Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8])[CH2:3][OH:4].[N:23]#[C:24]Br>>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([N:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH:7]([CH3:8])[CH3:9])=[CH:15][CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CBr
Reactant: CC(C)N(C[C@H](N)CO)c1ccc(Cc2ccccc2)cc1
Product: CC(C)N(C[C@H]1COC(N)=N1)c1ccc(Cc2ccccc2)cc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-[(4-benzyl-phenyl)-isopropyl-amino]-propan-1-ol was reacted with cyanogen bromide to give (S)-4-{[(4-benzyl-phenyl)-isopropyl-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine. Light yellow gum. MS (ISP): 324.4 ([M+H]+)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CCC(=O)O
Reaction time: 2.5 h
Yield: 100.8 %

Procedure:
4.0 g (11.0 mmol) of 5'-O-(tert-Butyldimethylsilyl)-2'-deoxy-5-fluorouridine was dried by twice dissolving the nucleoside in 25 ml of anhydrous pyridine in a round bottom flask and evaporating the pyridine on a rotary evaporator. To the thus dried protected nucleoside re-dissolved in 20 ml pyridine was added 0.54 g (4.4 mmol) of 4-dimethylaminopyridine all at once and 0.84 g (8.4 mmol) succinic anhydride (Aldrich Chemical Company, Milwaukee, Wis. 53233) in three portions over 90 min. After stirring for 2.5 hrs, another equal portion of 4-dimethylaminopyridine was added. The flask was sealed with a serum stopper and the mixture was allowed to stir overnight. After this time, pyridine was removed on the rotary evaporator by co-evaporation with 4×50 ml toluene to give a tan foam. The foam was dissolved in 100 ml dichloromethane and extracted with 3×100 ml cold aqueous 10% citric acid, followed by 100 ml water. The dichloromethane layer was dried over magnesium sulphate, filtered, and the solvent was removed on a rotary evaporator to give 3.9 g of a tan foam. This foam was dissolved in a minimal amount of dichloromethane and applied to a column (4.5×30 cm) packed with silica gel (350 g, 230-400 mesh) in dichloromethane. Under medium air pressure (9-12 psi) the column was first eluted with 1 L of chloroform followed by elution with 1 L of 1% methanol in chloroform. The percentage of methanol was increased 1% for each successive litre. The product was eluted into fractions between 2% and 10% methanol in chloroform. Product fractions were pooled and the solvent was removed on the rotary evaporator to give 2.0 g (4.3 mmol) of a white solid: m.p. 133.4°-135.3° C.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([SH:11])[CH3:10].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH:9]([CH3:10])[CH3:8])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC(C)S
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol 60% in mineral oil) were added 2-propanethiol (1.0 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (160 mg, 0.62 mmol) in order. The mixture was stirred under heating at 100° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 61%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[CH:15][N:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:21][CH3:22])[CH:12]=2)[N:17]=[N:16][CH:15]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Cl)cnnc2cc1O
Yield: 93.9 %

Procedure:
The starting material, 4-chloro-7-hydroxy-6-methoxycinnoline was obtained by heating a solution of 7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride (3.06 g, 9 mmol), (prepared as described for the starting material in Example 6), in TFA (30 ml) at reflux for 5 hours. After evaporation of the solvent, the residue was suspended in water and adjusted to pH7 with saturated aqueous sodium hydrogen carbonate solution. The resulting solid was filtered off, washed with water and ether and dried under vacuum to give 4-chloro-7-hydroxy-6-methoxycinnoline as a yellow solid (1.78 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[N:12]=[C:11]([NH:22]C(=O)C(C)(C)C)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[N:12]=[C:11]([NH2:22])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Yield: 76 %

Procedure:
Using the general procedure described above, the reaction of 7 (209 mg, 0.47 mmol) and 1 N NaOH provided 128 mg of AAG103 as a white solid in 76% yield. TLC Rf 0.36 (chloroform-methanol 15:1); mp 233.6° C.; 1H NMR (DMSO-d6) δ 6.26 (s, 2H, NH2, exch), 7.09-8.09 (m, 8H, Ar—H), 8.44 (s, 1H, 4-NH, exch), 11.32 (s, 1H, 9-NH, exch). Anal. Calculated (C16H12BrN5): C, 54.25; H, 3.41; N, 19.77; Br, 22.55. Found: C, 54.38; H, 3.48; N, 19.56; Br, 22.29.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]2[CH2:15][C@@H:14]([C:16]3[N:20]4[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]4=[CH:18][N:17]=3)[CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S(OC[C@H]2C[C@H](C3N4C=CN=C(Cl)C4=CN=3)C2)(=O)=O)=CC=1.[C:53]([Si:57](Cl)([CH3:59])[CH3:58])([CH3:56])([CH3:55])[CH3:54]>>[Si:57]([O:10][CH2:11][C@@H:12]1[CH2:13][C@H:14]([C:16]2[N:20]3[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]3=[CH:18][N:17]=2)[CH2:15]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:59])[CH3:58]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ncc4c(Cl)nccn43)C2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ncc4c(Cl)nccn43)C2)cc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](c2ncc3c(Cl)nccn32)C1

Procedure:
cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine and trans-3-[3-(tert-butyldimethylsilanyloxymethyl)cyclobutl]-8-chloroimidazo[1,5-a]pyrazine were prepared according to the general procedure for the preparation for cis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate and trans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate, except tert-butylchlorodimethylsilane was used instead of p-toluenesulfonic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=C.N#N.CSC.C[OH:26]>ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[O:26]
Reactant: CO
Reactant: C=CC(C(C)(C)O[SiH2]C(C)(C)C)C(C)(C)C(=O)OC
Agent: N#N
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(C)(C)C(C=O)C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Example 2C (3.5 g, 12.2 mmol)in dichloromethane (25 mL) and methanol (2.5 mL) was cooled to −78° C. and O3 was bubbled for twenty-five minutes. The reaction was purged with N2 and DMS (5.29 g, 85.4 mmol) was added. The reaction was stirred at room temperature for three hours. The solvent was evaporated in vacuo and the product purified by flash column chromatography (hexanes:ethyl acetate) 100:0 to 50:50) to provide the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:18])[CH:12]=3)[C:3]=12.[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:33]=[C:32]([CH3:41])[CH:37]=[CH:36][CH:35]=4)=[O:40])=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N)c(F)c3)c3c(N)ncnc32)CC1
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ncnc(N)c34)cc2F)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 30.8 %

Procedure:
tert-Butyl 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (600 mg, 1.41 mmol) was dissolved in pyridine (25 mL) and cooled to 0° C. m-Tolylisocyanate (206 mg, 1.54 mmol) was added and the reaction was stirred at 0° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to yield the crude product as a brownish-yellow foam (841 mg). Purification by column chromatography on silica gel using a 25% to 50% ethyl acetate/heptane gradient followed by 5% methanol/dichloromethane as the eluent afforded tert-butyl 4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate as a light yellow solid (243 mg, 0.434 mmol). HPLC-RT: 17.82 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=561.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[OH:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][N:39]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][C:49]=3[CH3:50])[C:40]2=[O:43])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.CCCCCC.C(OC(=O)C)C>[CH3:50][C:49]1[CH:48]=[CH:47][N:46]=[CH:45][C:44]=1[N:39]1[CH2:38][CH2:37][C:36]2[C:41](=[CH:42][C:33]([O:32][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)=[CH:34][CH:35]=2)[C:40]1=[O:43]
Reactant: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccncc1N1CCc2ccc(Oc3cc(C(F)(F)F)ccn3)cc2C1=O
Temperature: 110 °C
Yield: 12.7 %

Procedure:
2-Chloro-4-trifluoromethyl-pyridine (97 mg, 0.59 mmol), KOH (26.4 mg, 0.471 mmol) and 18-crown-6-ether (156 mg, 0.59 mmol) were added to a solution of 7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (35B: 100 mg, 0.393 mmol) in toluene (3 mL). The resulting mixture was heated to 110° C. for 3 hours. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was filtered and the filtrate was concentrated to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 20 mg of the product (12.8% yield).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Cl[Si](C)(C)C.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>CN(C=O)C.C(N(CC)CC)C>[OH:5][CH2:1][CH2:2][C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCO
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCO)c21
Temperature: 70 °C

Procedure:
Using Method I above, 3-butyn-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL DMF and 2 mL triethylamine, and to this solution was added chlorotrimethylsilane (0.13 mL, 1 mmol). The reaction was stirred at room temperature for 1 h, at which time (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) was added and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P)2PdCl2 (13 mg) and Cul (7 mg) were added and the reaction was heated at 70° C. for 14h. The reaction mixture was then poured into 25 mL 1 N HCl and the yellow precipitate was filtered off. The product was purified via flash column chromatography to obtain (Z)-1,3-dihydro-4-(4-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 35 mg, 30%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6]O)[CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[S:21]([CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (tetrahydrofuran-3-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (5 mL) and triethylamine (1.98 g, 19.6 mmol) was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 12 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL) The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:13].[K+]>C(O)C>[CH3:2][C:1]([CH3:11])([CH2:10][OH:13])[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[OH:12]
Reactant: O=Cc1cccc2ccccc12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CO)C(O)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 196.3 %

Procedure:
1-Naphthoaldehyde (57.72 g, 0.37 mol) and isobutylaldehyde (55.0 g, 0.76 mol) was mixed and 85% potassium hydroxide (24.5 g, 0.37 mol) dissolved in ethanol (340 ml) was added dropwise thereto with stirring. Exothermic reaction started immediately, and the temperature reached to 65° C. and then decreased. After dropping for about 15 min, the mixture was stirred at 55° C. for 4.5 hr. The reaction solution was concentrated, and water (300 ml) was added thereto. The mixture was extracted with chloroform (200 ml) twice. The extract was washed with saturated brine, dehydrated with anhydrous sodium sulfate and concentrated to give the title compound as a brown oil (83.62 g, yield 98.1%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:32][C:33]1[CH:62]=[CH:61][C:36]([CH2:37][NH:38][C:39]2[N:44]=[C:43]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[N:42]=[C:41]([NH:51][C:52]3[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=3)[N:40]=2)=[CH:35][CH:34]=1.[NH2:63][CH2:64][CH:65]([OH:80])[CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:69][CH2:68]1>CN(C=O)C.CCOC(C)=O>[OH:80][CH:65]([CH2:64][NH:63][C:56](=[O:57])[C:55]1[CH:59]=[CH:60][C:52]([NH:51][C:41]2[N:40]=[C:39]([NH:38][CH2:37][C:36]3[CH:61]=[CH:62][C:33]([OH:32])=[CH:34][CH:35]=3)[N:44]=[C:43]([O:45][CH2:46][C:47]([F:49])([F:50])[F:48])[N:42]=2)=[CH:53][CH:54]=1)[CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([O:75][C:76]([CH3:77])([CH3:79])[CH3:78])=[O:74])[CH2:69][CH2:68]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)CN)CC1
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(O)CNC(=O)c2ccc(Nc3nc(NCc4ccc(O)cc4)nc(OCC(F)(F)F)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
N,N-diisopropylethylamine (0.30 g) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (0.44 g) were added into a solution of 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.5 g) and tert-butyl 4-(3-amino-2-hydroxypropyl)piperazine-1-carboxylate (0.33 g) in DMF (2 mL). The mixture was stirred at room temperature for 16 hours. Then, 50 mL of EtOAc was added into the reaction mixture which was sequentially washed with water (2×20 mL) and brine (15 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to give a residue which was purified by silica gel chromatography to provide tert-butyl 4-(2-hydroxy-3-(4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propyl)piperazine-1-carboxylate (0.20 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-:24])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ncccc1OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Yield: 94.6 %

Procedure:
A solution of methyl 3-benzyloxypicolinate (4.86 g) and 3-chloroperoxybenzoic acid (5.75 g, 60% peracid) in CH2Cl2 (100 mL) was stirred at room temperature for 40 hours. The reaction mixture was then extracted with 5% sodium bisulfite solution (100 mL) then with 0.5N NaOH solution (150 mL). After drying (MgSO4), the solvent was evaporated to give 4.9 g of methyl 3-benzyloxypicolinate-1-oxide as a white solid. Recrystallization from methylcyclohexane/toluene gave a crystalline solid, m.p. 104-106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](=O)[NH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=NN(C2C=CC(OC(F)(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:28]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][C:16]([F:30])([F:15])[F:31])=[CH:19][CH:20]=3)[N:25]=[CH:26][N:27]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(OC(F)(F)F)cc1
Agent: C[C@@H](n1cnn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(OC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 29.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.53 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 1.50 g of 2-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone (829 mg) and 778 mg of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethoxyphenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])=[O:2].S(=O)(=O)([OH:17])N.Cl([O-])=O.[Na+].CCOC(C)=O>O1CCOCC1.O>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]([OH:17])=[O:2]
Reactant: NS(=O)(=O)O
Reactant: COC(=O)c1ccc(OC)c(C=O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(C(=O)O)c1

Procedure:
Crude methyl 3-formyl-4-(methyloxy)benzoate from the previous step was dissolved in 40 mL of dioxane with stirring. Sulfamic acid (5.87 g, 60.5 mmol) in 20 mL of H2O was added to the stirring solution. Sodium chlorite (1.68 g, 80% by weight, 18.6 mmol) in 20 mL of H2O was added dropwise via addition funnel. The reaction was stirred for 40 min and poured into EtOAc and H2O. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was transferred to an Erlenmeyer flask with the aid of 30-40 mL of DCM. Approximately 50 mL of hexanes was added. Air was blown over the solution to allow most of the DCM to evaporate. Diethyl ether was added (20-30 mL), and the suspension was filtered. The solid was washed with hexanes, collected, and dried to afford 1.96 g (82% over 2 steps) of the desired compound. 1H NMR (400 MHz, DMSO-d6): δ 12.92 (br s, 1H), 8.22 (d, J=2.2 Hz, 1H), 8.07 (dd, J=8.8, 2.2 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:1]([CH:3]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of Na3PO4 (9.84 g, 60.0 mmol), methyl cyanoacetate (2.38 g, 24.0 mmol), and tert-butyl 4-bromobenzoate (5.14 g, 20.0 mmol) were added Pd(dba)2 (575 mg, 1.00 mmol), toluene (60 mL), and P(t-Bu)3 (10% wt in hexanes, 11.56 mL, 3.89 mmol). After degassing for 20 minutes, the reaction was stirred at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (0-15% EtOAc/hexanes) gave tert-butyl 4-(1-cyano-2-methoxy-2-oxoethyl)benzoate as a white solid. 1H NMR (CDCl3) δ8.02 (d, J=7.9 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 4.79 (s, 1H), 3.79 (s, 3H), 1.58 (s, 9H). MS (ESI) calcd [M+H]+ 276.1, found 276.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([O:22]C)=[O:21])[C:3]=1[Cl:24].[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([OH:22])=[O:21])[C:3]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(F)c2)c(C)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2ccc(C(F)(F)F)c(F)c2)nc(C(=O)O)c(Cl)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To methyl 4-amino-3-chloro-6-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methylpicolinate (0.35 g, 0.96 mmol) in methanol (6.4 mL) was added 2 N NaOH (1.93 mL, 3.9 mmol), and the reaction was stirred at room temperature for 18 h. The solution was acidified with 2 N HCl and the precipitate was vacuum filtered to afford the title compound as a white powder (199 mg, 59%).