Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CC(C)([O-])C.[K+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2F)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A flask was charged with 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol) and tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.112 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treated with potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was evaporated in vacuo and the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH)+ LC tr=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2.C1CCN2C(=NCCC2)CC1>CC#N>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 4-chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester (1 g, 2.93 mmol) in CH3CN (30 mL), 5-hydroxy-indole (0.779 g, 5.85 mmol) and DBU (0.88 mL, 5.85 mmol) are added. After heating at 60° C. for 5 h the reaction is evaporated and the product isolated using FCC eluting with heptane:EtOAc 1:1. MS (ESI) m/z 439.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][OH:21])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:29][C:30]([F:38])(S(F)(=O)=O)C(O)=O>C(#N)C.C(OCC)C.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][O:21][CH:30]([F:38])[F:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)OCc1ccccc1
Agent: [Cu]I
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 39.2 %

Procedure:
To a stirred solution of the compound of Formula XII(a), benzyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (1 g, 3.38 mmol) in acetonitrile (10 mL) was added copper(I) iodide (64.4 mg, 0.338 mmol) and sodium sulfate (48.1 mg, 0.338 mmol). The resulting mixture was stirred at 60° C. and treated with 2,2-difluoro-2-fluorosulfonylacetic acid (524 μL, 5.08 mmol), dropwise, as a solution in acetonitrile (2 mL) over a period of 1.5 h. Upon completion of the addition, the mixture was stirred for a further 30 min then cooled to room temperature. The mixture was diluted with diethyl ether and washed with brine (2×), water (3×) and brine (1×). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-30% ethyl acetate in hexanes, to provide the compound of Formula XIII(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid benzyl ester (458 mg, 40%) as a colorless sticky oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.32-7.38 (m, 5H), 6.18 (wt, 1H), 5.28 (dd, 1H), 5.19 (dd, 2H), 4.55 (dt, 1H) 4.22 (td, 1H), 4.15 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:16][C:10]2[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]3[C:5]([F:18])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:17])[N:9]=2)([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:38][CH:37]=1
Reactant: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazine-2-ylamine (5 g, 15.43 mmol, Example 1 intermediate h) was dissolved in DCM (154 ml) under argon, triethylamine (4.30 mL, 30.9 mmol) and 4,4′-dimethoxytrityl chloride (5.75 g, 16.97 mmol) were added and the reaction mixture was stirred at rt for 18 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The organic layer was washed with aq 10% citric acid, water, aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl) to give the title compound: 8.16 g (69.2% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=1>CN(C=O)C>[CH2:1]([N:24]1[CH2:23][CH2:22][CH:21]([N:19]2[CH:20]=[C:16]([Br:15])[CH:17]=[N:18]2)[CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Brc1cnn(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Benzyl bromide (0.42 mL, 3.56 mmol) and potassium carbonate (670 mg, 4.85 mmol) were added to a solution of 4-(4-bromo-1H-pyrazol-1-yl)piperidine (743.7 mg, 3.23 mmol) in DMF (10 mL), and the reaction stirred at room temperature overnight. The reaction was quenched with the addition of water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined and washed with water (2×50 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford 1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine (673 mg, 65%) as a light yellow oil. MS (ESI, pos. ion) m/z 321 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:12][C:9]2([CH2:11][CH2:10]2)[CH2:8][C@H:7]1[C:13](O)=[O:14])=[O:5])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[OH:14][CH2:13][CH:7]1[CH2:8][C:9]2([CH2:10][CH2:11]2)[CH2:12][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)[C@@H]1CC2(CC2)C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CC2(CC2)CC1CO
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
trans-6-(Ethoxycarbonyl)spiro[2.4]heptane-5-carboxylic acid (165 mg, 832 mmol) was placed in a 25 mL round bottom flask. After flushing the flask with nitrogen, tetrahydrofuran (1.6 mL) was added and the reaction mixture was cooled to −78° C. 4-Methylmorpholine (0.11 mL, 1.0 mmol) and isobutyl chloroformate (0.12 mL, 0.93 mmol) were added and the reaction mixture was allowed to warm to ambient temperature. After 15 min., the reaction mixture was recooled to −78° C. and sodium borohydride (60 mg, 1.6 mmol) was added. Methanol (1.3 mL) was added and the reaction mixture was warmed to ambient temperature over 2 h and then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with saturated aqueous sodium chloride solution and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on silica gel using 35:65 ethyl acetate:hexanes as eluent provided ethyl(5R/S,6R/S)-6-(hydroxymethyl)spiro[2.4]heptane-5-carboxylate as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][C@@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of (S)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (Klein, J. P.; Leigh, A, J.; Michnick, J.; Kumar, A. M.; Underiner, G. E. Asymmetric Synthesis of Chiral Secondary Alcohols, U.S. Pat. No. 5,629,423 (May 13, 1997)) (14 g, 50 mmol) and triethylamine (14 ml) was cooled to 0° C. in dichloromethane (200 ml) and methanesulfonyl chloride (5.80 ml. 75 mmol) was added slowly at 0° C. After stirring for an additional 4 hours at 0° C., the reaction was quenched by the addition of water and extracted with dichloromethane (4x 150 ml). The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g).
Reaction SMILES: [NH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([O:11][CH3:12])[N:4]=1)[NH2:2].CC(O)C.[N:17]#[C:18]Br>C(#N)C>[NH2:17][C:18]1[N:4]2[C:5]([O:11][CH3:12])=[N:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]2=[N:1][N:2]=1
Reactant: N#CBr
Reactant: COc1ncc(OC)c(NN)n1
Solvent: CC(C)O
Solvent: CC#N
Product: COc1cnc(OC)n2c(N)nnc12
Temperature: 42 °C
Yield: 87.3 %

Procedure:
4-Hydrazino-2, 5-dimethoxypyrimidine (8.522 g, 0.050 mole) was loaded into a 500 mL three necked flask equipped with an overhead stirrer, condenser, and thermocouple temperature probe. IPA (100 mL) was added and the mixture was stirred to form a slurry. A solution of cyanogen bromide (8.546 g, 0.081 mole) in acetonitrile (15 mL) was added, resulting in a 3° C. endotherm, followed by a 6° C. exotherm. The mixture wash heated to 42° C. for 3.5 h, then cooled to room temperature. A solution of sodium carbonate (5.92 g) in water (100 mL) was added, and the resulting mixture was stirred for 3.3 h. The product precipitated from the solution an d was recovered by filtration through Whatman #54 paper using a Buchner funnel and aspirator vacuum. The solids w ere dried overnight in vacuo at room temperature to give 8.516 g of 3-amino-5,8-dimethoxy[1,2,4]triazolo[4,3-c]pyrimidine (yield=87.1%): mp=232-235° C. 1H NMR (300 MHz, DMSO-d6) 3.83 (s, 3H), 3.97 (s, 3H), 6.45 (br s, 2H), 6.84 (s, 1H); 13C NMR (75.47 MHz, DMSO-d6) 55.4, 56.4, 115.5, 139.7, 142.0, 142.5, 148.3.
Reaction SMILES: N#N.[CH:3]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:28]([O:31]C(CCl)CCl)CCl.Cl>O.ClC1C=CC=CC=1Cl>[CH:6]1[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:3]=[CH:4][C:5]=1[CH:28]=[O:31]
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=Cc1ccc2c3ccccc3c3ccccc3c2c1
Reaction time: 16 h

Procedure:
A 1 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with triphenylene (Aldrich Chemical Co., Milwaukee, WI, 53201, 30 g, 0.131 mol) and o-dichlorobenzene (150 mL). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 58 g, 0.223 mol, 26 mL), was added in one portion to the mixture. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 25.6 g, 0.223 mol, 20 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40° over 2 h and further stirred for 16 h. Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100 g) and filtered again. The solvent was removed to give a crude yellow oil which was purified by preparative HPLC using PhCH3 as the eluting solvent. The fractions containing the aldehyde were combined and the solvent removed to give an oil which solidified (8.31 g, 25%). This material was used without further purification. Recrystallization from CH2Cl2 /CH3OH gave pure 2-triphenylenecarbaldehyde mp 160°-161.5°, (C,H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][CH:21]([CH3:41])[CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[OH:24].O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][N:44]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:20][CH:21]([CH3:41])[CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[O:24][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][N:44]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: CC(C)CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A mixture of triphenylphosphine (1.34 g, 5.09 mmol), 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (942 mg, 3.06 mmol), and methyl 6-hydroxynicotinate (0.390 g, 2.55 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 0.5 hours. Diisopropyl azodicarboxylate (1.02 g, 5.09 mmol) was added dropwise. After consumption of the starting material, as indicated by TLC, the mixture was concentrated. Purification by column chromatography gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinate (400.0 mg, 36%). 1H NMR (400 MHz, CDCl3, δ): 8.69 (d, 1H), 8.04-8.06 (m, 1H), 7.56-7.61 (m, 4H), 7.42-7.48 (m, 4H), 6.72 (d, 1H), 6.20-6.24 (m, 1H), 3.78 (s, 3H), 1.94-2.01 (m, 1H), 1.58-1.72 9 (m, 2H), 0.89-0.94 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.O[Li].O.Cl>C1COCC1.O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2cccc(O)c2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C#Cc2cccc(O)c2)cc1

Procedure:
Ethyl 2-(4-((3-hydroxyphenyl)ethynyl)phenoxy)acetate (48.0 mg, 0.162 mmol) was dissolved in THF (1 mL), and LiOH.H2O (20.4 mg, 0.486 mmol) in water (1 mL) was added. The mixture was stirred over night. and 14% HCl (0.2 mL) was added until pH<1. Water (10 mL) was added, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was white/yellow and solid (39.5 mg, 92%). Rf=0.02 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6): □ 4.52 (s, 2H, CH2OH); 7.1 (m, 8H, Ph); 9.71 (s, 1H, OH); 12.94 (s, 1H, COOH). 13C-NMR (DMSO-d6): □ 64.5 (OCH2); 88.2 (CC); 88.7 (CC); 114.7, 114.9, 116.0, 117.6, 122.0, 123.5, 129.8, 132.9, 157.3, 158.0 (Ph); 169.9 (COO). EI-MS: m/z calculated for C16H12O4 [M]+268; [C14H9O2]+209; [C8H8O3]+ 152. found 268, 207, 152.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:27])=[O:26]
Reactant: O=C(Oc1cccnc1)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)Oc2cccnc2)CC1
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-yl 4-hydroxypiperidine-1-carboxylate (330 mg), triethylamine (0.25 mL) and DCM (7 mL) was added slowly dropwise methanesulfonic acid chloride (0.13 mL) at room temperature. After stirring overnight, the reaction liquid was purified directly by silica gel column chromatography (hexane/ethyl acetate=50/50 to 0/100) to obtain pyridin-3-yl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (390 mg) as a colorless solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)=[C:14]([O:28][CH3:29])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([O:28][CH3:29])[CH:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CCCO[Si](C)(C)C(C)(C)C)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
A mixture of Example 451A (828 mg, 2.0 mmol) and 1M LiOH (3 mL) in THF (10 mL) was heated to 50° C., stirred for 3 hours, diluted with ethyl acetate, washed with saturated sodium monobasic phosphate (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=1>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=5)[CH2:20]4)=[O:16])=[CH:25][CH:26]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCCNC4)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCCN(Cc5cccc(C(F)(F)F)c5)C4)cc3)oc12
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4-(5-Cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(3S)-piperidin-3-ylmethyl]benzamide (20 mg) was taken up in methanol (3 ml) and then potassium carbonate (14 mg) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (14 □l) were added. The mixture was stirred for 1.5 h and then added directly to a Biotage 40M samplet for purification via column chromatography on a Biotage Horizon 40M column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes to provide the title compound (20 mg, 71%). Mass spectrum (ESI) 561.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.59 (s, 1H), 7.55 (m, 3H), 7.41 (t, J=7.7 Hz, 2H), 6.43 (t, J=5.8 Hz, 1H), 3.47 (m, 3H), 2.72 (m, 3H), 2.34 (s, 3H), 2.03 (m, 2H), 1.90 (t, J=11.4 Hz, 2H), 1.47 (d, J=6.9 Hz, 6H), 1.31 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:56])[F:58])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (114 mg, 1.1 equiv), ethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B3) (139 mg, 1 equiv), DMF (1.2 ml) and DIPEA (0.16 ml, 3 equiv) was shaken at room temperature, then HATU (176 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 30 min. A further portion of Intermediate D5 (21 mg, 0.2 equiv) was added, followed 1 h later by further HATU (23 mg, 0.2 equiv), then shaking was continued for 18 h. Reverse phase HPLC (Preparative Method B) gave ethyl 2-{4-[{[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate as a white solid (149 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1Cl
Yield: 74.6 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 75%). MS (ISP) 389.2 [(M+H)+]; mp 247° C.