Stark trap, the product was diluted with diethyl ether, collected via filtration over a short bed of silica, washed 4 times with saturated sodium bicarbonate, once with water and dried over magnesium sulfate. The diethyl ether was removed via rotary evaporation. Di-(2-methylbutyl)-DL-malate was obtained as a low viscosity, clear, very light yellow liquid with no detectable odor (139.8 g, 68% yield) after removing residual 2-methyl-1-butanol via vacuum distillation.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[O:5][C:4](=[O:12])[NH:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>CN(C=O)C>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:20]([N:3]2[C@@H:2]([CH3:1])[C@H:6]([C:7]3[S:8][CH:9]=[CH:10][N:11]=3)[O:5][C:4]2=[O:12])[CH:21]=1
Reactant: C[C@@H]1NC(=O)O[C@H]1c1nccs1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](c2nccs2)OC(=O)N1c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
(4S,5R)-4-Methyl-5-thiazol-2-yl-oxazolidin-2-one (4.70 g, 20.1 mmol) was dissolved in 70 mL of DMF and cooled to 0° C. NaH (964 mg, 60% in oil, 24.1 mmol) was added under argon, and the reaction mixture was stirred for 30 minutes at 0° C. 4-(4,6-dichloropyrimidin-2-yl)morpholine (3.70 g, 20.1 mmol) dissolved in 30 mL of DMF was added, and the reaction mixture was stirred for 3 hours at 0° C., followed by stirring at RT for 2 hours. The reaction was then quenched by addition of aqueous NH4Cl, followed by dilution with EtOAc; the organic solvents were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (80 g SiO2) using EtOAc in hexane from 0% to 100% in order to give the title compound (3.64 g, 48%). LC-MS: [M+H] 382.2, 384.1; Rt 1.10 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.77 (d, 1H), 7.38-7.33 (m, 2H), 5.39 (d, 1H), 5.07-4.98 (m, 1H), 3.75-3.55 (m, 8H), 1.64 (d, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:30][N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)cn2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate 21) and tert-butyl-4-((5-bromopyridin-2-yl)oxy)piperidine-1-carboxylate (intermediate 65) (0.610 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N:23]1([C:29]([CH2:31][CH2:32][C:33](O)=[O:34])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:23]1([C:29]([CH2:31][CH2:32][C:33]([O:8][C:7]2[CH:6]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]3=[O:21])[C:4]([F:22])=[CH:3][C:2]=2[Cl:1])=[O:34])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)CCC(=O)N1CCCCC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)CCC(=O)N3CCCCC3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 3-[piperidino(carbonyl)]-propionic acid with N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine as the catalyst in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenyl 3-[piperidino(carbonyl)]propionate. 1H-NMR (CDC3, 400 MHz): 7.35 ppm (d,1H), 7.20 ppm (d,1H), 6.36 ppm (s,1H), 3.50-3.60 ppm (m,5H), 3.42 ppm (t,2H). 2.94 ppm (t,2H), 2.74 ppm (t,2H), 1.49°-1.70 ppm (m.6H);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a solution of pyridine-3-boronic acid (515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was heated under reflux for 90 min. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the catalyst. The filtrate was partitioned between water and methylene chloride, and the layers were separated. The aqueous layer was further extracted with methylene chloride (75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester (800 mg, 92%) as a brown oil: EI-HRMS m/e calcd for C20H23NO2 (M+) 309.1729, found 309.1728.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][C:20]=1[CH3:21].O>CN1CCCC1=O>[N+:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[CH:8]=2)=[CH:16][C:17]=1[CH3:25])([O-:24])=[O:23]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.4 g of 60% in oil) in dry N-methylpyrrolidinone (10 ml) was slowly added 3-tert-butylphenol (1.62 g). When effervescence had ceased, 3-chloro-6-nitro-p-xylene (1.85 g) was added and the mixture stirred at 120-40° C. for 5 hours. On cooling, the mixture was poured into water and the mixture extracted with diethyl ether (×3). The combined ether extracts were dried over magnesium sulphate, filtered and evaporated to give the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:4]1[C:5]([O:7]C(C)(C)C)=[O:6])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:3]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:4]1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,1-Dimethylethyl 1-ethyl-5-oxo-prolinate (0.965 g) was dissolved in dichloromethane (˜5 ml) and treated with trifluoroacetic acid (1 ml). The mixture was stirred at room temperature for 1.5 hrs and then evaporated. The resulting material was mostly starting material so a further amount of trifluoroacetic acid (1 ml) and dichloromethane (˜5 ml) was added and the mixture stirred at room temperature for 36 hrs. The mixture was evaporated and then toluene was added to the residue and this was in turn also evaporated. After repeating this process once more, crude 1-ethyl-5-oxo-proline was obtained as a dark yellow oil which was used without additional purification.
Reaction SMILES: [CH2:1]([C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[C:4]1=[O:16])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[C:4]1=[O:16])[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCNC(N)=O)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCN(CCNC(N)=O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {2-[3-ethyl-3-(3-methoxy-phenyl)-2-oxo-azepan-1-yl]-ethyl}-urea (as described above in Step B) (0.14 g, 0.421 mmol) in CH2Cl2 (10 mL) at −78° C. was added BBr3 (1M, 0.842 mL, 0.842 rnmol). After stirring for 1 hr at 25° C. the reaction was quenched with H2O and partitioned with EtOAc and 10% HCl. The organic layer was washed with brine and dried (MgSO4), and the solvent removed in vacuo to obtain the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:12][C:11]3[CH:10]=[N:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:15][CH:14]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccccc4)nc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 6-phenoxynicotinaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 430.1 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][C:22](=[O:38])[N:23]2[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37].CI.Cl[C:42]1C=CC=CC=1C1C=C(O)C=C2C=1C=CC(=O)N2C1C(Cl)=CC=CC=1Cl>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[CH2:20][CH:21]([CH3:42])[C:22](=[O:38])[N:23]2[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(O)cc2n1-c1c(Cl)cccc1Cl
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)C(C)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 1 mL of THF at −78° C. was added 130 μL of a 1M solution of lithium bis(trimethylsilyl)amide in THF, then a solution of 50 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxyquinolin-2(1H)-one (INTERMEDIATE 6) in 2 mL of THF dropwise. The mixture was stirred for 30 min at −78° C.; then 57 mg of methyl iodide was added dropwise. The mixture was stirred 10 min at −78° C., then removed from the bath and allowed to warm to rt. The reaction was quenched by addition of 100 μL of MeOH, then poured into 10 mL of water and extracted with 2×10 mL of CH2Cl2. The combined organics were washed with 10 mL of brine, dried (MgSO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-acetone, to yield a 1:1.5 mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxyquinolin-2(1H)-one and the title compound. Mass spectrum (ESI) 446 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@@H:13]([C:16]1[CH:17]=[C:18]([CH:24](CC)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[C:20]([F:23])[C:21]=1[F:22])[CH2:14][OH:15]>N1C=CC=CC=1>[F:23][C:20]1[CH:19]=[C:18]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=[C:16]([C@H:13]([OH:12])[CH2:14][O:15][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:21]=1[F:22]
Reactant: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H](O)CO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: -15 °C
Yield: 79.7 %

Procedure:
p-Toluenesulfonyl chloride (9.03 g, 0.0474 mol) in pyridine (25 mL) was added dropwise to a cooled (−15° C.) solution of ethyl 3-{3-[(1S)-1,2-dihydroxyethyl]-4,5-difluorophenyl}pentanoate (13.02 g, 0.043 mol) in pyridine (50 mL) under N2. The reaction was stirred at −15° C. and warmed to RT overnight. The reaction mixture was quenched with H2O and extracted three times with ethyl ether. The combined ether layers were washed with 1N HCl, sat. CuSO4, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (hexane:ethylacetate, 0-30%) yielded the desired product (14.68 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cc(C)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 5 1) and 2-bromoacetyl4-methylpyridine hydrobromide (F. H. Case et al., J. Am. Chem. Soc., 1956, 78, 5842).