Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Br:16]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:16][C:13]1[S:12][C:11]([C:2]([CH3:1])([CH3:10])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[N:15][CH:14]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)C(C)(C)c1nccs1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(C)(C)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
The product from Step 1 (935 mg, 4.11 mmol) was taken up in CHCl3 (20 mL) and placed in a cool water bath. NaHCO3 (380 mg, 4.52 mmol) was added, followed by bromine (1.315 g, 8.23 mmol). After stirring for 2 h at room temperature, some starting material remained, so additional NaHCO3 (380 mg, 4.52 mmol) and bromine (1.315 g, 8.23 mmol) were added. After another 2 h at room temperature, the reaction was diluted with aqueous 10% Na2S2O3 and aqueous saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated. Flash chromatography (0-10% ethyl acetate in hexanes) afforded tert-butyl 2-(5-bromo-1,3-thiazol-2-yl)-2-methylpropanoate (1.032 g, 82%) as a colorless oil. MS ESI: [M-t-Bu]+ m/z 249.9/251.9.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:13][CH:14]=1
Reactant: BrCCCBr
Reactant: CCOC(=O)C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1ccc(OCCCBr)cc1

Procedure:
A solution of ethyl 4-hydroxymandelate (19.6 g, 0.1 mol), 1,3-dibromopropane (60.75 g, 0.3 mol) and cesium carbonate (35.75 g, 0.11 mol) in dry DMF (200 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was then filtered and the solvent remove in vacuo. The resulting oil was chromatographed on silica gel, using a gradient of 100% hexane to methylene chloride/hexane (2:1) to yield the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[N:33][N:32]([CH:40]([CH3:42])[CH3:41])[C:31]2=[O:43])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:37]([C:34]2[C:35](=[O:36])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[C:31](=[O:43])[N:32]([CH:40]([CH3:42])[CH3:41])[N:33]=2)=[O:38])=[CH:20][CH:21]=1
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Nc3ccc(N)cc3)c2cc1OC
Product: COc1cc2nccc(Nc3ccc(NC(=O)c4nn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3)c2cc1OC

Procedure:
This compound was synthesized using N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamine and 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylic acid by the method for example 134. mp=152-155° C.; LCMS m/z=571 (M+1); 1H NMR (DMSO-d6) δ: 8.67 (s, 1H), 7.68 (d, 2H, J=8.87 Hz), 7.54 (d, 2H, J=8.68 Hz), 7.20-7.34 (m, 12H), 7.10 (brs, 1H), 6.99 (s, 1H), 6.60 (d, 2H, J=8.6 Hz), 4.04 (d, 7H, J=2.2 Hz), 3.79 (brs, 2H), 1.21 (t, 1H, J=7.0 Hz), 0.81-0.91 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].S(Cl)(Cl)=O.CC(C)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([N:22]=[N+:23]=[N-:24])=[O:13])[CH:6]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C(=O)O)nn1C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)N=[N+]=[N-])nn1C
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
1-Methyl-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (641, 3.2 g, 17.0 mmol) was combined with thionyl chloride (5 mL). The reaction was heated to reflux for 40 minutes and then concentrated twice from toluene. The resulting solid was dried under reduced pressure overnight. The product was dissolved into acetone (20 mL) and sodium azide (3.5 g, 54.0 mmol) was added in water (10 mL) rapidly at once. The obtained solution was stirred for one minute and then poured into ice-water (50 mL). The precipitate was filtered and dried under reduced pressure. The final compound was used without further purification (642, 2.8 g, 77%).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([OH:7])[CH:5]([OH:8])[CH:4]([CH3:9])[O:3]1.O=O>[Ag].[Cu]>[CH3:1][CH:2]1[C:6](=[O:7])[CH:5]([OH:8])[CH:4]([CH3:9])[O:3]1
Reactant: CC1OC(C)C(O)C1O
Agent: [Ag]
Agent: [Cu]
Agent: O=O
Product: CC1OC(C)C(O)C1=O

Procedure:
2,5-Dimethyl-4-hydroxy-2,3-dihydrofuran-3-one is prepared by first epoxidizing hex-3-ene-2,5-diol in the liquid phase with hydrogen peroxide to give the novel compound 3,4-epoxy-hexane-2,5-diol, which at 40°-280° C. is converted, by means of a catalytic amount of an acid, to the novel compound 2,5-dimethyl-3,4-dihydroxy-tetrahydro-furan. The latter is dehydrogenated by means of oxygen over a silver catalyst or copper catalyst to give the nove compound 2,5-dimethyl-4-hydroxy-tetrahydrofuran-3-one, which is oxidized by means of bismuth oxide, in concentrated acetic acid solution, to give the desired compound 2,5-dimethyl-4-hydroxy-2,3-dihydrofuran-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2ccccc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A40) the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)Oc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
44 gm (0.211 mol) of methyl 2-(4-formyl-phenoxy)-propionate were dissolved in 500 ml of methanol, and 8 gm (0.211 mol) of sodium borohydride were added in small portions to the solution. The resulting mixture was stirred at room temperature for 30 minutes and then at 60° C. for 30 minutes. Thereafter, the reaction mixture was evaporated in vacuo to one-half its original volume, poured into water, neutralized with hydrochloric acid, and extracted with ether. The ethereal extract solution was washed, dried and evaporated, leaving 20 gm of methyl 2-(4-hydroxymethyl-phenoxy)-propionate as a colorless oil which was purified on a silicagel column with chloroform as the flow agent.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:22]=[CH:21][C:10]2[S:11][C:12]3[S:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[C:13]=3[C:9]=2[CH:8]=1)(=O)=O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH:54]1[C:62]2[C:61]3[CH:63]=[CH:64][CH:65]=[CH:66][C:60]=3[S:59][C:58]=2[C:57]([C:67]2[CH:68]=[C:69]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75](B4OC(C)(C)C(C)(C)O4)[CH:74]=3)[CH:70]=[CH:71][CH:72]=2)=[CH:56][CH:55]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:54]1[C:62]2[C:61]3[CH:63]=[CH:64][CH:65]=[CH:66][C:60]=3[S:59][C:58]=2[C:57]([C:67]2[CH:68]=[C:69]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([C:7]4[CH:22]=[CH:21][C:10]5[S:11][C:12]6[S:16][C:15]7[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=7[C:13]=6[C:9]=5[CH:8]=4)[CH:74]=3)[CH:70]=[CH:71][CH:72]=2)=[CH:56][CH:55]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc(-c4cccc5c4sc4ccccc45)c3)c2)OC1(C)C
Reactant: O=S(=O)(Oc1ccc2sc3sc4ccccc4c3c2c1)C(F)(F)F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)cc(-c2ccc3sc4sc5ccccc5c4c3c2)c1
Yield: 77.9 %

Procedure:
Benzo[b]benzo[4,5]thieno[3,2-d]thiophen-2-yl trifluoromethanesulfonate (1.3 g, 3.35 mmol), Pd2(dba)3 (0.061 g, 0.067 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.11 g, 0.268 mmol), 2-(3′-(dibenzo[b,d]thiophen-4-yl)-[1,1′-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.625 g, 3.51 mmol), K3PO4 (2.13 g, 10.04 mmol), toluene (90 mL) and water (10 mL) were charged in a 250 mL flask. This mixture was bubbled with nitrogen for 30 minutes then heated to reflux overnight. After purification, 1.5 g (78%) of a white solid was obtained. The compound was confirmed by NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-methoxy-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[CH:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[C:16][CH3:32])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 78 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethynyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole (100 mg, 0.21 mmol) in tetrahydrofuran (15 ml) at 78° C., lithium bis(trimethylsilyl)amide (0.23 ml, 1.0 M solution in tetrahydrofuran, 0.23 mmol) was added slowly not to warm up the reaction solution. After stirring at 78° C. for 10 minutes, iodomethane (0.04 ml, 0.7 mmol) was added quickly. The resulting solution was stirred for 20 minutes, and then it was warmed up to room temperature slowly. After quenching with saturated ammonium solution, the organic layer was separated with ethyl acetate. The organic solution was evaporated in reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 to hexane/ethyl acetate=5/1) to produce title compound (13 mg, 13% yield) as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH3:18][O:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27](Br)=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[CH3:1])=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:21]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c2cc(-c3ccc(O)cc3C)ccc12
Temperature: 100 °C
Yield: 62.8 %

Procedure:
A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (213 mg, 0.910 mmol), 6-bromo-1H-indole-3-carboxylic acid methyl ester (193 mg, 0.759 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.046 mmol), DMF (2.7 mL), ethanol (1.34 mL) and 2M aqueous potassium carbonate (1.34 mL) is heated to 100° C. for 60 hours. The reaction is cooled to room temperature, diluted with water and acidified with 1 N HCl. The resulting solution is extracted with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated. The residue is purified with flash chromatography eluting with 25 to 40% ethyl acetate/heptane to give the title compound (134 mg, 63%). ES/MS m/e 280.3 (M−1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:21]([O:35][CH3:36])[C:20]([O:37][CH3:38])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:21]([O:35][CH3:36])[C:20]([O:37][CH3:38])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCCCCOc1c(CN2CCN(Cc3ccccc3)CC2)ccc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2CCN(Cc3ccccc3)CC2)c(OCCCCCCC(=O)O)c1OC

Procedure:
10 g of the compound obtained in Example 1 are added to a solution containing 4 g of sodium hydroxide in 250 ml of ethanol. The whole is maintained for 6 hours without stirring. After removal of the solvent by evaporation, the residue is purified by chromatography over a silica column using a gradient of dichloromethane/methanol (95/5 to 0/100). The expected product is obtained in the form of the base and is converted to the corresponding dihydrochloride
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)#N.[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H]([OH:40])C1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:9][CH2:8][C@H:7]1[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4][C@@H:3]1[CH:1]=[O:40])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirred solution of 3'-cyano-2',3'-dideoxy-5'-O-trityluridine (0.96 g, 2 mmol), (prepared in a manner equivalent to that of the thymidine analog above) in dry THF (20 ml) under argon, was added a solution of DIBAL-H in toluene (Aldrich) (1M, 4 ml) at -10° C. over a period of 10 min. After 30 mins the reaction was quenched with MeOH (5 ml) at -10° C. The mixture was further stirred at ambient temperature for 30 mins and diluted with CH2Cl2 (25 ml) before concentrating under vacuum. This process was repeated with CH2Cl2 (3×25 ml) in order to remove the residual THF. The residue was purified by flash chromatography on silica gel (25 g). Elution with CH2Cl2 (9:1, v/v) and crystallization from CH2Cl2 /MeOH gave 5'-O-trityl-3'-C-formyl-2',3'-dideoxyuridine (0.53 g, 53%); mp 100° C.; 1H NMR (CDCl3) δ 2.25-2.8 (m, 2, CH2), 3.4 (m, 1, C3'H), 3.45-3.6 (m, 2, C5'CH2), 4.37 (m, 1, C4'H), 5.4 (d, 1, C5H), 6.1 (m, 1, C1'H), 7.2-7.4 (m, 15, C6H5), 7.81 (d, 1, C6H), 7.95 (br s, 1, NH), 9.61 (s, 1, HC=O).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[NH:20][N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:42])[C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=4[F:41])=[C:25]([O:43][CH3:44])[CH:24]=3)[C:15]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:64]1[CH2:69][CH2:68][CH:67](O)[CH2:66][CH2:65]1>O1CCCC1>[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:67]3[CH2:68][CH2:69][O:64][CH2:65][CH2:66]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:42])[C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][C:32]=4[F:41])=[C:25]([O:43][CH3:44])[CH:24]=3)[C:15]=12
Reactant: COc1cc(-c2n[nH]c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2nn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Diethyl azodicarboxylate (0.07 mL, 0.45 mmol) was added into a mixture of N1-[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.10 g, 0.22 mmol), triphenylphosphine (0.12 g, 0.45 mmol) and tetrahydro-4H-pyran-4-ol (0.04 g, 0.34 mmol) in tetrahydrofuran (5 mL) and the mixture was stirred at ambient temperature overnight. Tetrahydro-4H-pyran-4-ol (0.01 g, 0.11 mmol), triphenylphosphine (0.04 g, 0.15 mmol) and diethyl azodicarboxylate (0.02 mL, 0.15 mmol) were added and the mixture was stirred at ambient temperature for 5 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield N1-[4-(4-amino-1-tetrahydro-2H-4-pyranyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.03 g, 0.06 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (dd, 1H), 8.30(d, 1H), 8.25 (s, 1H), 8.00 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.34 (s, 1H), 7.31 (d, 1H), 6.90 (br, 2H), 4.95 (m, 1H), 4.02 (m, 2H), 3.95 (s, 3H), 3.56 (t, 2H), 2.22 (m, 2H), 1.89 (m, 2H); MS: MH+ 531.
Reaction SMILES: [O:1]=[C:2]1[N:7](C(OCC[Si](C)(C)C)=O)[CH2:6][CH2:5][N:4]2[C:17]([C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)=[N:18][N:19]=[C:3]12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:17]1[N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[C:3]2=[N:19][N:18]=1
Reactant: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCn2c1nnc2-c1cnccn1
Reaction time: 1 h
Yield: 191.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl 8-oxo-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 2.9 mmol) in DCM (29 mL) was added TFA (5.7 mL, 75 mmol). After 1 h, the reaction mixture was concentrated. The crude residue was diluted with EtOAc, sonicated, and filtered to provide the desired product as a white solid (1.2 g, 95%). MS (ESI): mass calcd. for C9H8N6O, 216.1; m/z found, 217.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.39 (d, J=1.1 Hz, 1H), 8.77 (q, J=2.6 Hz, 2H), 8.56 (s, 1H), 4.73-4.60 (m, 2H), 3.67-3.55 (m, 2H).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:14]([O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:18])[C:15]([CH3:17])=[CH2:16].[CH2:24](C(C)=O)C(C)C.N(C(C)(CC)C([O-])=O)=NC(C)(CC)C([O-])=O>CCCCCCC>[C:1]([O:6][CH:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:14]([O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:18])[C:15]([CH3:17])=[CH2:16].[C:14]([O:19][CH:20]([CH3:24])[CH2:21][O:23][CH3:22])(=[O:18])[CH3:15]
Reactant: CC(=O)CC(C)C
Agent: C=C(C)C(=O)OC(C)OCCCC
Agent: C=C(C)C(=O)OCC1CO1
Agent: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Solvent: CCCCCCC
Product: COCC(C)OC(C)=O
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 67.1 g (0.36 mol) of 1-n-butoxyethyl methacrylate, 34.1 g (0.24 mol) of glycidyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in propylene glycol monomethyl ether acetate, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A-1 (1-n-butoxyethyl methacrylate/glycidyl methacrylate) as a propylene glycol monomethyl ether acetate solution.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.[CH3:46][NH2:47]>C(O)(C)C>[OH:44][C@@H:43]([CH2:45][NH:47][CH3:46])[CH2:42][O:41][C:2]([CH3:40])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:37])([CH3:39])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN
Solvent: CC(C)O
Product: CNC[C@H](O)COC(C)(C)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 16.2 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (87.5 mg, 0.133 mmol), isopropyl alcohol (2 mL), and methylamine (1.0 mL, 2 mmol, 2 M in methanol; old bottle) was microwaved at 130° C. for 15 min. The solvent evaporated under reduced pressure. The resulting oil was purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid {1-[2-((S)-2-hydroxy-3-methylamino-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (14.9 mg, 16.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H42Cl2F2N6O3S+H [(M+H)+]: 691.2737. found: 691.2731.