Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([O:32]C)=[O:31])[CH2:26][CH2:25]4)=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:34][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnc(C[C@H]3CC[C@H](C(=O)O)CC3)nc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylate (60 mg, 0.13 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (16 mg, 0.39 mmol) and then the reaction mixture was stirred at 60° C. for 8 hours. After cooling to room temperature, water was added to the mixture and the pH was adjusted to pH 2 by the addition of aqueous 1M HCl. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylic acid. MS ESI calc'd for C24H26F2N5O2 [M+H]+ 454. found 454. 1H NMR: (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.95 (s, 2H), 8.72 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 6.88 (t, J=54.4 Hz, 1H), 3.14-3.13 (m, 1H), 2.79-2.77 (m, 2H), 2.35 (s, 3H), 2.07-2.04 (m, 1H), 1.87-1.84 (m, 2H), 1.66 (s, 1H), 1.30-1.21 (m, 3H), 1.07-1.03 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[F-].[Cs+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccccc3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.3 %

Procedure:
4-Chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (100 mg, 0.159 mmol) was dissolved in dimethoxyethane (5.0 mL), and the solution was added with phenylboronic acid (58.2 mg, 0.478 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (10.4 mg, 0.0130 mmol) and cesium fluoride (145 mg, 0.954 mmol), followed by stirring at 90° C. for 6.0 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to obtain 4-chloro-5-phenyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (44.5 mg, yield 50%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[C:13]3[C:8]([C:9]([F:23])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCC=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]1([N:6]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[C:13]3[C:8]([C:9]([F:23])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 2-cyclopentyl-7-fluoro-3-(4-methoxyphenyl)-2H-indazole (0.055 g, 0.177 mmol) in CH2Cl2 containing excess equivalents of cyclohexene (0.3 mL) at −78° C. was treated with boron tribromide (0.70 mL, 0.74 mmol, 4 eq.) and slowly allowed to warm to ambient temperature. The reaction mixture was quenched by dropwise addition of CH3OH to the cooled reaction mixture. The solvent was removed in vacuo and the residue partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product. Pure product was obtained by crystallization or flash chromatography through water deactivated silica gel to give the product (0.03 g) as an amber solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH2:62].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:62][CH:61]=[CH2:60])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 1.5 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (53 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compounds (21 mg 4"-ether; 17 mg 3"-ether).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH-].[Na+].[Co:7]>CC(C)=O>[C:1]([O-:4])(=[O:3])[CH3:2].[Co+2:7].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: [Co]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)[O-]
Product: [Co+2]

Procedure:
To a reaction flask equipped with a mechanical stirrer and thermometer was charged 9.50 g (0.158 mole) of acetic acid, 9.0 g of mineral spirits and 40 g of 0.1N sodium hydroxide. Cobalt foil was used as the anode and a graphite rod as the cathode. After passing 14,970 coulombs of electricity, 4.32 g (0.073 mole) of cobalt was consumed. The organics were isolated and were tertiurated with acetone. A solid precipitated out of the solution which was filtered and dried. This gave a violet solid material that contained 31.02% cobalt.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])(=[O:23])C.[Na+]>CC(O)=O>[OH:23][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c(CO)c(-c2ccc(O)cc2)oc2ccccc12
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.50 g, 1.5 mmol) and sodium acetate (1.24 g, 15.0 mmol) in AcOH (20 mL) was heated to reflux for 15 h. AcOH was removed and the residue was poured into water and extracted with EtOAc (100 mL). The organic phase was further washed with brine and dried over sodium sulfate. The residue was mixed with potassium carbonate (0.52 g) and MeOH (10 mL) and stirred for 2 h. AcOH (1.0 mL) was added and MeOH was removed. The residue was poured into water and the solid was washed additionally with water and hexane to give 3-(hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.265 g, 62.6%). MS (ES) m/z: 269.94 (M+1), 268.94 (M); Mp. 234-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:4]=1[C:10]([CH3:20])([CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:16])[F:17])[CH:13]2[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 3.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 288 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 90 mg of the imine is reacted by reaction with 0.4 ml of titanium tetrachloride (1 M in dichloromethane) in 5 ml of dichloromethane, and 25 mg of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g of 2,3-dimethyl-4-nitropyridine 1-oxide in 50 ml of absolute methanol was treated with 0.883 g of sodium methylate, whereupon the mixture was stirred at room temperature under argon for 2 days. The reaction mixture was concentrated and the residue was extracted with methylene chloride and saturated sodium chloride solution. The methylene chloride phase was dried and evaporated. The residue, crystallized from methylene chloride/ether, gave 4-methoxy-2,3-dimethylpyridine 1-oxide of melting point 80-83°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:38][CH:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:26][O:25][C:18]2[C:19]([C:21]([O:23][CH3:24])=[O:22])=[N:20][C:15]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH2:28][CH2:29]1)=[O:34])[CH3:37]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1nc(Br)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(S(C)(=O)=O)cc2)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Yield: 70.3 %

Procedure:
The title compound (0.785 g, 82%) was prepared as a light yellow solid from [4-(methylsulfonyl)phenyl]boronic acid (0.48 g, 2.36 mmol), methyl 6-bromo-3-{[(1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-2-pyridinecarboxylate (0.945 g, 86% pure), Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol), 2M Na2CO3 (6 mL) and DME (20 mL) in a manner similar to Example 21, Step 3. The crude material was purified by chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 followed by trituration with hot hexanes containing 1% of MeOH to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 2H, J=8.3 Hz), 8.01 (d, 2H, J=8.5 Hz), 7.86 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.99 (s, 3H), 3.94 (d, 2H, J=6.3 Hz), 3.06 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 491 (M+H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C@H:14]([NH2:18])([CH2:16][CH3:17])[CH3:15].CCOC(C)=O.CCCCCC>O1CCOCC1>[C@H:14]([NH:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: N#CCc1ccc2nc(Br)sc2c1
Reactant: CC[C@@H](C)N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@@H](C)Nc1nc2ccc(CC#N)cc2s1
Temperature: 135 °C
Yield: 69.7 %

Procedure:
A mixture of 2-(2-bromobenzo[d]thiazol-6-yl)acetonitrile (2.00 g, 7.90 mmol) and (R)-sec-butylamine (4.0 mL, 39.4 mmol) in 1,4-dioxane (30 mL) was heated at 135° C. in a sealed bottle for 3.5 hr. The excess (R)-sec-butylamine and 1,4-Dioxane were removed under vacuum. The residue was diluted with AcOEt (150 mL), washed successively with saturated NaHCO3 solution (twice) and brine, and dried over anhydrous MgSO4. The title compound (1.35 g, 70% yield) was isolated as a light orange oil by ISCO (40% AcOEt/hexane).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][NH2:24])=[O:22]>C(O)C.O.Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][N:24]=[C:14]([C:11]1[NH:12][CH:13]=[C:9]([C@@H:2]([OH:1])[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6])[N:10]=1)[CH3:15])=[O:22]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=NNC(=O)c1cccc(Cl)c1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (194 mg, 0.84 mmol) was suspended in ethanol (4 ml) and water (1 ml). 3-Chlorobenzoic acid hydrazide (170 mg, 1.0 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as a ˜3:1 E:Z mixture, as a white solid: 108 mg (33%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH2:11][C@H:12]([CH3:39])[O:13][C:14]1[CH:15]=[C:16]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=2)=[O:31])[CH:29]=1)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.CN(C(ON1N=N[C:50]2[CH:51]=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[OH:10][CH2:11][C@H:12]([CH3:39])[O:13][C:14]1[CH:29]=[C:28]([CH:27]=[C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:54]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]3)=[O:24])=[CH:20][CH:19]=2)[CH:15]=1)[C:30]([NH:32][C:33]1[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=1)=[O:31]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCCCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
DIPEA (0.36 mL, 1.95 mmol) was added to a suspension of 4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoic acid (200 mg, 0.49 mmol), HATU (390 mg, 1.02 mmol) and piperidine (0.19 mL, 1.95 mmol) in DMF (3 mL) and the mixture stirred at, ambient temperature for 24 hours. The solvent was evaporated. Water (30 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried, (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% methanol in ethyl acetate, to give the desired compound (167 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14]CC)=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].N1C=CC=CC=1>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)c1cc2c(cc1O)OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 1.1 g sample of racemic ethyl 7-hydroxychroman-2-carboxylate was treated with 10 ml of 1:1 acetic anhydride-pyridine and stirred for 17 hours at room temperature. After removal of the solvents, the residual product (1.2 g) was dissolved in 12 ml of glacial acetic acid and treated with 1.26 ml of borontrifluoride etherate. The reaction mixture was gently refluxed for 17 hours, cooled, poured carefully into a mixture of sodium bicarbonate and ice and the product extracted with 1:1 tetrahydrofuran-ether. After evaporation of the solvent, 1.1 g of crude racemic-7-hydroxy-6-acetylchroman-2-carboxylic acid was obtained. Conversion of this material into the corresponding ethyl ester was achieved by refluxing 1.1 g of the crude acid in absolute ethanol in the presence of 10 mg of p-toluenesulfonic acid for 17 hours. After removal of most of the solvent, the product was extracted with 1:1 tetrahydrofuran-ether, washed with saturated sodium bicarbonate solution, water, dried and the solvents concentrated to give 1.2 g of crude ethyl ester as a mixture of the 6-acetyl and 8-acetyl derivatives in a ratio of about 7:1. This material was purified by column chromatography on silica gel to afford 0.7 g (53.5%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester as a colorless crystalline material mp 93.5°-95.5° C. (from ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:14])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
First, 1.0 g (6.1 nmmol) of trans-4-ethylcyclohexane carboxylic acid was mixed with 1.1 g (9.2 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 60° C. for hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude trans-4-ethylcyclohexylcarbonylchloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: OCCC1(c2cccnc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 5.2.2 using 3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine, 3,4,5-trimethoxybenzoyl chloride, and sodium bicarbonate to give, after chromatography on silica gel eluting with dichloromethane/methanol 5/1, the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[S:11])[NH:8][CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:12](O)(=O)[CH3:13]>[OH-].[K+].O>[CH2:12]([S:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][N:3]=[C:2]([I:1])[C:10]=12)[CH3:13]
Reactant: S=c1[nH]cnc2[nH]nc(I)c12
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCSc1ncnc2[nH]nc(I)c12
Temperature: 25 °C

Procedure:
Compound 5 (43.5 g, 157 mmol) was stirred in potassium hydroxide solution (38.6 g KOH in 350 mL of water) for 30 min. The mixture was filtered and the filtrate was acidified to pH 10,by addition of acetic acid and then diluted with 350 mL of absolute ethanol. Iodoethane (10 mL) was added and the solution was stirred at room temperature. Additional 10 mL aliquots of iodoethane were added after 30 min. and 1.0 h. The reaction was complete after a total of 90 min. Other runs required further addition of iodoethane to complete the reaction. The reaction solution was diluted with 700 mL of water and 20 mL of acetic acid. The mixture was cooled in an ice-bath and the solid was filtered, rinsed with water and dried. This crude product was dissolved in 300 of DMF and stirred at 90° C. for 15 min. Insoluble material was filtered away and the filtrate was diluted with 1 L of water and cooled in an ice-water bath. The solid was filtered, rinsed with water and dried: 19 g (40%) yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([OH:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)CC(C)(C)c1ccc(F)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(F)c(OC)c1
Yield: 89.8 %

Procedure:
2.78 g (9.78 mmol) of ethyl-4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate is oxidized to the corresponding α-ketoester with SO3/Py in dichloromethane as in Example 273. After chromatography on a Flashmaster, 2.48 g (89.9%) of the desired compound is obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:12]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15]2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C@:24]1([CH3:30])[CH2:28][O:27]C(=O)[NH:25]1)=[CH:8]2.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][C@H:14]3[CH2:15][CH2:16][C@@H:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19]3)[C:3]=2[C:2]([F:31])([F:32])[F:1])[CH:8]=1)([CH3:30])[CH2:28][OH:27]
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Yield: 99.2 %

Procedure:
The mixture of (R)-4-(5-trifluoromethyl-6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (324.6 mg, 0.0007221 mol) and lithium hydroxide (190 mg, 0.0079 mol) in ethanol (10 mL, 0.2 mol) and water (3 mL, 0.1 mol) was heated to reflux for overnight. LCMS showed reaction completed. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product (303.5 mg, 99% yield). LCMS 407.28 ([M−NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.92 (t, J=6.8 Hz, 3H), 1.20-1.69 (m, 13H), 1.51 (s, 3H), 2.05 (dd, J=13.2, 2.3 Hz, 2H), 3.66 (d, J=10.9 Hz, 1H), 3.73 (d, J=10.9 Hz, 1H), 4.83 (brs, 1H), 7.43 (d, J=9.4 Hz, 1H), 7.68 (dd, J=9.4, 2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 8.03 (d, J=9.4 Hz, 1H), 8.12 (dd, J=9.0, 1.8 Hz, 1H).