Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[N:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C>ClCCl>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Nc1cnc2cccnc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cnc2cccnc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
A solution of valeryl chloride (4.4 mL, 37 mmol) in dichloromethane (25 mL) was added dropwise to a stirred suspension of 3-amino[1,5]naphthyridin-4-ol (5.0 g, 31 mmol) and triethylamine (6.6 mL, 47 mmol) in dichloromethane (100 mL), and the reaction was stirred for three days at room temperature. An analysis by LC/MS indicated the reaction was complete after 1.5 hours. The volatiles were removed under reduced pressure, and the residue was stirred with water (100 mL) for 15 minutes. The resulting solid was isolated by filtration and washed with water (100 mL) and diethyl ether (4×50 mL) to provide 5.35 g of N-(4-hydroxy[1,5]naphthyridin-3-yl)pentanamide.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:19]>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:19]
Reactant: O=C1CCc2ccccc2N1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Methyl bromoacetate (5.72 g, 37.4 mmol) was slowly added to a stirred solution of sodium hydride (1.5 g, 37.4 mmol) and 3,4-dihydro-2 (1H)quinolinone (5.0 g, 34 mmol) in THF. The mixture was stirred at RT for 3 h. After removing the solvent, the residue was diluted with water and ether. The layers were separated and the aqueous layer was extracted with ether (3×50 mL). The combined organics were dried with MgSO4 and condensed to afford the desired product, compound 49A (7.06 g, 95%) as a yellow solid. MS m/z 220 (M+1). Step 2. Preparation of (6-Chlorosulfonyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl) acetic acid methyl ester (Compound 49B).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 72.6 %

Procedure:
To (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g) were added toluene (4.2 ml) and ethanol (16.7 ml). Sodium borohydride (133 mg) was added by portions at −10° C. and the mixture was stirred for 1 hr and 40 min. The reaction was quenched by adding acetic acid (0.40 ml). The reaction mixture was warmed to 60° C. over 1 hr and further stirred 60° C. for 30 min. The reaction mixture was then cooled to −10° C. over 1 hr and 50 min and further stirred at −10° C. for 6 hr. The obtained crystals were collected by filtration, washed with toluene (10.4 ml) and water of 0° C., and dried under reduced pressure to give the objective (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g, yield 83%). The obtained dry crystals were analyzed by HPLC and found to be (2S,3S):(2R,3S)=99.2:0.8 crystals.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH2:9])=[S:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O>>[CH:1]1([NH:6][C:7]2[S:8][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NC1CCCC1
Product: CC(C)c1ccc(-c2csc(NC3CCCC3)n2)cc1

Procedure:
Cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amine was prepared following procedure B using cyclopentyl-thiourea (1.6 g, 10.7 mmol) and 2-bromo-1-(4-isopropyl-phenyl)-ethanone (2.6 g, 10.7 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the product (2.9 g). LCMS m/z: 287 (M+1)+.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:40])[C:7]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25]C(=O)C)[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36]C(=O)C)C>O.C(O)C>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:8]1[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][C:7]=1[C:6]([OH:40])=[O:5]
Reactant: CCOC(=O)c1cc(OCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(OCCCCCCO)c(C(=O)O)cc1OCCCCCCO

Procedure:
A solution of 25.0 g (379 mmol) 85% KOH in 300 ml water is added to 40.0 g (74.3 mmol) diethyl-2,5-bis-(6-acetoxyhexoxy)terephthalate in 250 ml ethanol and the whole is heated under reflux for 1.5 hours. After distilling off approx. 150 ml ethanol, the reaction mixture is acidified by adding 40.0 g conc. HCl and stored at 2° C. for 20 hours for complete crystallization of the crude product. The colourless crude product is then filtered off, washed neutral with water and recrystallized from ethanol.
Reaction SMILES: [H-].[Na+].C(S)C.[CH3:6][CH:7]([S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[CH2:8][CH3:9].S(=O)(=O)(O)O>CN(C=O)C>[CH3:6][CH:7]([S:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:8][CH3:9]
Reactant: CCC(C)Sc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCC(C)Sc1ccc(O)cc1
Reaction time: 1.5 h

Procedure:
To sodium hydride (6.6 g, 275 mmol; prewashed with pentane) in 100 ml of DMF, under N2 and at 5°, is slowly added ethyl mercaptan (41.0 ml, 550.0 mmol) in 50 ml of DMF. This mixture is stirred for 1.5 hours, after which is added 4-(1-methylpropylthio)anisole (46.0 g, 250.0 mmol) and DMF. The mixture is heated to 150° with stirring overnight. After cooling to 20°, 10% aqueous sulfuric acid is added and the mixture is extracted with ether. The combined organic layers are washed with water and extracted with 5% NaOH. The aqueous portion is reacidified with conc. sulfuric acid and extracted with ether. The combined ether extracts are washed with water and with brine, dried and the solvent removed to give 4-(1-methylpropylthio)phenol.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[N:29]=[C:28]([C:30](OC)=[O:31])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1.Cl>C(OCC)C.CCCCCC.C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[N:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)c1cccc(Oc2ccnc(Cl)c2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCc1cccc(Oc2ccnc(Cl)c2)n1
Temperature: -50 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A one molar solution of diisobutylaluminum hydride in tetrahydrofuran (200 mL, 0.2 mol) is added over 45 minutes to a solution of methyl 6-[(2-chloro-4-pyridyl)oxy]picolinate (18.15 g, 0.069 mol) in diethyl ether (300 mL) at -50° C. Under a nitrogen atmosphere. The reaction mixture is stirred at -50° C. for two hours, allowed to warm to 0° C. and acidified with dilute hydrochloric acid. The phases are separated and the aqueous phase is extracted with diethyl ether. The organic extracts are combined with the organic phase and the resultant solution is washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 7:3 hexane/ethyl acetate solution gives the title product as a colorless oil (10.2 g, 62.5%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH3:33])[CH:27]=4)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[CH:23]=[C:22]([C:34]([F:36])([F:37])[F:35])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:27][C:28]=1[CH3:33]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(N)(=O)=O)s4)c3)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.1 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.14 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.048 g, 26%). MS (ISP) 511.1 [(M+H)+]; mp 280° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:12][O-:13].[Na+]>CN(C=O)C>[CH3:12][O:13][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(C(F)(F)F)c1

Procedure:
To a solution of 3-bromo-5-trifluoromethylpyridin (2.25 g 10 mmol, prepared as described in Eur. J. Org. Chem. 2002, 327-330, in DMF was added sodium methoxide (0.8 g, 15 mmol). The resultant solution is stirred for 20 hours at 40° C. The title compound is obtained after evaporation of the solvent under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH3:35])=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:39]3[CH2:38][CH2:37][N:36]([C@@H:34]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)[CH3:35])[CH2:41][CH2:40]3)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1
Product: COC[C@H](C)Nc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(N2CCN([C@H](C)c3ccc(F)cc3)CC2)n1

Procedure:
The reaction of (S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (75 mg, 0.2 mmol, Example 122(b)) with (R)-1-(1-(4-fluorophenyl)ethyl)piperazine (42 mg, 0.2 mmol, prepared as described in US 2005/0176726A1) under the condition of Example 104(c) provided the title compound. MS (ESI, pos. ion) m/z: 549 (M+1).
Reaction SMILES: C(NC(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH:34]=[C:35]([CH3:39])[C:36]([OH:38])=[O:37].[CH:40]1[C:45]([N+:46]([O-:48])=[O:47])=[CH:44][CH:43]=[C:42](O)[CH:41]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:46]([C:45]1[CH:40]=[CH:41][C:42]([O:37][C:36](=[O:38])[C:35]([CH3:39])=[CH:34][C:28]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=2[NH2:26])=[CH:43][CH:44]=1)([O-:48])=[O:47]
Reactant: CC(=Cc1ccc(Cl)cc1N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Solvent: ClCCl
Product: CC(=Cc1ccc(Cl)cc1N)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Into 20 ml of dichloromethane, 0.81 g (3.8 mmol) of (E) 3-(2-amino-4-chlorophenyl)-2-methyl-2-propenoic acid and 1.0 g of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 40 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. Further, while the mixture was stirred under cooling with ice, 1.0 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. This liquid was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Thereafter, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 1.2 g of the aimed product were obtained as a crystal (yield: 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH2:13][C:14]([OH:16])=O)/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[CH:13]=[C:14]2[OH:16]
Reactant: O=C(O)C/C(=C\c1ccc(F)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C(O)c1cc(O)c2cc(F)ccc2c1
Yield: 71.7 %

Procedure:
A solution of 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-succinic acid (0.100 g, 0.44 mmol) in trifluoromethanesulfonic acid (0.5 mL) was stirred at room temperature for 16 hours. The resulting mixture was carefully poured into ice cold water with continuous stirring to obtain a solid precipitate, which was filtered, washed with water and dried under vacuum to yield 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid (0.065 g, 71%) as yellow solid. This crude product was pure enough to proceed to next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[C:24]4[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=4[C:22]([O:30][CH3:31])=[CH:21][CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:32]1(=[O:38])[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1>>[CH3:31][O:30][C:22]1[C:23]2[O:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]=2[C:19]([C:13]2[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:36]4[C:32](=[O:38])[CH2:33][CH2:34][C:35]4=[O:37])[CH2:10][CH2:9]3)[N:12]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: O=C1CCC(=O)N1
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A5) and succinimide as starting compounds.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:19]=2[CH3:18])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (1.26 g, 5.20 mmol), 2,3-dimethylbenzoic acid (0.820 g, 5.46 mmol), HOBT (0.70 g, 5.20 mmol), EDC.HCl (1.09 g, 5.72 mmol) and triethylamine to adjust the pH to 7. The crude product was chromatographed on silica gel with 20% ethyl acetate in hexane. The title compound was obtained as a thick oil (1.76 g). NMR (300 MHz, DMSO-d6) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[B:29]([OH:32])[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1B(O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a stirred solution of 2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (197 mg, 0.526 mmol) in THF (1.3 mL) cooled to −78° C. was added n-butyl lithium (2.5 M in hexanes, 232 uL, 0.579 mmol). The solution was stirred for 15 minutes after which time trimethyl borate (235 uL, 2.11 mmol) was added and the solution was allowed to slowly warm to RT overnight. The reaction was quenched by addition of 0.1 M HCl and was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. Flash column chromatography (12 g silica, 0-100% ethyl acetate in DCM over 30 column volumes) provided (2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (63 mg) as a white foam. MS=340.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.46 (m, 5H), 7.25 (d, J=1.01 Hz, 1H), 7.08 (br. s, 1H), 6.85 (d, J=1.01 Hz, 1H), 5.17 (s, 2H), 3.95 (s, 3H), 2.38 (d, J=1.52 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:31])[C:26]([O:28]CC)=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:31])[C:26]([OH:28])=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Yield: 63.1 %

Procedure:
[1-Benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [1-benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetate (0.540 g, 1.24 mmol), and potassium hydroxide (0.218 g, 3.89 mmol) in THF (6 mL) and water (6 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from methylene chloride/hexane and drying at 85° C. furnished the title compound as a white solid (0.319 g, 63%), mp: 145-146° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 408; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.3 (br s, 1H), 8.75 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 7.8 (dd, 1H, J=7.2 Hz and 2.3 Hz), 7.65-7.7 (m, 2H), 7.6 (dd, 1H, J=8.5 Hz and 2.0 Hz), 7.5 (t, 1H, J=8.9 Hz), 7.25-7.35 (m, 5H), and 5.6 ppm (s, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([NH:39][C@@H:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=3)[O:19][N:18]=2)=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]([NH:39][C@@H:40]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH3:41])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[C:24]([C:35]([F:36])([F:37])[F:38])[CH:23]=3)[O:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(CO[Si](C)(C)C(C)(C)C)N[C@H](C)C(=O)OC(C)(C)C)cc3)no2)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(CO)N[C@H](C)C(=O)OC(C)(C)C)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl N-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethyl]-D-alaninate (1.2 g, 0.0017 mol) in THF (25 ml) was added TBAF (50 mg, 0.1 eq) at RT. The reaction mixture was stirred at RT for 30 min and quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The crude material was purified by column chromatography using chloroform and methanol (90:10) as an eluent to afford tert-butyl N-[2-hydroxy-1-(4-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethyl]-D-alaninate as brown oil, as mixture of two diastereomers (0.7 g, 77%). The two diastereomers were separated by chromatography (SFC on Chiralpak ADH, 20% Co-solvent: 0.5% DEA in Ethanol, Total Flow: 3 ml/min), with the first eluting isomer Rt at 4.06 min and the second eluting isomer Rt at 5.25 min.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[C:4]([CH3:12])([CH3:11])[CH2:3]1.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])=[O:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: NCCCN1CCCC1=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)NCCCN4CCCC4=O)C(C)(C)C3)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (102 mg, 0.20 mmol), N-(3-aminopropyl)-2-pyrrolidinone (85 μL, 0.60 mmol), EDC (58 mg, 0.30 mmol), and HOBt (46 mg, 0.30 mmol) was added N,N-dimethylformamide (2 mL) and triethylamine (140 μL, 1.01 mmol). The mixture was stirred at room temperature for 16 h, quenched with 1:1 water:brine, and extracted with EtOAc. The organic layer was washed with 1:1 water:brine (3×). The organic layer was dried over magnesium sulfate, filtered and purified by reverse phase HPLC (C-18, eluting with a 45:55 to 80:20 gradient of acetonitrile:water+0.1% TFA). The combined fractions were diluted with ethyl acetate and dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to afford the title compound (97 mg, 0.15 mmol, 76% yield) as a white solid. MS ESI: [M+H]+ m/z 631.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.68 (t, J=5.6, 1H), 7.46 (s, 1H), 7.28 (d, J=4.9, 1H), 7.14 (s, 1H), 5.86 (s, 1H), 3.29 (s, 1H), 3.24-3.12 (m, 2H), 3.12-3.03 (m, 1H), 2.99-2.88 (m, 1H), 2.31 (s, 3H), 2.19 (m, 2H), 2.02 (m, 2H), 1.86 (m, 5H), 1.66-1.50 (m, 3H), 1.40 (m, 1H), 1.11 (s, 3H), 0.92 (s, 3H).