Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][O:14][C:15]=2[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].O.ClCCl>O1CCOCC1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:13][O:14][C:15]=2[CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)C(C)c1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C(=O)O)c1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]propanoate from Step 2 (198 mg, 0.495 mmol) and aqueous sodium hydroxide (10%, 0.30 mL) were dissolved in dioxane (15 mL). The solution was heated to reflux and held for 16 hours. Upon cooling to room temperature, water (20 mL) was added, and the solution was extracted with ether (2×30 mL). The combined ethereal solution was extracted with dilute sodium hydroxide (5%, 2×30 mL). All of the aqueous phases were combined and acidified with hydrochloric acid (conc.) to pH<2. The acidic aqueous phase was extracted with ether (2×30 mL). The final ether solution was dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude solid. Trituration with dichloromethane yielded crystals. The suspension was cooled to 0° C., filtered, washed with hexane and dried to yield [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]propanoic acid as a white crystalline solid (135 mg, 73%): mp 207° C. Mass spectrum: MH+=373. Anal. Calc'd. for C18H16N2O5S: C, 58.06; H, 4.33; N, 7.52; S, 8.61. Found: C, 57.87; H, 4.35; N, 7.49; S, 8.54.
Reaction SMILES: O[CH2:2]C(CO)(C(C)C)CS.[OH:11][CH2:12][C:13]([CH2:20][OH:21])([CH:16](C)[CH2:17][CH3:18])[CH2:14][SH:15].CO[C:24](OC)(OC)[C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1>>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]23[S:15][CH2:14][C:13]([CH2:16][CH:17]([CH3:18])[CH3:2])([CH2:12][O:11]2)[CH2:20][O:21]3)=[CH:26][CH:27]=1
Reactant: CC(C)C(CO)(CO)CS
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Reactant: CCC(C)C(CO)(CO)CS
Product: CC(C)CC12COC(c3ccc(Br)cc3)(OC1)SC2

Procedure:
In an analogous manner, from 2,2-di-hydroxymethyl-3-methyl-butan-1-thiol or 2,2-di-hydroxymethyl-3-methyl-pentan-1-thiol and trimethyl 4-bromoorthobenzoate or trimethyl 4-chloro-orthobenzoate or trimethyl orthocyclohexyl-carboxylate the following compounds were prepared:
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:30]=[CH:29][C:13]2[NH:14][C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1.CO.[OH-].[Li+].Cl>CCOC(C)=O.O>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:15]2[NH:14][C:13]3[CH:29]=[CH:30][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:31])=[O:2])=[CH:11][C:12]=3[N:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 90.9 %

Procedure:
To a solution of 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzoic acid methyl ester (0.494 g, 1.16 mmol) in mixed solvent (30 mL, MeOH: H2O=3:1) was added lithium hydroxide (0.166 g, 6.95 mmol). After stirring for 12 hours, the reaction mixture was diluted with EtOAc and acidified by aqueous 3N HCl. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (0.435 g, 91%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[F:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48](OC)=[O:49])=[CH:46][CH:45]=2)[CH2:39][CH2:38]1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[CH:13]=[C:12]([NH:11][C:48](=[O:49])[C:47]3[CH:46]=[CH:45][C:44]([CH2:43][N:40]4[CH2:39][CH2:38][CH:37]([F:36])[CH2:42][CH2:41]4)=[CH:53][CH:52]=3)[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(CN2CCC(F)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN4CCC(F)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.65 ml, 0.65 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (150 mg, 0.43 mmol, 1 eq) and methyl 4-[(4-fluoropiperidin-1-yl)methyl]benzoate (131 mg, 0.52 mmol, 1.2 eq) in THF (0.5 ml). The reaction mixture was stirred at ambient temperature for 1 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 39-49% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (33 mg, 16% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[CH:12]=[C:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]#[N:22])[C:15]=2[CH:23]=1)(=[O:10])[CH3:9].[Br:28]N1C(=O)CCC1=O.C(OCC)(=O)C>O1CCCC1>[Br:28][CH2:9][C:8]([C:11]1[CH:12]=[C:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]#[N:22])[C:15]=2[CH:23]=1)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCCN2CC#N
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Triethylamine (0.76 ml, 5.5 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.73 g, 5.5 mmol) were added to a solution of [6-acetyl-8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-4-yl]methyl cyanide (0.5 g, 1.8 mmol) in tetrahydrofuran (50 ml) while cooling on ice and the mixture was stirred at the same temperature for 30 minutes, after which N-bromosuccinimide (0.49 g, 2.7 mmol) was added and stirring was continued for 30 minutes. Ethyl acetate was added, the reaction mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (310 mg) as a light yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1F
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example A7, 10.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-[1-(2-fluorophenyl)ethoxy]thiophene-2-carboxylate and 950 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH2:8]([O:10][C:11](=[O:40])[C@H:12]([CH:19](COC(=O)C)[C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[C:22]([CH3:34])[CH:21]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:9].Cl[CH2:42]Cl>>[CH2:8]([O:10][C:11](=[O:40])[C@@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:34])[C:21]=1[CH2:42][O:5][C:3](=[O:4])[CH3:2])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C[C@H](C(=O)OCC)C(COC(C)=O)c1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: ClCCl
Product: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of 2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinic acid diethyl ester (4.6 g, 9.9 mmol) in dichloromethane (40 mL). Reaction mixture was stirred at room temperature for 1.5 hours. Mixture was concentrated in vacuo. Residue was dissolved in dichloromethane (75 mL) and washed successively with saturated aqueous sodium bicarbonate (2×50 mL) and brine (30 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo to yield the desired product in 99% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=6.85 (d, J=8.1, 1H), 6.67 (d, J=8.4, 1H), 5.18 (m, 2H), 4.09 (m, 4H), 3.09 (dd, J1=6.2, J2=13.9, 1H), 2.96 (m, 1H), 2.66 (m, 2H), 2.37 (dd, J1=4.6, J2=16.7, 1H), 2.15 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e (M−C2H4O2+H)+=306.2.
Reaction SMILES: [OH-].[Na+].O.Cl.[NH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8].ClC(Cl)(O[C:16](=[O:22])OC(Cl)(Cl)Cl)Cl.Cl.O1CCO[CH2:27][CH2:26]1>O>[O:22]=[C:16]1[NH:5][C@H:6]([C:9]([O:11][CH2:26][CH3:27])=[O:10])[CH2:7][S:8]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: C1COCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@@H]1CSC(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution comprising 2 liters of water containing 180 g of sodium hydroxide was dissolved 175.6 g of L-cysteine monohydrochloride monohydrate under ice-cooling and under nitrogen atmosphere. To the solution was added dropwise 700 ml of a 1,4-dioxane solution containing 118.7 g of triphosgene at 25° C. to 29° C. over 1 hour and 30 minutes, and further stirred at the same temperature for 3 hours. To the reaction mixture was added conc. hydrochloric acid to adjust the mixture to weak acidic solution, and then, the solvent was removed under reduced pressure. To the concentrated residue was added 200 ml of toluene, and the solvent was removed again under reduced pressure. To the concentrated residue was added 700 ml of ethanol, 131 g of thionyl chloride was added to the mixture under ice-cooling over 40 minutes, and the resulting mixture was stirred for 19 hours while raising the temperature to room temperature. The solvent was removed under reduced pressure, and then, the concentrated residue was dissolved in 1 liter of ethyl acetate, and the mixture was successively washed with 700 ml of water, 300 ml of an aqueous saturated sodium bicarbonate solution and 500 ml of saturated brine. After the mixture was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 162 g of ethyl (4R)-2-oxothiazolidin-4-carboxylate as oily product.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.[CH2:19]([SH:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:19]([S:21][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1)[CH3:20]
Reactant: CCS
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(SCC)CCS2
Temperature: 25 °C
Reaction time: 48 h
Yield: 139.5 %

Procedure:
0.8 Gram (2.6 mmol) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman was dissolved in 5 ml of N,N-dimethylformamide, and 0.15 ml (3.1 mmol) of ethanethiol and 0.43 g (3.1 mmol) of potassium carbonate were added. The mixture was stirred at room temperature for 2 days. After the completion of the reaction, 20 ml of water was added, and the reaction mixture was extracted with ethyl acetate twice. An organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.2 g (yield 100%) of 4-ethylthio-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[C:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[NH2:15][C:16]1[S:17][C:18]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][N:20]=1.O>CN(C)C(=O)C>[C:23]1([C:21]([C:18]2[S:17][C:16]([NH:15][C:8](=[O:9])[C:7]([OH:12])([CH3:11])[C:6]([F:14])([F:13])[F:5])=[N:20][CH:19]=2)=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ncc(C(=O)c2ccccc2)s1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ncc(C(=O)c2ccccc2)s1)C(F)(F)F
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Thionyl chloride (80 μl, 1.1 mmol) is added to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (150 mg, 0.949 mmol) in 5 ml of N,N-dimethylacetamide at -15°/-10° C. and the mixture is stirred at this temperature for one hour. After addition of 2-amino-5-(phenylcarbonyl)thiazole (130 mg, 0.636 mmol) and equilibration to room temperature, the reaction mixture is stirred for 2.5 hours, then poured into 100 ml of water and subjected to extraction with 3×100 ml of ethyl acetate. The combined organic phases are washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent is distilled off. The oil which remains is purified by flash chromatography (eluent: 33% v/v ethyl acetate in petroleum ether (40/60)) to give N-[5-(phenylcarbonyl)thiazol-2-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.10 g, 46%) as pale yellow crystals. These crystals are digested in dichloromethane.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].C([NH+](CC)CC)C>C1C=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:30](=[O:31])[NH:29][C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Agent: CC[NH+](CC)CC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccccc2)C(=O)C1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
The solution of 13 g of 1-phenyl-3-methyl-2-pyrazolin-5-one in 150 ml of benzene and 9.1 g of triethylamine is combined at ambient temperature with the solution of 14.0 g of 3,4-dichlorophenylisocyanate in the minimum amount of benzene. The triethylammonium salt separates after 2 hours standing at room temperature and the mixture is evaporated. The residue is poured into 0.3 N hydrochloric acid, the solid collected, washed with water, dried, triturated with cold methanol and recrystallized from ethyl acetate to yield the 1-phenyl-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=H, R'=3--Cl and R"=Cl, melting at 228°-231° (dec.).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH2:22])[C:10]=12.[CH3:23][O:24][C@H:25]([CH3:29])[C:26](O)=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH:22][C:26](=[O:27])[C@H:25]([O:24][CH3:23])[CH3:29])[C:10]=12
Reactant: CO[C@H](C)C(=O)O
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
Triethylamine (430 mg, 0.592 mL, 4.25 mmol) was slowly added to a mixture of 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.849 mmol; Example 12, Step G), (R)-2-methoxypropanoic acid (106 mg, 1.02 mmol) and bis(2-oxooxazolidin-3-yl)phosphinic chloride (238 mg, 0.934 mmol) in anhydrous dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue stirred in THF (5 mL) and treated with water (20 mL). The solid, which separated, was collected by filtration and washed with water then dried under vacuum to yield (R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (263 mg, 96% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.49 (br s, 1H), 9.48 (s, 1H), 8.59 (s, 1H), 7.89 (d, 1H), 3.93 (q, 1H), 3.41 (s, 3H), 1.36 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[CH:10][C:9]2=[O:30])=[CH:4][C:3]=1[F:31].NC1C=CC(N2C=CC(OC3CCN(C4N=[CH:56][C:55]([CH2:58]CC)=[CH:54]N=4)CC3)=CC2=O)=CC=1.[C:62](Cl)(=[O:66])C(C)C>>[F:31][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][N:22]=4)[CH2:19][CH2:20]3)=[CH:10][C:9]2=[O:30])[CH:6]=[CH:7][C:2]=1[NH:1][C:62](=[O:66])[C:55]([CH3:54])([CH3:56])[CH3:58]
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(N)c(F)c4)c(=O)c3)CC2)nc1
Reactant: CC(C)C(=O)Cl
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(N)cc4)c(=O)c3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(NC(=O)C(C)(C)C)c(F)c4)c(=O)c3)CC2)nc1

Procedure:
Example 239 was prepared according to procedures described in Example 208 substituting 1-(4-amino-3-fluorophenyl)-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one for 1-(4-aminophenyl)-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one and substituting pivaloyl chloride (Aldrich) for Isobutyryl chloride except that the crude solid purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (t, J=8.66 Hz, 1 H), 8.19 (s, 2 H), 7.68 (d, J=3.51 Hz, 1 H), 7.25-7.30 (m, 1 H), 7.17-7.25 (m, 1 H), 7.12 (d, J=8.78 Hz, 1 H), 5.96-6.06 (m, 2H), 4.51-4.63 (m, 1 H), 4.15-4.26 (m, 2 H), 3.59-3.69 (m, 2H), 2.43 (t, J=7.53 Hz, 2 H), 1.97-2.15 (m, 2H), 1.79-1.97 (m, 2 H), 1.54-1.65 (m, 2 H), 1.36 (s, 9 H), 0.96 (t, J=7.28 Hz, 3 H). MS (ESI) 508 (M+H).
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[NH:17]([C:24]1[S:25][CH:26]=[C:27]([CH:29]=[CH:30][C:31](OCC)=[O:32])[N:28]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.CO>[NH:17]([C:24]1[S:25][CH:26]=[C:27]([CH:29]=[CH:30][CH2:31][OH:32])[N:28]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C=Cc1csc(Nc2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: OCC=Cc1csc(Nc2ccccc2)n1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
58 ml of a 1M hexane solution of diisobutyl aluminum hydride was added dropwise at -60° C. to a solution of 4 g of ethyl 3-(2-anilinothiazol-4-yl)acrylate (prepared by the procedure described in Preparation 48) in 40 ml of tetrahydrofuran. The resulting mixture was stirred at -50° C. for 2 hours, then the excess of the reducing reagent was decomposed with 90% aqueous methanol. The mixture was then neutralized with 3N hydrochloric acid and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate. the solvent was evaporated off under reduced pressure, giving crude 3-(2-anilinothiazol-4-yl)allyl alcohol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (10 g, 28.41 mmol) and DMAP (1.8 g, 14.21 mmol, 0.5 eq) in dry CH2Cl2 (150 mL), Et3N (8.62 g, 11.42 mL, 85.23 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (10.95 mL, 142.05 mmol, 5 eq) in dry CH2Cl2 (60 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. Water (80 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×50 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by silica gel to afford (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (11.3 g, 97%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:12]=[N:11][N:10]([CH3:13])[C:9]=1[C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[OH:20].CS(O[CH2:39][C:40]([CH3:45])([N+:42]([O-:44])=[O:43])[CH3:41])(=O)=O.O>CC(N(C)C)=O>[N+:42]([C:40]([CH3:45])([CH3:41])[CH2:39][O:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:9]1[N:10]([CH3:13])[N:11]=[CH:12][C:8]=1[Cl:7])([O-:44])=[O:43]
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Cesium carbonate (815 mg, 2.50 mmol) was added to a solution of N-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (396 mg, 1.00 mmol) and 2-methyl-2-nitropropyl methanesulfonate (276 mg, 1.40 mmol) in DMA (2.0 mL) and the mixture was stirred at 160° C. After 1 hr, the mixture was allowed to cool to room temperature and poured into water, and the resulting suspension was extracted with dichloromethane. The extract was dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate—hexanes 1:2) to afford the product (338 mg, 68%) as a yellow oil. LCMS m/z (%)=499.5 (M+H 37Cl 31.5%), 497.4 (M+H 35Cl 100.0%). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (s, 3 H), 1.57 (s, 3 H), 3.64 (s, 3 H), 4.01 (d, J=9.85 Hz, 1 H), 4.49 (d, J=9.85 Hz, 1 H), 7.08 (d, J=8.84 Hz, 1 H), 7.49 (d, J=2.53 Hz, 1 H), 7.51 (s, 1 H), 7.65 (t, J=7.71 Hz, 1 H), 7.80-7.90 (m, 3 H), 8.07 (d, J=7.83 Hz, 1 H), 8.13 (s, 1H).