Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to that found in Example 13, Step 1, except that 4-fluorobenzyl bromide was used in place of iodomethane. Purification was achieved by flash column chromatography on silica gel using a gradient elution of 0-6% MeOH/CH2Cl2, and collection and concentration of appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (d, 2H), 7.38-7.29 (m, 5H), 7.08-7.03 (m, 2H), 5.40 (s, 2H), 4.74 (s, 2H), 4.33-4.30 (t, 2H), 3.93 (s, 3H), 3.63-3.59 (t, 2H); ES MS (M+1)=410.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)Cl
Reactant: O=C1NC(Cc2ccccc2)CO1
Product: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
Using the procedure of Example 100A but replacing 4-(2-propyl)-oxazolidine-2-one with 4-benzyloxazolidine-2-one and replacing 4-methylpentanoyl chloride with isovaleryl chloride provided the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>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>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[C:24]([F:26])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCNC(=O)c1nnc2c(-c3cc(F)cc(F)c3)cccc2c1N
Yield: 89.9 %

Procedure:
Using method B, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (200 mg, 0.65 mmol), 3,5-difluorophenyl boronic acid (300 mg, 1.90 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.034 mmol) were reacted to afford the title compound (200 mg, 89.7% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.92 (dd, J=8.1, Hz, J′=1.4 Hz, 1H), 7.67-7.82 (m, 2H), 7.22 (m, 2H), 6.88 (m, 1H), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=343 (M+H). HPLC 2.14 min.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)[N:12]=[C:11]([N:31]3[CH2:36][CH2:35][CH:34]([NH:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:33][CH2:32]3)[N:10]=1)[CH2:2]2.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)=[O:23])=[CH:19][CH:20]=3)[N:12]=[C:11]([N:31]3[CH2:36][CH2:35][CH:34]([NH:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:33][CH2:32]3)[N:10]=1)[CH2:2]2.[C:48]([OH:50])([C:47]([F:52])([F:51])[F:46])=[O:49]
Reactant: CC(C)(C)OC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate (28 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1 mL) and then concentrated to dryness to give the title compound as its TFA salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:35]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)NC1=O
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of (R)-1-((5)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.6 g, 1.45 mmol) in CH2Cl2 (15 mL) was added to m-CPBA (0.59 g, 2.9 mmol). The resulting solution was stirred overnight. The mixture was diluted with methyl tert-butyl ether (100 mL) and washed with 30 wt % aq sodium thiosulfate (3×50 mL) and saturated aqueous sodium bicarbonate (3×50 mL). The organic layer was dried over Na2SO4, filtered and then concentrated to afford (4S)-1-((S)-1-(4-bromophenyl)ethyl)-4-((2-methyloxiran-2-yl)methyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.61 g, Yield: 98%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:27]([F:30])([F:29])[F:28])=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:27]([F:30])([F:28])[F:29])=[N:10]2)=[CH:5][CH:4]=1)=[O:39]
Reactant: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reaction time: 18 h
Yield: 79.9 %

Procedure:
A mixture of N-(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea (250 mg) and mCPBA (326 mg) in CH2Cl2 (10 ml) was stirred for 18 hrs. sat. NaHCO3 and CH2Cl2 was added. Aqueous layer was separated and extracted. The combined organic layer was washed with sat. NaHCO3 (twice), dried and evaporated to give 207 mg (79.9%) of crude product. The crude product was column chromatographed by preparative TLC to give 207 mg (80%) of N-(2-{4-[1-[4-(methylsulfinyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea as an amorphous.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C[O-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>CO.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)[N:16]=1
Reactant: SC1=NCCS1
Reactant: COc1cc(CCl)nc(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(CSC2=NCCS2)nc(N)n1
Reaction time: 1 h

Procedure:
11.9 g of 4,5-dihydro-2-mercapto-thiazole are suspended in 100 ml of methanol, and to the suspension are added 18.0 g of 30% methanolic sodium methylate solution. To the formed clear solution are subsequently added 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and refluxing is carried out for 1 hour. After the solution has cooled, it is diluted with about 1 litre of water, and the product which precipitates is separated and dried. The yield is 22.5 g (88% of theory) of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl-thiomethyl)-pyrimidine, m.p. 122°-124° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[CH2:8]([O:10][C:11]([C:13]#[C:14][C:15](OCC)=[O:16])=[O:12])[CH3:9]>C(O)C>[CH2:8]([O:10][C:11]([C:13]1[N:6]2[CH:5]=[C:4]([CH3:7])[S:3][C:2]2=[N:1][C:15](=[O:16])[CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Cc1cnc(N)s1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(C)cn12
Reaction time: 72 h

Procedure:
A mixture of 3.4 g 2-amino-5-methylthiazole, 70 ml of ethanol and 5.1 g of acetylene dicarboxylic acid diethyl ester is left standing for 3 days. The solution is evaporated to dryness and the residue is triturated with ethyl acetate, crystallization occurring. The product is filtered off under suction, washed with ether and dried. The 2-methyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained in a yield of 4.5 g (63% of the theoretical) melts at 119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(N2CCOCC2)cc1N
Solvent: CC(C)=O
Product: COc1ccc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-5-morpholin-4-yl-phenylamine (4.6 g, 22 mmol) in acetone (140 ml) is added a solution of benzoyl isothiocyanate (3.4 ml, 25 mmol) in acetone (80 ml) and the reaction mixture is stirred for further 30 min at ambient temperature. After removal of the volatile components in vacuo, the product is isolated by flash chromatography (silica, eluent ethyl acetate/n-hexane 1:4, then 1:2) as a yellow solid (8.0 g, 97%). MS: m/e=272 (M+).
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([Br:13])=[CH:4][CH:3]=1.N([O-])=[O:15].[Na+].OS(O)(=O)=O>O>[Br:13][C:5]1[C:6]([CH3:12])=[C:7]([C:2]([OH:15])=[CH:3][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(N)ccc(Br)c1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(O)ccc(Br)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
A 0° C. suspension of Example 106A (1 g, 4.1 mmol) in water (6 mL) was treated dropwise with a solution of NaNO2 (285 mg) in water (1.25 mL), stirred at 0° C. for 15 minutes, then added slowly to a 90° C. solution of concentrated H2SO4 (4 mL) in water (4 mL). The reaction was stirred at 90° C. for 45 minutes, cooled to room temperature, and extracted three times with diethyl ether. The combined extracts were washed with aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to give 0.87 g of the desired product. MS (ESI(−)) m/e 226 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:28]([O:37]C(OC(C)(C)C)=O)[C:27]([C:45]([F:48])([F:47])[F:46])=[CH:26][CH:25]=1>>[C:33]([O:32][C:30]([C:29]1[C:28]([OH:37])=[C:27]([C:45]([F:46])([F:47])[F:48])[CH:26]=[CH:25][C:24]=1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3[N+](=O)[O-])cc2)ccc(C(F)(F)F)c1O
Yield: 7 %

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from methyl (4′-hydroxy-2-nitro-1,1′-biphenyl-4-yl)acetate (1.71 g, 3.76 mmol) obtained in Example (37-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (1.08 g, 3.76 mmol) obtained in Example (28-5), the title compound was obtained as a yellow oil (138 mg, three-step total yield: 7%).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[CH:6](Cl)[Cl:7])[CH:2]=[CH2:3].COCCOCCOC.C(Cl)[Cl:23]>>[CH2:1]([N:4]1[CH2:10][CH:11]([CH2:12][Cl:23])[CH:6]([Cl:7])[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)C(=O)C(Cl)Cl
Reactant: ClCCl
Solvent: COCCOCCOC
Product: C=CCN1CC(CCl)C(Cl)C1=O
Reaction time: 0.5 h

Procedure:
Twenty and eight-tenths grams of N,N-diallyl dichloroacetamide was mixed with 25 g. of diethylene glycol dimethyl ether (diglyme), 1 g. of ferrous chloride (FeCl2.4H2O) added and the mixture was heated at reflux for 30 minutes. The conversion was monitored by the appearance of a new carbonyl peak at ~5.8 microns in the infrared. An additional gram of ferrous chloride (FeCl2.4H2O) was added and heating was continued for an additional 30 minutes. The reaction mixture was diluted with methylene chloride, washed with water and dried and stripped. The dark liquid product was distilled under vacuum to give 8.4 g. of light yellow oil, b.p. 124°-127° C. at 0.25 mm. nD30 1.4850.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[I:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[N:11]=[C:10]2[I:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
In a round-bottomed flask, 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1H-indazole (1.65 g, 4.41 mmol) was dissolved in THF (16 ml). The solution was cooled to 0° C. and potassium tert-butoxide (697 mg, 6.22 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then methyl iodide (0.38 ml, 6.08 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-10% EtOAc) to give 770 mg (45%) of 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1-methyl-1H-indazole as a light yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].[CH3:15]I>O>[CH3:15][S:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: O=c1[nH]c(S)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 2-mercaptoquinazolin-4(3H)-one (4.45 g, 25 mmol) and NaOH (1.1 g, 27.5 mmol) in water (125 mL) was added methyl iodide (1.72 mL, 27.5 mmol) and the mixture was stirred at 25° C. for 3 h. The precipitate was collected by filtration, washed with water (3×20 mL) and dried in vacuum desiccator over silica gel for 24 h to give 3.66 g (73%) of the title compound as colorless solid: mp 224-225° C. An analytical sample was recrystallized from methanol-water: mp 225° C.; 1H NMR (CDCl3) δ 11.25 (br s, 1H, NH), 8.27 (dd, 1H, J=1.25, 6.3 Hz, ArH), 7.62 (d, 1H, J=7.3 Hz), 7.44-7.38 (m, 1H, ArH), 2.70 (s, 3H, SCH3); 13C NMR (CDCl3) δ 163.73, 155.76, 149.77, 135.50, 127.30, 126.96, 126.40, 120.37, 13.97.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCc2ccccc2)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A cooled (0°) suspension of 60% sodium hydride/oil dispersion (7.2 g, 180 mmol) in anhydrous N,N-dimethylformamide (200 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (30.24 g, 150 mmol) so as to keep the pot temperature below 20° C. After one hour at 40° C., the mixture was treated with benzyl bromide (30.8 g, 180 mmol) and heated to 100°±5° C. for one hour, then cooled to room temperature and added to water (600 mL). The aqueous solution was extracted with methylene chloride (3×250 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through a short column of alumina (eluted with methylene chloride). The filtrate was concentrated in vacuo, taken up in a mixture of 50% sodium hydroxide (50 mL), water (50 mL), and ethanol (100 mL), and refluxed for one hour. Most of the ethanol was removed in vacuo and water (400 mL) was added to dissolve all solid. The aqueous solution was extracted with ether (100 mL), then with petroleum ethers (30° C.-60° C., 100 mL), cooled (0° C.), and acidified to pH 3 with concentrated hydrochloric acid (about 90 mL). The resultant precipitate was filtered and the solid was washed with water, air dried, and recrystallized (2 crops) from ethanol to afford 25.51 g (61%) of tan crystals; mp 182°-184° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][C:35]1([CH3:41])[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[N:37]3[CH2:38][CH2:39][CH2:40][C:35]([CH3:41])([CH3:34])[CH2:36]3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1(C)CCCNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1N1CCCC(C)(C)C1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.837 mmol), 3,3-dimethylpiperidine (142.5 mg, 1.26 mmol), Bis(tri-t-butylphosphine)palladium (0) (43 mg, 0.084 mmol), cesium carbonate (685 mg, 2.10 mmol) and 1,4-dioxane (5 mL) were sealed in a microwave vessel. The reaction mixture was irradiated by microwave at 170° C. for 30 minutes. Reaction crude was purified by SiO2 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3,3-dimethylpiperidin-1-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=582.19; found=583.44 (M+1)+. 1H NMR signals are doubled because of atropoisomerism 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.77 (s, 2H), 7.58 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 5.72 (d, J=8.0 Hz, 1H), 4.76 (d, J=16 Hz, 1H), 4.57 (d, J=15.5 Hz, 1H), 3.94-3.87 (m, 1H), 2.84 (br s, 1H), 2.68 (br s, 1H), 2.63 (d, J=11 Hz, 1H), 2.52 (d, J=11 Hz, 1H), 1.81 (br s, 1H), 1.71 (br s, 1H), 1.38 (br s, 2H), 1.06 (s, 3H), 0.99 (s, 3H), 0.67, 0.66 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
6-Bromohexanoyl chloride (16.2 g) was dissolved in methylene chloride (50 ml), and aluminum chloride (10.6 g) was added, which was followed by stirring at room temperature for 30 min. The reaction mixture was ice-cooled, and benzene (5.0 g) was dropwise added, which was followed by stirring for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 18.2 g of 6-bromo-1-phenyl-1-hexanone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 22 (475 mg, 1.06 mmol) is treated with acid chloride 8 (338 mg, 1.27 mmol) using Method D to give the title compound.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([CH2:18][CH2:19][C:20]([F:21])([F:22])[F:23])[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:24])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(CCC(F)(F)F)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(CCC(F)(F)F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 10 %

Procedure:
As described for example 1e, 6-[5-methyl-3-(3,3,3-trifluoro-propyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (215 mg, 0.62 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (26 mg, 10%) which was obtained as a white solid after purification by chromatography (silica, 0 to 60% ethyl acetate in heptane) and trituration with ethyl acetate and hexane. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [C:1]([C:9]1([OH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22]O.OS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][O:16][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:18])=[O:17]
Reactant: O=C(O)C1CCCCC1(O)C(=O)c1ccccc1
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)CCOC(=O)C1CCCCC1(O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
10 g (0.04 mol) of 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid (of example 1), 7.05 mol 3-methyl-butan-1-ol and 0.5 g H2SO4 are dissolved in 200 ml CHCl3 and heated to reflux during 18 hours using a water separator to remove the water formed during the reaction. The reaction mixture is then cooled to room temperature, washed with sodium bicarbonate and water and dried over Mg2SO4. After distillation of the solvent, the crude reaction product is purified by flash chromatography (silica gel, eluant petroleum ether/ethyl acetate 1:1) to give 3 g 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid 3-methyl-butyl ester as a colorless liquid.