Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:18](O)([CH3:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)CCc1nc(-c2ccc(Cl)cc2)co1
Yield: 91 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) and isopropanol (30 ml) was added conc. sulfuric acid (0.3 ml), and the resultant was refluxed for 5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer was washed succesively with a saturated sodium hydrogen carbonate aqueous solution and water, and dried over MgSO4. The ether was distilled off to give crystals of isopropyl 4-(4-chlorophenyl)-2-oxazolepropionate (530 mg, 91%). Recrystallization from hexane gave colorless prism crystals of mp 30°-31° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:28]>>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:28])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 65 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=65%. Colorless solid. MS: m/e=353.1 (M++H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:9][SiH:10]([CH3:12])[Cl:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:12])([CH3:9])[Cl:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: C[SiH](C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](C)(C)Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
123 g (1.1 mol) 1-octene and 100 microliters of a 2% toluene solution of chloroplatinic acid were placed in a 500-mL four-neck flask equipped with a stirrer, thermometer, addition funnel, and condenser and were heated to 70° C. After the temperature had been raised, the heating mantle was removed and 94.5 g (1 mol) dimethylchlorosilane was added dropwise from the addition funnel. Heat generation was observed immediately, and the dropwise addition was carried out gradually so as to avoid having the temperature of the reaction solution exceed 80° C. After the completion of this addition, the reaction was continued for 30 minutes at 80° C. Gas chromatographic analysis of the resulting reaction solution gave 88% octyldimethylchlorosilane. The reaction solution was cooled to room temperature and 200 g toluene was introduced. The addition funnel was then replaced with a Teflon tube and ammonia was bubbled in until the pH of the reaction solution reached 10. The ammonium chloride product was removed by filtration, and the filtrate was then distillatively purified at 160° C./0.5 mmHg to obtain the following disilazane in a purity of 98 weight %. ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(#N)C>O>[CH2:12]([S:19][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: SCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1cc(SCc2ccccc2)n2nccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (4.1 g, 22 mmol) was added along with benzyl mercaptan (2.8 mL, 22 mmol), triethylamine (3.1 mL, 22 mmol), and acetonitrile (71 mL). The reaction was stirred at room temperature for 3 hours then diluted with water, filtered and washed with water. The product, 7-(benzylthio)-5-chloropyrazolo[1,5-a]pyrimidine, was collected as a solid in 96% yield after drying under vacuum overnight. LCMS (M+1=276)
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13](=O)[N:14]([C:22]3[C:23](=[O:36])[N:24]([CH2:33][CH2:34][CH3:35])[C:25](=[O:32])[N:26]([CH2:29][CH2:30][CH3:31])[C:27]=3[NH2:28])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].[OH-].[K+]>CC(O)C.O>[CH2:15]([N:14]1[C:22]2[C:23](=[O:36])[N:24]([CH2:33][CH2:34][CH3:35])[C:25](=[O:32])[N:26]([CH2:29][CH2:30][CH3:31])[C:27]=2[N:28]=[C:13]1[C:8]12[CH2:7][CH2:6][C:5]([C:3]([OH:2])=[O:4])([CH2:12][CH2:11]1)[CH2:10][CH2:9]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCn1c(N)c(N(Cc2ccccc2)C(=O)C23CCC(C(=O)OC)(CC2)CC3)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCn1c(=O)c2c(nc(C34CCC(C(=O)O)(CC3)CC4)n2Cc2ccccc2)n(CCC)c1=O

Procedure:
To a stirred solution of 4-[(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-benzyl-carbamoyl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (430 mg, 0.843 mmol) in i-PrOH (20 ml) was added 2 N KOH (4.0 eq, 3.37 mmol, 1.7 ml) and the resulting mixture was heated at reflux for 26 h. The cool reaction mixture was concentrated in vacuo to give a semi-solid residue that was diluted with water and extracted with CHCl3. The aqueous phase was acidified with concentrated HCl to afford a white precipitate that was collected and dried (381 mg, 91%). MS: 479 (MH+).
Reaction SMILES: C([O:8][C:9]([CH2:11][C@H:12]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([O:26][CH3:27])=[O:25])=[O:14])=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:9]([CH2:11][C@H:12]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([O:26][CH3:27])=[O:25])=[O:14])([OH:10])=[O:8]
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F

Procedure:
A solution of methyl 1-[(S)-3-(benzyloxycarbonyl)-2-(trifluoroacetylamino)propionyl]-2,3-dihydroindole-2-(S)-carboxylate (30.1 g, 63 mmol) in ethyl acetate (450 mL) is hydrogenated on the Parr apparatus at 50 psi in the presence of 10% palladium on carbon (15 g) for 105 minutes. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether (350 mL) and water (100 mL). The organic layer is washed successively with 1N HCl (100 mL) and water (2×100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrated is decolorized with charcoal, then filtered through a thin layer of silica gel (flash grade). The product is eluted with ether (200 mL). The solvent is evaporated under reduced pressure and the residue crystallized from ether-hexane (1:1). The white crystals are collected and dried under high vacuum for 1 hour at 40° C., then for 18 hours at room temperature to yield methyl 1-[(S)-3-carboxy-2-(trifluoroacetylamino)-propionyl]-2,3-dihydroindole-2-(S)-carboxylate, m.p. 157°-158° C.; [α]D =-188.76 (CHCl3, c 1.1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: COC(=O)CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 60 h

Procedure:
To a solution of 40 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 1 mL of acetonitrile was added 0.011 mL of methyl 3-bromo-proprionate and 0.046 mL of DIPEA. The reaction was heated at 50° C. for 24 hours, then an additional 0.011 mL of methyl 3-bromoproprionate and 0.030 mL of DIPEA were added and heating continued at 80° C. for 60 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (5% methanol in methylene chloride) to give 39 mg of title compound. Mass spec (ESI): 536 (M+1).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:14]=2[CH:13]=1)(=[O:11])[CH3:10].S1C2C=CC=CC=2C=C1.[H-].[K+]>O1CCCC1.C(O)(=O)C>[CH3:7][O:6][C:3](=[O:8])[CH2:10][C:9]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:14]=2[CH:13]=1)=[O:11]
Reactant: COc1cc2cc(C(C)=O)sc2cc1OC
Reactant: COC(=O)OC
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1cc2cc(OC)c(OC)cc2s1
Temperature: 0 °C

Procedure:
A mixture of sodium hydride (60% dispersion in oil, 10.9 g) and dimethyl carbonate (18.7 ml) in dry tetrahydrofuran (210 ml) was stirred and heated at reflux under an atmosphere of nitrogen. A solution of 2-acetyl-5,6-dimethoxy-benzo[b]thiophene (21.0 g) in dry tetrahydrofuran (315 ml) was added dropwise over 30 min. Shortly after the addition of the benzothiophene solution had commenced potassium hydride (22.7% dispersion in oil) was added to initiate the reaction (sufficient to cause a permanent pink colour). When the evolution of gas had ceased (90 min.) the reaction mixture was cooled in an ice bath and treated with glacial acetic acid (34 ml). The resultant yellow solution was poured into ice-cold water (2 liter), stirred, and the yellow solid was filtered, washed with n-hexane and dried at 50° C. under vacuum to give 3-(5,6-dimethoxybenzo[b]thien-2-yl)-3-oxo-propanoic acid methyl ester (22.0 g). A portion crystallized from dichloromethane/diethyl ether had m.p. 129°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)cs1
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a round bottom flask with 50 mL methylene chloride was added 2-((tert-butoxycarbonylamino)methyl)thiazole-4-carboxylic acid (2.0 g, 7.74 mmole) and methyl 2-amino-2-methylpropanoate hydrochloride salt (1.25 g, 8.13 mmole). To the mixture, triethylamine (5.4 mL, 38.7 mmole) was then added, followed by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (2.97 g, 15.5 mmole) and hydroxybenzotriazole (2.09 g, 15.5 mmole). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with methylene chloride. The mixture was then washed with water and the aqueous layer was extracted with methylene chloride. The combined organic layer was then dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 1:1 EtOAc/hexane to provide the desired product (2.40 g, 87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.OS([O-])=O.[Na+].[OH-].[NH4+:20]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:20])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: [NH4+]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ccc(N)cc2c1
Temperature: 25 °C
Yield: 70 %

Procedure:
The solution of 7-methoxynaphthalen-2-ol (6.5 g, 37.31 mmol) and NaHSO3 (11.6 g, 111.54 mmol) in ammonium hydroxide (100 ml) was stirred for 2 days at 140° C. in a sealed tube and then cooled to room temperature. The solids were collected by filtration to afford 7-methoxynaphthalen-2-amine as an off-white solid (4.5 g, 70%). (ES, m/z): [M+H]+ 174.1; 1H NMR (300 MHz, CDCl3): δ 7.57 (d, J=8.7 Hz, 2H), 6.97-6.87 (m, 3H), 6.79 (dd, J=8.7, 2.1 Hz, 1H), 3.90 (s, 3H), 3.84 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)nc1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recolled to 0° C., and saturated aqueous K2CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2% MeOH/CH2Cl2) gave 7.5 g (59%) of a yellow solid, mp 49°-51° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][Br:16])[CH:8]=[O:9])[C:2]#[CH:3].[BH4-].[Na+]>CO.C1COCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][Br:16])[C:2]#[CH:3]
Reactant: C#CCOc1cc(C=O)ccc1OCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCOc1cc(CO)ccc1OCCBr
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a two-neck flask with a nitrogen inlet, compound 9 (5.2 g, 18 mmol, 1 equiv) was dissolved in 200 mL methanol/THF (10/1). The solution was cooled to −10° C. in a salted ice bath, followed by the addition of sodium borohydride (0.8 g, 21 mmol, 1.2 equiv). The mixture was stirred at 0° C. for 20 min, then allowed to warm to rt and stirred for an additional 20 min. The mixture was concentrated under vacuum, cooled to 0° C. and acidified with diluted HCl solution. The aqueous solution was extracted with ethyl acetate. The combined organic extracts were washed with brine (200 mL) and dried over MgSO4. After filtration the solvent was removed under vacuum to afford crude product as a yellowish solid. This was chromatographed on a silica gel column (eluent: 0% to 5% of methanol in CH2Cl2) to give 10 as a white solid (4.95 g, yield: 95%). 1H NMR δ=7.10 (d, J=1.8, 1H), 6.97 (dd, J1=1.8, J2=8, 1H), 6.93 (d, J=8, 1H), 4.78 (d, J=2.3, 2H, —OCH2C≡CH), 4.64 (d, J=5.8, 2H, —CH2OH), 4.34 (t, J=6.6, 2H, —OCH2CH2Br), 3.66 (t, J=6.6, 2H, —OCH2CH2Br), 2.51 (t, J=2.3, 1H, —C≡CH), 1.68 (t, J=5.8, 1H, —CH2OH). 13C NMR δ=147.90, 145.60, 135.34, 121.32, 115.46, 114.92, 78.78 (—C≡CH), 76.12 (—C≡CH), 70.54 (—CH2OH), 66.28 (—OCH2CH2Br), 57.38 (—OCH2C≡CH), 29.32 (—OCH2CH2Br). HRMS calculated for C12H11BrO3 (M+Na+), 354.9807; found, 354.9810.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])([CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[F:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[O:35][C:5]([CH3:34])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is diluted with 1N HCl, extracted with CH2Cl2, dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.56-7.51 (m 1H), 7.48-7.33 (m, 2H), 7.26-7.21 (m, 3H), 7.11-6.98 (m, 4H), 6.74 (d, 2H, J=8.4 Hz), 4.49-4.34 (m, 2H), 3.98 (t, 2H, J=5.3 Hz), 3.74-3.67 (m, 1H), 3.42 (t, 1H, J=8.4 Hz), 3.35, 3.23 (ABq, 2H, J=14.5 Hz), 3.08-3.03 (m, 1H), 2.86 (s, 3H), 2.27-2.20 (m, 1H), 1.95-1.88 (m, 1H), 1.42 (s, 3H). MS [ES+] m/z exact mass calc'd for C30H31N2O5F4 575.2169, found 575.2175.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=CC(N=C=O)=CC=1>>[CH3:48][O:52][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COc1ccc(N=C=O)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 248 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 4-methoxy phenyl isocyanate. The compound of example 248 was used directly without isolation for the preparation of compound of example 249.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29]>>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: COc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Product: COc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 73.5 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(methyloxy)benzonitrile (0.30 mmol) and 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.083 g, 0.30 mmol) were employed in a similar process described herein to prepare the title compound (0.096 g, 74%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (s, 1H) 7.29-7.46 (m, 2H) 7.04 (s, 1H) 6.69-6.83 (m, 2H) 4.65 (s, 2H) 3.83 (s, 3H). ES-LCMS: m/z 435.8, 437.7 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:29])[CH:22]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 109 mg 3-pyridylacetic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. The residue is purified by silica gel flash chromatography. 146 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][NH:3]1.[H-].[Na+].FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O>CN(C=O)C>[O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:4][N:3]1[CH2:23][C:24]([F:27])([F:26])[F:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To a solution of (S)-tert-butyl (2-oxopyrrolidin-3-yl)carbamate (250 mg, 1.25 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (52.9 mg, 1.32 mmol). After stirring at rt for 1 h, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.18 mL, 1.25 mmol) was added then the reaction mixture was allowed to warm to rt and stirred for 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified on silica gel eluting with 0 to 75% EtOAc/DCM to give Compound 91a (95 mg, 27% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.11 (br. s., 1H), 4.24 (br. s., 1H), 4.07 (dq, J=15.0, 9.2 Hz, 1H), 3.91-3.67 (m, 1H), 3.63-3.37 (m, 2H), 2.84-2.47 (m, 1H), 2.12-1.84 (m, 1H), 1.53-1.42 (m, 9H). COSY NMR shows coupling of NH at 5.11 ppm to methine at 4.24 ppm, confirming regioselectivity of alkylation on the pyrrolidinone nitrogen. US 2009/760005 A1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[C@@H:10](O)([CH2:12][CH3:13])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C@H:10]([CH3:11])[CH2:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C)O
Reactant: Oc1ccc(F)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC[C@@H](C)Oc1ccc(F)c(Cl)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of 3-chloro-4-fluorophenol (2.10 g, 14.3 mmol) in toluene (14.3 ml) was added (S)-(+)-sec-butanol (1.39 ml, 15.0 mmol), triphenylphosphine (3.76 g, 14.3 mmol), and DIAD (3.06 ml, 15.76 mmol). The reaction warmed to rt overnight. The reaction mixture was filtered through a fritted funnel and washed with toluene. The filtrate was concentrated. The residue was diluted with EtOAc and washed with 1N NaOH. The aqueous phase was extracted with EtOAc (2 times). The combined organics were dried with MgSO4, filtered, and concentrated. The residue was purified on a silica gel cartridge (0% EtOAc/hexanes to 4% EtOAc/hexanes) to give the desired product.