Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (25 mg), ethyl β-alaninate (14 mg) and acetic acid (0.1 mL) in DCM (5 mL) was added sodium triacetoxyborohydride (26 mg). The reaction was stirred at 20° C. for 2 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with brine (25 mL), and evaporated to afford the crude product ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-β-alaninate (D90) (30 mg), which was used directly in the next step. MS (ES): C27H31ClN4O4 requires 510; found 511.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+]([O-])=O)[C:3]=1[Cl:12].S(=O)(=O)(O)[OH:14].S(O)(O)(=O)=O.ClC1C=C(Cl)C(Cl)=CC=1N.N([O-])=O.[Na+]>C(O)(C)C.[Pt].O>[Cl:8][C:5]1[CH:4]=[C:3]([Cl:12])[C:2]([Cl:1])=[CH:7][C:6]=1[OH:14]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1c(Cl)ccc(Cl)c1Cl
Agent: [Pt]
Agent: Nc1cc(Cl)c(Cl)cc1Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)O
Product: Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 1.5 h
Yield: 62 %

Procedure:
226.5 gm (1.0 mols) of 1,2,4-trichloronitrobenzene were dissolved in 226 gm of isopropanol and hydrogenated in the presence of 6.1 gm of wet 1% Platinum on charcoal at 100° C. and 100-200 psig over a 90 minute period. The reaction mixture was filtered to remove the catalyst and the clear solution slowly dropped into a hot solution of 1125 gm of H2O and 500 gm of 98% sulfuric acid (5.0 mols) under vacuum to remove the isopropanol by distillation. The finely divided 2,4,5-trichloroaniline sulfate slurry was then cooled to -5° C. with good agitation and 56.9 gm (0.95 mols) of NaNO2 in 125 ml of water were added over a 15 minute period while maintaining a maximum temperature of +5° C. After 30 minutes of agitation the reaction mixture was filtered to remove an insoluble impurity. The resulting 2,4,5-trichlorobenzenediazonium sulfate solution was then added cold (0°±5° C.) to a boiling solution of 1000 gm of cupric sulfate heptahydrate in 2000 ml of water. As the product is formed, it is removed from the zone of reaction by steam distillation. The product in the steam distillate is extracted with two 300 ml aliquots of methylene chloride and stripped to dryness to obtain 123 gm of crude 2,4,5-trichlorophenol (0.62 mol) which analyzed to be 95.1% pure.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26](O)=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)N4CCOCC4)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.8 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (prepared as in Example 3, 200 mg, 0.48 mmol) and morpholine (51 μL, 0.58 mmol) in dichloromethane (1 mL), N,N-dimethylformamide (500 μL) and N-methylmorpholine (152 μL, 1.45 mmol) was added 1-hydroxybenzotriazole hydrate (132 mg, 0.97 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (186 mg, 0.97 mmol) in one portion. The mixture was then stirred at 25° C. for 14 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1 N aqueous sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-morpholin-4-yl-methanone (85 mg, 36%) as a yellow solid: LC/MS m/e calcd for C26H31N3O4S [M+H]+ 482.62, observed 482.2; 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (m, 2H), 1.47 (m, 2H), 1.55-1.85 (m, 5H, H), 2.09 (m, 1H), 2.25 (m, 1H), 3.02 (s, 3H), 3.72 (br. s., 8H), 4.27 (t, J=7.9 Hz, 1H), 6.41 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.93 (d, J=1.9 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 11.01 (br, 1H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].C([O-])(=O)C.[Mg+2:10].C([O-])(=O)C>>[C:1]([O-:5])(=[O:4])[CH:2]=[O:3].[Mg+2:10].[C:1]([O-:5])(=[O:4])[CH:2]=[O:3]
Reactant: O=CC(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Product: O=CC(=O)[O-]
Yield: 98 %

Procedure:
To 148 g (1.00 mol) of a 50% aqueous glyoxylic acid solution was added 355.97 g (0.5 mol) of a 20% aqueous magnesium acetate solution. The resulting solution was concentrated by means of an evaporator and further dried at 50° C. for 1 hour to obtain 83.47 g (0.49 mol, yield: 98.0%) of magnesium glyoxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH2:27]([N:29]([CH2:30][CH3:31])[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1)[CH3:28]
Reactant: CCNCC
Reactant: Cc1cc(-c2noc(-c3cc(C)nc(Cl)c3)n2)ccn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN(CC)c1cc(-c2nc(-c3ccnc(C)c3)no2)cc(C)n1
Temperature: 90 °C
Reaction time: 72 h
Yield: 23.8 %

Procedure:
To a solution of 2-chloro-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (160 mg, 0.558 mmol, Example 43a)) in dioxane (10 mL), Cs2CO3 (636 mg, 1.95 mmol) and diethylamine (204 mg, 2.79 mmol) is added. The mixture is degassed and put under N2 before Pd(II) acetate (25 mg, 0.112 mmol) and Xantphos (116 mg, 0.201 mmol) is added. The mixture is stirred in a sealed vial at 90° C. for 72 h before it is cooled to rt. The mixture is filtered and the filtrate is evaporated. The crude product is purified on prep. TLC plates with heptane:EA 3:1 to give 2-diethylamino-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (43 mg) as a yellow solid; LC-MS: tR=0.66 min, [M+1]+=324.15; 1H NMR δ 1.26 (t, J=7.0 Hz, 6H), 2.51 (s, 3H), 2.71 (s, 3H), 3.63 (q, J=7.0 Hz, 4H), 7.01 (s, 1H), 7.09 (s, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 8.71 (d, J=5.0 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)(=[O:3])[CH3:2].CC(O)=[O:17]>O>[C:9]1([C:6]2[S:7][CH:8]=[C:4]([C:1]([CH:2]=[O:17])=[O:3])[N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1csc(-c2ccccc2)n1
Reactant: CC(=O)O
Solvent: O
Product: O=CC(=O)c1csc(-c2ccccc2)n1

Procedure:
4-Acetyl-2-phenylthiazole (16.9 g., 0.083 mol) was dissolved in a mixture of 165 ml. CH3CO2H and 65 ml. H2O by warming to 50°. SeO2 (19.4 g., 0.175 mol) was added and the mixture refluxed for 3 hours, then decolorized with activated carbon, filtered, the filtrate concentrated to an oil, the residue taken up in 600 ml. ethyl acetate, washed 2×300 ml. saturated NaHCO3 and 1×300 ml. brine, and stripped to solids (crude hydrate), 16.2 g. The latter (6 g.) was heated to melting (155°) in vacuo for 10 minutes and cooled to yield title product as a glass; 1H-nmr 7.4-7.7 (m, 3H), 7.9-8.2 (m, 2H), 8.8 (s, 1H), 9.9 (s, 1H).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>C(O)C>[CH3:35][Si:33]([CH3:36])([C:29]([CH3:32])([CH3:31])[CH3:30])[O:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
To a dimethylformamide (hereinafter, abbreviated as DMF in some cases) (100 mL) solution of (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (50 g) were sequentially added imidazole (29.22 g), and tert-butyldimethylchlorosilane (30.87 g) under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, a small amount of ethanol was added, the reaction solution was poured into ice water, and this was extracted with ethyl acetate:hexane (2:3). The extract was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution, water and a saturated saline, dried with sodium sulfate, and concentrated under reduced pressure to obtain a titled compound (76.2 g) having the following physical property values.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:47])[C:25](=[O:46])[N:26](COCC[Si](C)(C)C)[N:27]=2)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]([N:14]1[CH2:15][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:47])[C:25](=[O:46])[NH:26][N:27]=2)([CH3:18])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.020 g, 0.034 mmol) in DCM (0.5 mL) and TFA (0.25 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo. The residue was dissolved in THF (0.5 mL) and aqueous ammonium hydroxide solution (25%, 0.25 mL) was added. The mixture was stirred for additional 2 h at ambient temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo to give crude 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (0.015 g, 84%), which was used in next step directly. LC/MS (Table 1, Method 2) Rt=0.997 min.; MS m/z: 536 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH3:21][C:22]1([CH3:30])[O:26][C@@H:25]([CH2:27][O:28][NH2:29])[CH2:24][O:23]1.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1.O>[CH3:21][C:22]1([CH3:30])[O:26][C@@H:25]([CH2:27][O:28][NH:29][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=2[NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH2:24][O:23]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (39.3 g, 100.0 mmol) in dry tetrahydrofuran (500 mL, 0.2 M), under nitrogen atmosphere, was added (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (14.7 g, 100.0 mmol), followed by N-methylmorpholine (27.5 mL, 0.25 mole). The orange-colored solution was cooled with an ice-water bath. Diphenylphosphinic chloride (22.9 mL, 0.12 mole) was added dropwise. Some solid formed. The mixture was warmed to ambient temperature and stirred for 18 hrs. Water was added to quench the reaction and the tetrahydrofuran was evaporated in vacuo. The remaining oil was dissolved in ethyl acetate (500 mL), washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1) two times. The ethyl acetate was removed and the crude oily solid was purified by flash chromatography (silica gel, hexane-acetone/2:1) to give N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as an off-white solid after drying in a vacuum oven at 40° C. for 20 hrs: 41.7 g (79.8%), m.p. 124-125° C. The impure fractions were combined and purified by a second column chromatography using the same condition to give a 2nd batch of 6.4 g (12.3%), mp 124-125° C., total yield 48.1 g (92.1%). 1H NMR (d6-DMSO): δ 11.9 (s, br, 1H), 8.7 (s, br, 1H), 7.6 (d, 1H, J=10.99 Hz), 7.4 (m, 2H), 7.2 (m, 1H), 6.7 (m, 1H), 4.2 (m, 1H), 4.0 (t, 1H, J1=8.3 Hz, J2=6.8 Hz), 3.8 (m, 2H), 3.7 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H); 19F NMR (d6-DMSO): δ −128.0, −133.1, −144.3; MS: 523 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][CH2:27][C:28](=O)[CH2:29]Cl>C(O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:13][CH:29]=[C:28]([CH2:27][Cl:26])[N:14]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CCCO
Product: ClCc1coc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)n1

Procedure:
A 37.9 g quantity of 3,4-dibenzyloxybenzamide and 28.8 g of 1,3-dichloro-2-propanone were suspended in 500 ml of propanol, and the suspension was heated and refluxed for 3 days. After cooling, the reaction mixture was concentrated to half its original volume under reduced pressure and 300 ml of diisopropyl ether was added. The precipitated crystals were collected by filtration and recrystallized from acetone-methanol-diisopropyl ether. The obtained crystals were dried under reduced pressure to give 20.1 g of colorless powdery 2-(3,4-bis(benzyloxy)phenyl)-4-chloromethyloxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH:14]=[O:15])[C@@H:11]([O:16][Si](C)(C)C)[C@H:10]([O:21][Si](C)(C)C)[C@H:9]2[O:26][Si](C)(C)C)=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C=O.C[CH2:44][O-:45].[Na+].S(=O)(=O)(O)[O-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:31][CH3:32])[C@H:9]([OH:26])[C@@H:10]([OH:21])[C@H:11]([OH:16])[C:12]([CH2:44][OH:45])([CH2:14][OH:15])[O:13]2)=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](C=O)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Reactant: CC[O-]
Agent: C=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 55 °C

Procedure:
To a solution of (2S,3R,4S,5R,6S)-6-(4-chloro-3-(phenoxymethyl)phenyl)-6-methoxy-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-carbaldehyde (22.9 g, 36.7 mmol) in EtOH (92 mL) under nitrogen atmosphere, was added para-formaldehyde (33.0 g, 1.1 mol) at 55° C. followed by addition of 21% NaOEt in ethanol (23.12 g NaOEt/110 mL EtOH). The reaction mixture was heated at 55° C. overnight. After the completion of the reaction as confirmed by TLC, ethanol was evaporated. The crude compound was extracted with ethyl acetate (700 mL) followed by washing with sodium bisulphate solution (68.67 g, 660.6 mmol) in water (458.7 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound, which was purified by column chromatography (silica gel, 6:4 MeOH:DCM) to obtain the compound as a white solid (12 g).
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25]#[N:26])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)[CH:39]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:49]([O:48][C:46]([N:43]1[CH2:42][CH2:41][CH:40]([N:38]2[CH:39]=[C:35]([C:2]3[C:3]([O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[C:25]#[N:26])=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:36]=[N:37]2)[CH2:45][CH2:44]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: COC(=O)N1c2ccc(Br)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.068 g, 0.156 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.065 g, 0.172 mmol), XPhos Precatalyst 2nd Generation (0.012 g, 0.016 mmol), and cesium carbonate (0.153 g, 0.468 mmol) in dioxane (2.0 mL) and water (0.400 mL) was heated in the microwave at 100° C. for 2 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.057 g, 60%) as an off-white solid. MS (ESI, pos. ion) m/z 606 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(F)c(F)c3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BX) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 84%, 407.9815 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH:46]([SH:49])[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH:46]([S:49][C:2]2[CH:30]=[CH:29][C:5]3[N:6]([C:10]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(S)C1
Reactant: O=c1oc2cc(Br)ccc2n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc3c(c2)oc(=O)n3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Tris(dibenzylideneacetone)dipalladium chloroform complex (14 mg, 13.5 □mol) and 1,1′-bis(diphenylphosphino)ferrocene (30 mg, 54.1 □mol) in degassed and dry toluene (2 ml) were stirred at room temperature until the solution turned orange (15 minutes). 6-Bromo-3-trityl -3H-benzooxazol-2-one (0.2 g, 0.44 mmol), Cs2CO3 (0.22 g, 0.68 mmol) and (RS) -3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.49 mmol) in toluene (0.5 ml) were successively added. After 4 hours stirring at 100° C., the reaction mixture was cooled to room temperature and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 1:1) to provide (RS)-3-(2-oxo-3-trityl-2,3-dihydro-benzooxazol-6-yl-sulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.19 g 7 77%) as a white foam, MS: m/e=596.1 (M+NH4+).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[F:54][CH:55]1[CH2:58][N:57]([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:56]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:47])([F:48])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:62][S:59]([N:57]2[CH2:58][CH:55]([F:54])[CH2:56]2)(=[O:61])=[O:60])=[O:35])[CH2:28][CH2:27]1
Reactant: NS(=O)(=O)N1CC(F)C1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CC(F)C1)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.12 g, 43%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.77-8.64 (m, 1H), 7.64-7.55 (m, 1H), 6.62-6.53 (m, 1H), 5.43-5.13 (m, 1H), 4.57-4.31 (m, 4H), 3.94-3.86 (m, 2H), 2.27-2.11 (m, 2H), 2.09-1.68 (m, 6H), 1.61-1.43 (m, 2H), 0.99-0.90 (m, 2H), 0.71-0.63 (m, 2H); MS (ES+) m/z 465.0 (M+1).