Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH2:1]/[C:2](/[CH3:9])=[C:3](/[C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C(=O)Nc1ccc(Cl)cc1)=C(/C)N
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a stirred solution of 12.9 g (0.10 mole) of ethyl 3-aminocrotonate in 50 ml of anhydrous dimethylformamide is added during 10 min. 15.36 g (0.10 mole) of p-chlorophenyl isocyanate in 50 ml of the same solvent. A mild exotherm (5° C.) results. After stirring for 3 hours, the reaction solution is slowly added with stirring to 1.5 l of deionized water. The white solid product is collected by vacuum filtration, washed with water and air dried at 45°-55° to give 23 g of ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate. Recrystallization of a 2.0 g. portion of this material from 15 ml of ethanol gives 1.5 g of pure ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][N:9]2[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=3[C:36]([F:39])([F:38])[F:37])[N:20]=[CH:19]4)/[S:11][C:10]2=[O:40])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:41]1([C:44](Cl)=[O:45])[CH2:43][CH2:42]1>>[F:37][C:36]([F:38])([F:39])[C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:26]=1[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16](/[CH:15]=[C:12]3/[C:13](=[O:14])[N:9]([CH2:8][C:2]4([NH:1][C:44]([CH:41]5[CH2:43][CH2:42]5)=[O:45])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)[C:10](=[O:40])[S:11]/3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: O=C(Cl)C1CC1
Reactant: NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CCOCC1
Product: O=C(NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CCOCC1)C1CC1

Procedure:
N-(4-{[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}tetrahydro-2H-pyran-4-yl)cyclopropane carboxamide was prepared from (5Z)-3-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 310) and cyclopropanecarbonyl chloride following General Procedure R3.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>ClCCl>[OH:31][CH2:30][C:29]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([I:1])[CH:3]=1)([CH3:33])[CH3:32]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1cc(I)cc(C(F)(F)F)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cc(I)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-5-(trifluoromethyl)benzoic acid (2.32 g) and triethylamine (1.13 ml) in dichloromethane (20 ml) was added dropwise a solution of ethyl chloroformate (1.4 ml) in dichloromethane (2.0 ml) over 10 minutes at −30° C., and the mixture was stirred at −30° C. for 1 hour. 2-Amino-2-methyl-1-propanol was added dropwise to the mixture over 5 minutes at −30° C., and the mixture was stirred at −30° C. for 30 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous ammonium chloride solution at 0° C., and extracted with dichloromethane (X2). The combined organic extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine, and then dried over magnesium sulfate, evaporated, and purified with column chromatography (silica gel, ethyl acetate:hexane=20:80) to give N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluoromethyl)benzamide (2.10 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9]C)=O)=[N:3]1.[NH3:11].O>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH2:11])=[O:9])=[N:3]1
Reactant: N
Reactant: COC(=O)c1ccn(C)n1
Solvent: O
Product: Cn1ccc(C(N)=O)n1

Procedure:
A solution of methyl 1-methyl-1H-pyrazole-3-carboxylate (1.1 g, 7.9 mmol) in NH3.H2O (10 mL) was stirred for 2 h at room temperature. The solvent was evaporated to give the crude product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[O:7][C:6](=[S:32])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
The product was prepared, from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile and Lawesson's reagent using the procedure of Example 9, as a yellow solid: 248-249° C.; 1H-NMR (DMSO-d6) δ12.3 (s, 1H), 8.15 (bs, 1H), 8.02 (d, 1H, J=10.48 Hz), 7.85-7.78 (m, 3H), 7.13 (d, 1H, J=8.92 Hz), 1.71 (s, 6H); MS (APCI) m/z 313([M+H]+, 100%); Anal. Calc. For C17H13FN2OS: C, 65.37; H, 4.19; N, 8.97. Found: C, 65.26; H, 4.31; N, 8.61.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=2[S:9](=[O:22])(=[O:21])[C:8]2[C:3]1=[CH:4][C:5]([CH:23]([C:31](=[O:39])[NH:32][C:33]1[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26]1)=[CH:6][CH:7]=2.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[S:9](=[O:21])(=[O:22])[C:8]2[C:3]1=[CH:4][C:5]([CH:23]([C:31](=[O:39])[NH:32][C:33]1[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26]1)=[CH:6][CH:7]=2
Reactant: CCOC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(CC3CCC(=O)C3)C(=O)Nc3ccn(C)n3)cc1N2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1c2cc(C(CC3CCC(=O)C3)C(=O)Nc3ccn(C)n3)ccc2S(=O)(=O)c2cc(C(=O)O)ccc21

Procedure:
260 mg of ethyl 10-methyl-8-[1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2-(3-oxocyclopentyl)ethyl]-5,5-dioxo-5,10-dihydrophenothiazine-3-carboxylate are suspended in 10 ml of methanol, and 1.64 ml of a 2 M NaOH solution are added. The reaction mixture is heated at the boil under reflux for one hour. The methanol is removed under reduced pressure and the reaction mixture is adjusted to pH 4 by addition of concentrated hydrochloric acid. The mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. This gives 155 mg of 10-methyl-8-[1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2-(3-oxocyclopentyl)ethyl]-5,5-dioxo-5,10-dihydrophenothiazine-3-carboxylic acid.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:11]([O-:14])(=O)[CH3:12].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:14][CH2:11][C:12]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
Benzyl chloride (12.6 g; 0.1 mole), a 50 percent aqueous solution of sodium hydroxide (35 g; 0.44 mole), tetra-n-butylammonium bisulfate (1.7 g. 0.005 mole), and sodium acetate (0.4 g; 0.005 mole) were added to a reaction vessel fitted with a thermometer and magnetic stirrer. The contents were then stirred and heated to 60° C. The reaction was slightly exothermic raising the temperature of the reaction mass to 63° C. The reaction mass was sampled at various intervals and the samples were analyzed by gas-liquid chromatography. The results are tabulated in Table I. Upon completion of the reaction, the reaction mass consisted of a lemon yellow organic layer, a heavy, caustic emulsion and solid sodium chloride on the flask bottom.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:21][C@@H:22]([OH:24])[CH3:23])=O)(C)(C)C.C(OC(N1CCN(C(OC(C)(C)C)=O)C[C@@H]1C[C@H](O)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:24][C@H:22]([CH3:23])[CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: C[C@H](O)C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: C[C@@H](O)C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)C[C@H]1CNCCN1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 2(S)-(2(S)-hydroxypropyl) piperazine-1,4-dicarboxylic acid di-tert-butyl ester and 2(S)-(2(R)-hydroxypropyl) piperazine-1,4-dicarboxylic acid di-tert-butyl ester (5.11 g, 14.8 mmol) in dichloromethane (100 mL) stirring at 0° C., add trifluoroacetic acid (25 mL). Warm the mixture to room temperature and stir. After 18 hours evaporate to a yellow oil. Dilute the mixture with methanol and apply to a 60 g SCX column. Wash with methanol and elute with 2N ammonia in methanol to obtain the title compound (mixture of diastereoisomers) as an oil (1.932 g, 90%): mass spectrum (APCI): m/z =145.1 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:30]=1>>[Si:33]([O:32][CH2:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[CH:26]=[N:27][CH:28]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Yield: 62 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromo-5-(tert-butyldimethylsilyl)oxymethylpyridine (described in example 69b), the title compound was formed in 62% yield as an oil. TLC analysis (Rf 0.25, 30% ethyl acetate in hexane). MS (CI, CH4) m/z 527 (M+1,100), 555 (M+29,14), 509 (20),395 (20)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>[Fe]>[NH2:12][C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Yield: 73.3 %

Procedure:
2-Chloro-5-nitro-3-trifluoromethylpyridine (0.16 g, 0.68 mmol) and iron powder (0.2 g, 3.42 mmol, 325 Mesh) were reacted as described in example 762D. Purification of the crude product by Prep-TLC using 10% ether/CH2Cl2 as eluent gave compound 766B (0.098 g, 73%) as a yellow solid. HPLC: 89% at 2.52 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 197.01 [M+H]+.
Reaction SMILES: [BH4-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:7](OC)=[O:8].Cl.O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:11]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Br)ccc1Sc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Sc1ccccc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A stirred solution of 65 g of lithium borohydride in 1 litre of tetrahydrofuran is treated dropwise under a nitrogen atmosphere over a period of 120 minutes with a solution of 483 g of methyl 3-bromo-6-(phenylthio)-benzoate in 1 litre of tetrahydrofuran. The mixture is stirred for a further 4 hours under reflux. The solution is cooled to 5° C and treated dropwise over a period of 3 hours with 700 ml of 3-N hydrochloric acid. After the addition of approximately 5 litres of water, the mixture is extracted with ether. The organic solution is washed with water and dried over magnesium sulphate. There is obtained crude 3-bromo-6-(phenylthio)-benzyl alcohol as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[C:14]([C:19]([CH3:24])([CH3:23])[CH:20]([OH:22])[CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[C:14]([C:19]([CH3:24])([CH3:23])[C:20](=[O:22])[CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2
Reactant: CC(O)C(C)(C)c1ncccc1Oc1cnc2c(F)cccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)C(C)(C)c1ncccc1Oc1cnc2c(F)cccc2c1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
0.07 g of 3-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-3-methyl-butan-2-ol were dissolved in 3 ml of dichloromethane. 0.27 g of Dess-Martin reagent were added thereto at 0° C. followed by stirring for 30 minutes. Subsequently, the reaction solution was concentrated followed by purifying by silica gel column chromatography to obtain 0.04 g of 3-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-3-methyl-butan-2-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:11])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc(F)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of tert-butyl[(2S)-1-hydroxypropan-2-yl]carbamate (1.07 g, 6.11 mmol), 4-fluoro-2-(trifluoromethyl)phenol (1.10 g, 5.55 mmol) and triphenylphosphine-resin (2.80 g, 8.40 mmol) in tetrahydrofuran (50 mL) was added drop-wise diisopropyl azodicarboxylate (DIAD, 1.37 g, 6.66 mmol). The reaction was allowed to stir at room temperature for 3 days, then filtered and rinsed with ethyl acetate. The combined filtrate was washed with 0.5 N aqueous sodium hydroxide and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (50% ethyl acetate in heptane) afforded the title compound as a clear yellow oil. Sample contained some residual diisopropyl azodicarboxylate and carried forward without further purification. Yield: 2.52 g, 134%. LCMS m/z 282.0 {[M-(2-methyl-prop-1-ene)]+1}. 1H NMR (400 MHz, CDCl3) δ 1.31 (d, J=6.8 Hz, 3H), 1.45 (s, 9H), 3.98-4.03 (m, 2H), 4.04-4.13 (m, 1H), 6.95 (dd, J=9.2, 4.2 Hz, 1H), 7.16-7.22 (m, 1H), 7.30 (dd, J=8.3, 3.0 Hz, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]([F:24])([F:23])[F:22])(=O)=O.[CH2:25]([O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32]C)=[O:30])[CH3:26].C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1>[F:22][C:21]([F:24])([F:23])[C:9]1[N:8]([CH2:7][CH2:6][O:5][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH:28]([O:27][CH2:25][CH3:26])[C:29]([O:31][CH3:32])=[O:30])=[CH:40][CH:39]=2)[C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)OCCn1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(Cc1ccc(OCCn2c(C(F)(F)F)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)OC

Procedure:
2-[2,5-bis(trifluoromethyl)-1H-benzimidazol-1-yl]ethyl methanesulfonate (1.88 g, 5 mmol) and ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (1.19 g, 5 mmol) were taken in toluene (20 ml) and K2CO3 (1.38 g, 10 mmol) was added. The reaction mixture was heated under reflux for 30 hrs. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was dried and evaporated to the product which was purified by column chromatography on silica gel using ethyl acetate and hexanes as the solvent system (2.01 g, 77%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(OC(F)(F)F)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC(F)(F)F)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC(F)(F)Oc1ccc(NCC2CCCC2)cc1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC(F)(F)F)cc2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-trifluoromethoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: C[C@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C[C@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Yield: 41.4 %

Procedure:
To a solution of (S)-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (109 mg, 0.26 mmol), 2,4-difluorophenylboronic acid (49 mg, 0.31 mmol) and Pd(PPh3)4 (30 mg, 0.03 mmol) in dioxane (8 mL) was added a solution of CsCO3 (2 M, 1 mL) at 0□. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH2Cl2 twice. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((R)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (49 mg, 42%). LC-MS Method 3 tR=1.41, min, m/z=456; 1H NMR (CD3OD): 1.55 (m, 3H), 2.12 (m, 2H), 2.22-2.46 (m, 3H), 2.52 (m, 1H), 3.12 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 5.56 (m, 1H), 7.08 (m, 6H), 7.08 (m, 2H), 7.35 (m, 5H). 443-155-3.
Reaction SMILES: C(O[C:4]([C:6]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)=[O:5])C.[CH2:19]([NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:20]([CH3:23])([CH3:22])[CH3:21].Cl.C(N=C=NCCCN(C)C)C.C(O)C.[O-]CC.[Na+].Cl>CN(C)C=O.O>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:7]2[C:6]=1[C:4]([OH:5])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:24]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:8]2=[O:10]
Reactant: CCOC(=O)CNCC(C)(C)C
Reactant: CCOC(=O)c1c(C(=O)O)ccc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2c(OC)c(OC)ccc2c(=O)n1CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of 2-(ethoxycarbonyl)-3,4-dimethoxybenzoic acid (4.45 g, 17.5 mmol), ethyl 2-(neopentylamino)acetate (3.47 g, 20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.83 g, 20 mmol) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 3 h. The reactions mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (50 ml) and 20% sodium ethoxide ethanol solution (34.04 g, 100 mmol) was added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (150 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5,6-dimethoxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.21 g, 50.6%) as an oil.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:13]O>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: CO
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Product: COC(=O)C(Br)c1ccc(F)cc1
Yield: 87 %

Procedure:
The α-bromo-4-fluorophenylacetic acid from Part 1 was dissolved in methanol (100 ml) and was added Dowex-50X-400® (2.7 g) to the solution. The mixture was refluxed for 6 hours and the resin was removed by filtering through Celite® after cooling. The filtrate was evaporated to give an oily residue, which was purified by column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane to afford methyl α-bromo-4-fluorophenylacetate (87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2)=C([CH:9]=1)C#N.[OH-].[K+].O.[C:21]([O:24]CC)(=[O:23])[CH3:22]>COCCOCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH:12]([CH3:17])[CH2:13][CH:14]([CH3:16])[CH2:15]2)=[C:22]([CH:9]=1)[C:21]([OH:24])=[O:23]
Reactant: CCOC(C)=O
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C#N)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCO
Product: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile (1.05 g, 4.220 mmol) in Diethylene glycol monomethyl ether (2.50 mL) was added KOH (0.947 g, 16.883 mmol) and water (0.750 ml). The reaction was heated at 130–135° C. overnight. Upon cooling to rt, water and ethyl acetate was added the organic layer was discarded and the aqueous layer is acidified to pH˜6–7. The aqueous layer was then extracted with ethyl acetate three times. The combined organic layer was washed with water, brine, dried (Na2SO4), and concentrated to give required 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.850 g, 75%) as an off white solid. LCMS 268(M+1)+.