Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:48][CH2:47][C@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:48][CH2:47][C@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: O=C(N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
12 ml of trifluoroacetic acid and 0.38 ml of trifluoromethanesulfonic acid were added to a suspension of 1.47 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 2.3 ml of anisole, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed with hexane to remove the anisole, and then diethyl ether was added. The mixture was then cooled to -78° C., and the solidified product was broken up and separated by decantation. Several repetitions of this procedure yielded a powder and oily materials, which were dissolved in 100 ml of ethyl acetate to give a solution. The resulting solution was washed with an aqueous solution of sodium hydrogencarbonate, and the aqueous washings were extracted with 30 ml of ethyl acetate. The washings were combined with the ethyl acetate solution, and the combined organic phase was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.26 g of the title compound, as a powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCN(CC)CC.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.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(C#Cc2ccccc2)n1
Yield: 93.3 %

Procedure:
To a stirring solution 0.5 g (2.4 mmol) of 6-bromo-pyridine-2-carboxylic acid, 0.05 g (0.07 mmol) of dichlorobis(triphenylphosphine)-palladium(II), and 0.015 g (0.07 mmol) of copper (I) iodide in 10 mL of NEt3, 9.9 mL of 2 N Na2CO3 solution was added 0.38 g (3.7 mmol) of phenyl acetylene under nitrogen. After 12 h reflux under nitrogen, the reaction mixture was cooled and filtered. The filtrate was acidified using 2 N HCl (pH=5), and the resulting white precipitate was filtered, washed with water and dried to afford 0.5 g (51%) of 6-phenylethynyl-pyridine-2-carboxylic acid. LCMS: 224 (M+1)+.
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[CH:18][C:17](N)=[N:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:6].[ClH:29].C(O)(=O)C>O>[Cl:29][C:17]1[CH:18]=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([C:5]#[N:6])[CH:8]=2)[N:16]=1
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(SC)cc2)cc1C#N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(SC)cc2)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.36 g) in water (0.5 ml) was added to an ice cooled mixture of 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (1.08 g), concentrated hydrochloric acid (15 ml) and acetic acid (35 ml). The mixture was stirred at 0° C. for 30 minutes and added portionwise to a mixture of cuprous chloride (1.37 g) and concentrated hydrochloric acid (10 ml) at ambient temperature. The mixture was refluxed for 1 hour, poured into water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with toluene to give 3-chloro-1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (0.29 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:21]2[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=2[C:23](N(CC)CC)=O)=[C:16]([CH3:43])[CH:15]=1.C1C[O:47]CC1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=3[CH2:23][C:43](=[O:47])[C:16]=2[CH:15]=1
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)c1ccccc1N(Cc1ccc(OC)cc1)c1ccc(Cl)cc1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(CN2c3ccccc3CC(=O)c3cc(Cl)ccc32)cc1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a mixture of diisopropylamine (1.09 mL, 7.8 mmol) and N,N,N,N-tetramethylenediamine (1.17 mL, 7.8 mmol) in dry THF (19 mL) at −20° C. was added n-BuLi (5.54 mL, 1.4 M in hexane) and the resulting mixture was stirred at −20° C. for 5 minutes. Then a mixture of 2[(4-chloro-2-methylphenyl)-(4-methoxybenzyl)-amino]-N,N-diethylbenzamide (189JO26) (1.36 g, 3.1 mmol) in dry THF (38 mL) was added and the resulting mixture was stirred at −20° for 4 h. The reaction was quenched by addition of saturated aqueous NH4Cl-solution. The mixture was diluted with EtOAc, washed with water, dried (Na2SO4), concentrated, and flash chromatographed (SiO2, toluene:heptane, 7:1-1:0) to give 665 mg (59%) of the title compound (189JO27). 1H NMR (CDCl3) δ 8.15 (dd, 1H, J=1.8, 8.0 Hz), 7.43 (m, 1H), 7.24 (m, 4H), 7.17 (d, 1H, J=8.6 Hz), 7.12 (dd, 1H, J=2.4, 8.6 Hz), 7.00 (dt, 1H, J=0.8, 7.0 Hz), 6.81 (m, 2H), 5.09 (s, 2H), 4.00 (s, 2H), 3.75 (s, 3H); 13C NMR (CDCl3) δ 190.3, 159.1, 149.5, 146.2, 134.1, 132.4, 131.3, 131.1, 129.1, 129.0, 128.6, 127.3, 126.4, 123.4, 121.0, 118.5, 114.2, 55.5, 19.3. MS (ESI) 364 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([C:31](N)=[O:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH-:34].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([C:31]([OH:32])=[O:34])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](C(N)=O)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
This compound was prepared utilizing the same procedures as those used for the synthesis of cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylic acid amide except the reaction was monitored at short intervals to minimize the amide formation. The reaction generated a mixture of ester and amide (2:1), which was treated with NaOH (0.15 mL) in THF (0.95 mL) and MeOH (1 mL). The reaction was left to stir at rt for 3 h. The mixture was concentrated in vacuo, diluted with DCM and washed with water. The product was purified by MDP, to afford the title compound as a yellow solid; MS (ES+): m/z 436.27 (40) [MH+]; 1H NMR (400 MHz, DMSO-d6) δ 2.62-2.67 (m, 5H) 3.16 (s, 1H) 3.90-3.91 (m, 1H) 6.21 (s, 1H) 7.10 (d, J=5.2 Hz, 1H) 7.50-7.59 (m, 4H) 7.93 (dd, J=6.8, 1.6 Hz, 1H) 8.10 (d, J=8.4 Hz, 1H) 8.18 (d, J=8.8 Hz, 1H) 8.25 (s, 1H) 8.30-8.33 (m, 2H) 8.51 (d, J=8.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(O)c1coc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)O)co1
Reaction time: 48 h

Procedure:
A mixture of 57.2 g (0.300 mole) of 5-bromo-3-furoic acid, 121.0 g (0.45 mole) of cis-9-octadecenol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid, and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue is recrystallized from hexane to give 5-(cis-9-octadecen-1-yloxy)-3-furoic acid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:7]1[N:8]=[C:9]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:10][CH:11]=1)\[C:4]([OH:6])=[O:5].[C:32]1([C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N+]=[N-])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>ClCCl>[OH:1]/[N:2]=[C:3](/[C:7]1[N:8]=[C:9]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:10][CH:11]=1)\[C:4]([O:6][CH:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:5]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Z)-2-Hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (4.2 g) as a suspension in dichloromethane (150 ml) was treated with a solution of diphenyldiazomethane (1.91 g) in dichloromethane (50 ml) in a dropwise fashion, over 5 min. After 2 h stirring at room temperature, acetic acid (1 ml) was added and stirred for a further 30 min. The solution was washed with saturated sodium bicarbonate and water, dried and filtered. Removal of solvent in vacuo gave a yellow crisp foam which was purified by chromatography on silica gel eluting with ethyl acetate/hexane. The title compound was obtained as a white solid; νmax (CH2Cl2) 1735, 1520 and 1490 cm-1 ; δH (CDCl3) 6.16 (1H, s), 7.17 (1H, s). 7.22-7.50 (25H, m). [Mass spectrum: +ve ion (thioglycerol) MNa+ (596)].
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH2:9]=[CH:10][CH:11]=[CH2:12]>>[CH2:12]([C:2]1[CH:1]=[C:6]([OH:7])[CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:11][CH:10]=[CH2:9]
Reactant: Cc1ccc(O)cc1
Reactant: C=CC=C
Product: C=CCCc1cc(O)ccc1C

Procedure:
As shown in Reaction Scheme 2, para-cresol (p-CH3C6H4OH) is reacted with butadiene (C4H6) to form 3-(but-3-enyl)-4-methylphenol.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl-].[NH4+]>O1CCCC1>[C:5]1([C:11]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCCCCC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCCCCC1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To magnesium (1.2 g) in anhydrous tetrahydrofuran (60 mL) under an environment of nitrogen was added a crystal of iodine followed by bromobenzene (7.85 g) at such a rate that the reaction maintained a steady reflux. The reaction mixture was stirred for 20 minutes then cycloheptanone (4.48 g) was added with care. After stirring for 10 minutes saturated aqueous ammonium chloride (10 mL) was added and the reaction was partitioned to between water (100 mL) and isohexane (100 mL). The organic layer was dried (MgSO4) and evaporated to afford the sub-titled compound (7.6 g) as an oil.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CO>C(Cl)Cl.O>[Br:1][C:13]1[CH:12]=[C:7]([CH:6]=[CH:5][C:4]=1[OH:3])[C:8]([O:10][CH3:11])=[O:9]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
Dibromine (0.185 L, 3614.92 mmol) was added dropwise a stirred suspension of methyl 4-hydroxybenzoate (500 g, 3286 mmol) in DCM (4 L) at 0° C. under N2. The mixture was left to stir for 24 hrs at RT under N2 (need to trap HBr). A solution of sodium metabisulfite (62.5 g, 329 mmol) in 2 L of water was then added, while keeping the temperature around 15° C., followed by 500 mL of MeOH. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (710 g, 94%) as a white solid. NMR Spectrum (CDCl3): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[F:54][C:55]([F:59])([F:58])[CH2:56][NH2:57]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:57][CH2:56][C:55]([F:59])([F:58])[F:54])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:19])[F:20])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: NCC(F)(F)F
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: O=C(NCC(F)(F)F)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 98 %

Procedure:
As described for example 92, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, using 2,2,2-trifluoroethylamine instead of cyclopropylamine, to the title compound (115 mg, 98%) which was obtained as a white solid. MS: m/e=464.3 [M+H]+.
Reaction SMILES: N1CCCC1.C(OC([O:13][C:14]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:41][C:40]=3[C:50]#[N:51])=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)(C)(C)C>O1CCOCC1>[C:50]([C:40]1[CH:41]=[C:42]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[CH:43]=[CH:44][C:39]=1[C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:23]2[C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[C:14]([OH:13])[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:24]=2)=[CH:34][CH:35]=1)#[N:51]
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C#N)c1
Solvent: C1COCCO1
Solvent: C1CCNC1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c(C#N)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Pyrrolidine (33 μl, 0.39 mmol) was added to a solution of crude tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-cyano-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (125 mg) obtained in the above in 1,4-dioxane (4 ml), and the mixture was stirred at 50° C. for 2 hours. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to give tert-butyl 6-[({2′-cyano-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-2-hydroxy-3-(trifluoromethyl)benzoate (100 mg, 60%).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC(C)([O-])C.[K+].[Br:29]N1C(=O)CCC1=O.[OH-].[Na+]>C(#N)C.ClCCl>[Br:29][C:5]1[CH:6]=[CH:7][C:1]([O:8][CH3:9])=[C:2]([OH:3])[CH:4]=1
Reactant: COc1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Reaction time: 0.08 h
Yield: 98.5 %

Procedure:
To a solution of guaiacol (5.0 g, 0.04 mol) in acetonitrile (50 ml) at ambient temperature, was added trifluoroacetic anhydride (6.2 ml, 1.1 eq.). The solution was stirred for 5 min., then 1 M potassium tert-butoxide (4.0 ml, 0.1 eq.) was added slowly. The resultant mixture was stirred for 45 min. A solution of N-bromosuccinimide (7.83 g, 1.1 eq.) in acetonitrile (50 ml) was added via addition funnel slowly. The orange solution was stirred for 24 hours then the solvent was removed in rotary evaporator to give a residue which was suspended in dichloromethane (50 ml). A 6 N aqueous solution of sodium hydroxide (20 ml) was added and the organic layer was separated and discarded. The aqueous basic layer was acidified with concentrated hydrochloric acid until pH 2 was reached. Dichloromethane (50 ml) was added to extract the acidic aqueous layer. After being separated, the organic layer was washed with brine and concentrated on rotary evaporator to afford the desired product (8 g) as a redish oil in 90% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC1(C)CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of Example 8A (0.28 g, 2.2 mmol) and 1-tert-butoxycarbonylpiperazine (0.42 g, 2.2 mmol) in dichloroethane (5 mL) at room temperature was treated with acetic acid (100 μL) and sodium triacetoxyborohydride (0.53 g, 2.5 mmol), stirred overnight, diluted with ethyl acetate (300 mL), washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (650 mg, 95%). MS (ESI) m/e 297 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[Li].O.Cl>ClCCl>[CH2:16]([O:23][C:7]1[C:2]([F:1])=[C:3]([CH2:12][C:13](=[O:15])[CH3:14])[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH•H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford 1.6 g of the desired compound which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 um 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH: water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:31])[C:6]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:7][C:8]=1[NH:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-:32].[Na+].OO.O>CCO.CS(C)=O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([F:31])[C:6]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:7][C:8]=1[NH:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1)(=[O:32])[NH2:2]
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)cc2C#N)on1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)cc2C(N)=O)on1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude tert-butyl (1S,2R)-2-(5-cyano-3-fluoro-6-(3-methylisoxazol-5-ylamino)pyridin-2-ylamino)cyclohexylcarbamate in EtOH (2 mL) and DMSO (2 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 15 min. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give crude tert-butyl (1S,2R)-2-(5-carbamoyl-3-fluoro-6-(3-methylisoxazol-5-ylamino)pyridin-2-ylamino)cyclohexylcarbamate, which was then dissolved in TFA (4 mL). After 10 min, excess TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (18 mg). MS 349.3 (M+H); UV 201.0, 259.0, 295.8, 333.5 nm; t 0.450 min.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CCN(C(C)C)C(C)C.O.[OH-].[Li+].[ClH:38]>C(#N)C.O1CCOCC1.O>[ClH:38].[C:8]1([CH:2]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([O:16][C:15]([F:14])([F:24])[F:25])[CH:18]=2)[C:3]([OH:5])=[O:4])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: O=C(O)C(Nc1cccc(OC(F)(F)F)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Ethyl 2-bromo-2-phenylacetate (400 mg, 1.64 mmol), 3-(trifluoromethoxy)aniline (0.33 mL, 2.47 mmol), and DIPEA (0.43 mL, 2.47 mmol) are dissolved in acetonitrile (5 mL) and heated under MW irradiation at 100° C. for 1 hour (Conversion complete by UPLC/MS-UV). Water (5 mL) and lithium hydroxide hydrate (207 mg, 4.94 mmol) are directly added and the resulting mixture is stirred at RT for 1 hour. Then 4M HCl in dioxane is added until pH 1, the organic solvents are evaporated and the resulting crude oil is purified by filtration through a silica pad using DCM/MeOH=9/1 as the eluent. Intermediate I88 is collected as a brown oil (569 mg, quantitative yield).