Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[C@@H:4]([CH3:6])[OH:5].C(N(CC)CC)C.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:24]([NH:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[C@@H:4]([CH3:6])[OH:5])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Yield: 86.3 %

Procedure:
Methyl L-threoninate hydrochloride (16.9 g, 100 mmol), prepared by the method of Lall, J. Org. Chem., 67, pp. 1536-1547, was dissolved in 200 mL of anhydrous CH2Cl2 and the solution was cooled to 0° C. under N2. Triethylamine (27.8 mL, 200 mmol) was then added followed by triphenylmethylchloride (27.9 g, 100 mmol) and the reaction was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was then filtered and the resulting solid was rinsed with several portions of CH2Cl2. The combined filtrates were concentrated under reduced pressure and the resulting syrup was dissolved in 150 mL of ethyl acetate and then washed successively with 100 mL of saturated aqueous NaHCO3 solution, 100 mL of 10% aqueous citric acid solution, 50 mL of H2O and 50 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a syrup. The syrup was treated with 200 mL of hexanes and the mixture was stirred rapidly overnight to give a white solid. The solvent was decanted and the solid was washed with an additional portion of hexanes. The mixture was filtered and the isolated white solid was dried under vacuum for several days to give methyl N-trityl-L-threoninate (32.4 g) as a sticky, white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.CC1(C)[O:17][C:16](=O)[CH:15]=[C:14]([CH2:19][CH2:20][C@H:21]2[NH:24][C:23](=[O:25])[C@H:22]2[NH:26][C:27](=[O:35])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13]1>C1(C)C=CC=CC=1>[O:13]=[C:14]([CH2:19][CH2:20][C@H:21]1[NH:24][C:23](=[O:25])[C@H:22]1[NH:26][C:27](=[O:35])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:15][C:16]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: CC1(C)OC(=O)C=C(CC[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)O1
Reactant: COc1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)CC(=O)CC[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)cc1
Yield: 74 %

Procedure:
A solution of 4-methoxybenzyl alcohol (1.50 g, 10.87 mmol) in toluene (6 ml) was added to a solution of (3S,4R)-4-[(2,2-dimethyl-4H-1,3-dioxin-4-on-6-yl)ethyl]-3-phenylacetamidoazetidin-2-one (3.86 g, 10.78 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and the residue triturated with toluene to give the title compound (3.50 g, 75%) as a crude product; νmax (CH2Cl2) 3412, 1772, 1747, 1717, 1684 and 1514 cm-1 ; δH (CDCl3) 1.63 (2H, m), 2.39 (2H, t, J7.0 Hz), 3.37 (2H, s), 3.58 (2H, s), 3.68 (1H, m), 3.81 (3H, s), 5.09 (2H, s), 5.18 (1H, m), 6.26 (1H, br.s, exch.), 6.63 (1H, d, J 7.9 Hz), 6.89 (2H, d, J 8.6 Hz) and 7.21-7.38 (7H, m); m/z (FAB, -ve ion, thioglycerol) 437 (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.ClC1[N:15]=[CH:14][C:13](CCl)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:15][CH2:14][CH3:13])=[CH:5][N:6]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: ClCc1cnc(Cl)s1
Solvent: ClCCl
Product: CCNCc1cnc(Cl)s1

Procedure:
The reaction procedure of Reference Example 17 as repeated except that crude 2-chloro-5-chloromethylthiazole was used in lieu of 6-chloro-3-pyridylmethyl chloride and that CH2Cl2 was used as the extractant. The procedure gave the title compound as a crude oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[C:5]([NH2:10])[CH:4]=1.[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.O.CO>S1(CCCC1)(=O)=O>[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[S:9][C:6]3[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][C:5]=3[N:10]=2)=[CH:14][CH:13]=1
Reactant: Nc1cc(Br)ccc1S
Reactant: O=C(O)c1ccc(Br)cc1
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CO
Product: Brc1ccc(-c2nc3cc(Br)ccc3s2)cc1
Temperature: 70 °C

Procedure:
A mixture of 20 g (0.083 mole) of 4-bromo-2-aminothiophenol hydrochloride and 270 g of deoxygenated polyphosphoric acid was heated at 70° C. for 4 hours. To this mixture was added a solution containing 22 g (0.11 mole) of p-bromobenzoic acid dissolved in 109 g of sulfolane. The reaction mixture was slowly heated to 200° C. and maintained at that temperature for 1 hour. After cooling, the reaction mixture was poured into a 1:1 water-methanol solution to precipitate the product. The light tan precipitate was filtered, washed with dilute ammonium hydroxide, washed with water, and then air dried. The 2-(4-bromophenyl)-5-bromobenzothiazole was recrystallized from toluene to give 24.5 g (80% of theoretical), m.p. 162°-163° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:21]3[CH:22]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cc(F)c(/C=C/C(=O)O)cc1F
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1cc(F)c(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1F

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,5-difluoro-4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.86 min; [M+H]+=402.17.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([CH:15]=C)[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.O.I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([CH:15]=[O:27])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1
Reactant: C=Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 1 g of 3-bromo-5-(2,6-difluorophenyl)-7-vinyl-1H-pyrazolo[4,3-c]isoquinoline in 13 ml of THF and then 7 ml of water, 13 ml of tert-butanol, 0.79 ml of a solution of osmium tetroxide at 2.5% in 2-methyl-2-propanol, and 17 g of sodium periodate are added. The mixture is stirred at RT for 3 h and then poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. This gives 1.047 g of a crude product, which is purified by chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (95/5 by vol.), to give 686 mg of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (cream solid). MS (E/I): m/z=388 (M+); 1H NMR: 7.41 (d, J=7.9 Hz, 2H); 7.77 (m, 1H); 8.34 (broad s, 1H); 8.47 (dd, J=8.5, 1.2 Hz, 1H); 8.69 (d, J=8.5 Hz, 1H); 10.15 (s, 1H); 14.89 (broad m, 1H).
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[N:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[N:6][N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(N)C1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NC3CNCCC3c3cccc(C(F)(F)F)c3)nnnc12

Procedure:
Compound 21 was prepared following general synthesis scheme 9 wherein 4-hydroxybenzo[d][1,2,3]triazine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.98 (d, 1H), 8.84 (t, 1H), 8.54 (d, 1H), 8.50 (d, 1H), 8.30 (d, 1H), 8.04-7.89 (m, 2H), 7.67 (s, 1H), 7.59 (t, 1H), 7.45 (d, 2H), 5.42-5.26 (m, 1H), 3.64 (d, 1H), 3.49 (d, 1H), 3.35 (td, 1H), 3.23-2.90 (m, 2H), 2.52-2.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=[N:37][OH:38])CC(C3C=CC(F)=CC=3C3C=NC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:37][OH:38])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=NO
Reactant: Cn1cc(-c2cc(F)ccc2C2CC(=O)c3cnc(N)nc3C2)cn1
Product: Cn1cc(-c2cc(F)ccc2C2CC(=NO)c3cnc(N)nc3C2)cn1

Procedure:
The title compound was prepared from 2-amino-7-[4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one oxime (example 4/a stage 2).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][C@H:39]([CH2:47][OH:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[I-].[Na+].C(#N)C>CN1C(=O)CCC1>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][C@H:39]([CH2:47][OH:48])[CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@H](CO)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
N-{(1S,2R,3S,4R)-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (46.8 mg, 90 μmol) of Example 4, L-phenylalaninol (271 mg, 1.80 mmol) and sodium iodide (6.75 mg, 45 μmol) are placed in a 0.5-2.5 ml microwave vial. Acetonitrile (0.25 ml) and NMP (0.25 ml) are added and the reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 200° C. The reaction is shown to be complete by LCMS after 1 hour. The title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 636 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([OH:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:26]([O:29]CC=C)[CH:27]=[CH2:28].C(C1C=CC=C(C2C(F)=CC=CC=2F)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]2[O:15][CH:27]([CH2:26][OH:29])[CH2:28][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccccc1-c1c(F)cccc1F
Reactant: C=CCOCC=C
Agent: C=CCc1cccc(-c2c(F)cccc2F)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: C=CCBr
Solvent: Cc1cc(C)cc(C)c1
Product: OCC1Cc2cccc(-c3c(F)cccc3F)c2O1
Yield: 72 %

Procedure:
Treatment of 2′,6′-difluoro-1,1′-biphenyl-2-ol (3.8 g, 18.43 mmol) with potassium carbonate (10.19 g, 73.72 mmol) and allyl bromide (2.67 g, 22.11 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,6′-difluoro-1,1′-biphenyl-2-ol. Treatment of the 3-allyl-2′,6′-difluoro-1,1′-biphenyl-2-ol (3.41 g, 13.85 mmol) with 3-chloroperoxybenzoic acid (7.25 g, 41.54 mmol, 77%) followed by potassium carbonate (4.78 g, 34.62 mmol) generally according to the procedure described for Intermediate 9 afforded 3.5 g (72%) of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol as an amber oil. Anal. calcd. for C15H12F2O2: C, 68.7; H, 4.61. Found C, 67.26; H, 4.5.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2([OH:33])[C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:32])[CH3:31])[CH:9]=[CH:10][CH:11]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH:2]([C:6]1[CH:7]=[C:8]([C:12]2([OH:33])[C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:32])[CH3:31])[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL, 10.9 mmol) in THF (20 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol), and the resulting mixture was stirred for 30 minutes. To the reaction solution was added dropwise at −78° C. a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (1.0 g, 3.30 mmol) obtained in Reference Example 65 in THF (10 mL), and the resulting mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.38 g (yield: 92%) of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide as an amorphous powder. To a mixed solution of the obtained N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.66 mmol) in acetone (4 mL)-water (0.3 mL) was added pyridinium p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture was stirred for 30 minutes. The reaction solution was cooled to room temperature, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from THF-diisopropyl ether to obtain 194 mg (yield: 72%) of the title compound. Melting point: 189-190° C.
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:50]=[CH:49][C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[CH:47][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[OH:23][C:24]1[CH:50]=[CH:49][C:48]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)=[CH:47][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:39]=[CH:38][C:30]=1[C:31]([OH:33])=[O:32])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccs2)ccc1C(=O)O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
Thioanisole (2.0 mL) and trifluoroacetic acid (6.8 mL) were added to the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(thiophen-2-yl)benzoate (0.19 g), followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solid substance was collected by filtration, and water and 2-propanol were added to the obtained solid substance. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.11 g of 2-(2-hydroxy-5-(morpholin-4-yl)benzamido)-4-(thiophen-2-yl)benzoic acid as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:15]([O:17][C:18]([C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:23]=[N:22][C:21]=1[C:34]([OH:36])=O)=[O:19])[CH3:16].P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]2[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[C:21]([C:34](=[O:36])[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:22]=[N:23]2)=[CH:31][CH:30]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c(C(=O)O)nnn1Cc1ccc(OC)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(=O)N(C)c2ccccc2)nnn1Cc1ccc(OC)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Under the argon atmosphere, N-methylaniline (0.1 ml, 0.923 mmole) and pyridine (0.32 ml, 3.96 mmole) were added to a solution of 5-ethoxycarbonyl-l-(4-methoxybenzyl)-1,2, 3-triazole-4-carboxylic acid (311 mg, 1.02 mmole) in methylene chloride (3 ml). To the reaction mixture, which had been cooled to -30° C., was added a solution of phosphorus oxychloride (192 mg, 1.25 mmole) in methylene chloride (0.5 ml). After the mixture was stirred at -30° C. for 1 hour, the reaction was quenched by adding water. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate and a saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate =1:1) to give ethyl 1-(4-methoxybenzyl)-4-(N-methyl-N-phenylcarbamoyl)-1,2,3-triazole-5-carboxylate as a yellow crystalline powder (329 mg, 90.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][O:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[O:33][C:34]([C:40]([F:43])([F:42])[F:41])=[C:35]([C:37](O)=[O:38])[N:36]=1.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>[CH3:31][C:32]1[O:33][C:34]([C:40]([F:43])([F:41])[F:42])=[C:35]([C:37]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH:14]4[CH2:19][O:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[O:22])[CH2:16][CH2:15]4)=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)=[O:38])[N:36]=1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1ccc(-c2ccc(C3CCC(CC(=O)OCc4ccccc4)OC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)Nc2ccc(-c3ccc(C4CCC(CC(=O)OCc5ccccc5)OC4)cc3)cc2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of benzyl 2-(5-(4′-amino-[1,1′-biphenyl]-4-yl)tetrahydro-2H-pyran-2-yl)acetate (118 mg, 0.294 mmol) in DMF (2 ml) at room temperature was added 2-methyl-5-(trifluoromethyl)oxazole-4-carboxylic acid (74.5 mg, 0.382 mmol) and DIPEA (0.103 ml, 0.588 mmol) and the reaction was stirred at room temperature for 10 min then was added HATU (145 mg, 0.382 mmol). The reaction was stirred at room temperature for 30 min. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc/Heptane) to give the title compound 138 mg (yield 81%). MS (ESI) m/z 579.4 (M+1). Retention time 1.69 min (condition A).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:20]([O:22][C:23]3[N:24]=[C:25]4[C:30](=[C:31]5[C:36]=3[CH:35]=[CH:34][CH:33]=[CH:32]5)[CH:29]=[CH:28][CH:27]=[CH:26]4)[CH2:21][C@H:15]2[C:14](=[O:37])[NH:13][C@:12]2([C:39]([NH:41][S:42]([CH:45]3[CH2:47][CH2:46]3)(=[O:44])=[O:43])=[O:40])[CH2:38][C@H:11]2[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[N:48]1[CH:53]=[CH:52][N:51]=[CH:50][C:49]=1[C:54](O)=[O:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:45]1([S:42]([NH:41][C:39]([C@@:12]23[CH2:38][C@H:11]2[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:2][C:54]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][N:48]=2)=[O:55])[C:17](=[O:18])[N:16]2[CH2:19][C@H:20]([O:22][C:23]4[N:24]=[C:25]5[C:30](=[C:31]6[C:36]=4[CH:35]=[CH:34][CH:33]=[CH:32]6)[CH:29]=[CH:28][CH:27]=[CH:26]5)[CH2:21][C@H:15]2[C:14](=[O:37])[NH:13]3)=[O:40])(=[O:43])=[O:44])[CH2:46][CH2:47]1
Reactant: N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Reactant: O=C(O)c1cnccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O)c1cnccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 25a (320 mg, 0.47 mmol) in dimethylformamide (5 mL) was added pyrazinecarboxylic acid (0.065 g, 0.52 mmol), HATU (214 mg, 0.56 mmol) and diisopropylethylamine (0.2 mL, 1.18 mmol). The reaction mixture was stirred at 25° C. for 2 h and then partitioned between 5% aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by crystallization from ethyl acetate I hexane to give the desired product (155 mg, 44% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1OCC#Cc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: OCc1cc(F)ccc1OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.50 g (10.3 mmol) of 5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]benzoic acid are suspended in 10 ml of THF, 1.04 g (10.3 mmol) of N-methylmorpholine are added, the mixture cooled to 0° C., and 1.12 g (10.3 mmol) of ethyl chloroformate are added. The mixture is warmed to room temperature and stirred for 30 min. 1.17 g (31.0 mmol) of sodium borohydride are added to this solution, and the mixture is stirred at room temperature for 5 h. Then methanol is added until gas evolution has subsided, and subsequently 1 N hydrochloric acid is used to acidify. The solvent is distilled out in vacuo, and the residue is taken up in ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent is distilled out in vacuo. 4.62 g (8.69 mmol, 85% of theory) of the title compound are isolated.