Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[NH2:1][C:2]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cc1N
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A mixture of 2-amino-5-bromobenzonitrile (1.0 g, 5 mmol), phenylboronic acid (0.92 g, 7.5 mmol), tetrakis(triphenylphosphine)palladium (50 mg) and potassium carbonate (3.5 g, 25 mmol) in dimethoxyethane/water 2:1 (60 mL) was heated at reflux for 4 hours. After cooling to room temperature the reaction was diluted with water and extracted with ethyl acetate. The organic phase was dried and solvent evaporated. Trituation with petroleum ether gave 0.89 g of the desired compound.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: c1ccc2c(c1)CCN(C[C@H]1CO1)C2
Reactant: N
Solvent: CCO
Product: NC[C@@H](O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 90 %

Procedure:
To a solution of (S)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (2.2 g, 0.012 mol) in EtOH (30 mL), NH3 was bubbled to the solution under −78° C. The reaction mixture was then sealed and heated at 80° C. for 3 h. After LCMS indicated completion of the reaction, the mixture was concentrated and the crude product was used in next step without further purification (2.2 g, Yield 90%). LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [C:1](=O)([O:17]N1C(=O)CCC1=O)[O:2][CH2:3][CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[NH2:26][C:27]1([C:31]([OH:33])=[O:32])[CH2:30][O:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH:15]1[C:16]2[CH:4]([CH2:3][O:2][C:1]([NH:26][C:27]3([C:31]([OH:33])=[O:32])[CH2:30][O:29][CH2:28]3)=[O:17])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1(C(=O)O)COC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (3.2 g, 9.5 mmol) in dioxane (30 ml) was added to a solution of 3-amino-oxetane-3-carboxylic acid (1.17 g, mmol) and potassium carbonate (2.76 g, 20.0 mmol) in water (30 ml). The light yellow opaque solution was stirred at room temperature for 75 minutes. During that time, a white solid precipitated. The mixture was diluted with water and extracted two times with diethyl ether. The white solid did not dissolve and was kept therefore in the aqueous layer, which was acidified to pH 2 by addition of 1N HCl and extracted three times with EtOAc. The combined EtOAc layers were washed with brine, dried with Na2SO4 and evaporated. The crude title compound was obtained as white solid and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:16]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[C:10]1([C:3]2[C:2]3[N:1]=[N:16][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1snc(-c2ccccc2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nnc2c(-c3ccccc3)nsc12
Reaction time: 8 h
Yield: 71.3 %

Procedure:
219 mg of 4-amino-3-phenyl-5-isothiazolecarboxamide in 7.2 ml of glacial acetic acid and 4 ml of concentrated hydrochloric acid were stirred at 0° C. during the addition of a solution of 80 mg of sodium nitrite in 1.2 ml of water. The mixture was held at below room temperature overnight and the precipitated product was filtered off and recrystallized from methanol to give 164 mg of 7-phenylisothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one. A sample recrystallized from aqueous methanol melted at 179°-180° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26])(=[O:5])=[O:4]
Reactant: O=C1OCCC1CCCCO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCCC1CCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.64 mL, 3.8 mmol) was added dropwise to a 0° C. solution of 3-(4-hydroxybutyl)-dihydrofuran-2(3H)-one (0.50 g, 3.2 mmol) and DIEA (0.94 mL, 5.4 mmol) in CH2Cl2 (15 mL). After stirring at 0° C. for 1.5 hours, the reaction was diluted with CH2Cl2 and washed sequentially with water, 1 M HCl, and water. The organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed (1:2 EtOAc/hexanes) to afford the product as a colorless oil (0.21 g, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N+:6]([O-])[O:7][N:8]=[C:4]2[CH:3]=1.P(OCC)(OCC)OCC>C(O)C.CCCCCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1
Reactant: [O-][n+]1onc2cc(Br)ccc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Solvent: CCCCCC
Product: Brc1ccc2nonc2c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a stirred solution of 5-bromobenzo[c][1,2,5]oxadiazole1-oxide (6.0 g, 28.436 mmol) in ethanol (60 mL) was added triethyl phosphite (6.2 mL, 34.123 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 60° C. for 1 h., cooled to RT, diluted with hexane (100 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-bromobenzo[c][1,2,5]oxadiazole (4.0 g, 71%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.Br[C:11]1[C:12](Cl)=[N:13]C=C(O)[CH:16]=1.ClC(C)C#N.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([CH3:16])[C:12]#[N:13])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Oc1cc(Br)cnc1Cl
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C#N)Oc1cc(Br)cnc1Cl
Reaction time: 0.05 h

Procedure:
A dry 5 mL, one neck round bottom flask was charged with a 95-5 mixture of 5-bromo-2-chloropyridin-3-ol and 3-bromo-2-chloropyridin-5-ol (0.2031 g, 0.9744 mmol), a stirbar, 2 mL dry DMF and 2-chloropropanenitrile (0.4310 ml, 4.872 mmol). To the mixture was added cesium carbonate (CS2CO3) (0.3492 g, 1.072 mmol), and the flask was sealed with a septa. The reaction was heated using a 100° C. oil bath for 4 h, and cooled. The DMF was diluted with 4 mL THF, and the slurry was loaded onto 5 g of SiO2 wet-packed with THF. The silica was eluted with 50 mL THF, and the eluted volume was concentrated in vacuo. A sample was scouted for prep purification using a 2.1×50 mm Xterra MS C18 column with a 3.5 μm particle size (PN 186000400); A=10 mM NH4 HCO3 in water, pH adjusted with concentrated NH4OH to 9.6; B=ACN; gradient: initial@1 mL/min, 10% B; 0→5 min@1 mL/min, linear gradient to 100% B; 5→6.9 min@1 mL/min, isocratic at 100% B; 6.9→6.95 min@1 mL/min, linear gradient to 10% B, 8 min end. A major peak was observed at 2.87 minutes. The sample was purified using a 30×100 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186001942); Gradient: 0→5 min@35 mL/min, 10% B; 5→20 min@35 mL/min, linear gradient to 40% B; 20→24.9 min@35 mL/min, isocratic at 40% B; 25.0 min→29.9 min@35 mL/min, step to 100% B; 30→40 min@35 mL/min, step to 10% B; 40 min end. A=10 mM NH4 HCO3 in water, pH adjusted with concentrated NOH to 9.6; B=ACN. A band that eluted from 23.6 to 25.4 minutes was isolated. The solvent was removed in vacuo to afford 2-(5-bromo-2-chloropyridin-3-yloxy)propanenitrile and 2-(5-bromo-2-chloropyridin-3-yloxy)propanenitrile (0.1316 g).
Reaction SMILES: FC(S(O[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([NH:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:10]=1)(=O)=O)(F)F.O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:11]1[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C#N)cc2)n1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(C#N)cc2)cc(N2CCOCC2)n1
Temperature: 90 °C

Procedure:
2-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-6-(4-cyanophenyl)pyrimidin-4-yl (trifluoromethyl)sulfonate (134 mg, 0.275 mmol) was dissolved in a 2 M solution of morpholine in acetonitrile and the resulting solution heated to 90° C. for 18h. The solution was cooled, water added and the suspension extracted thoroughly with ethyl acetate. Concentration of the combined organic layers gave a crude solid which was chromatographed (silica gel, 2% methanol/methylene chloride) to afford 234 mg of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide as a off white solid. Removal of the tert-butoxy protecting group was accomplished in the following manner: the (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide produced as described above was dissolved in anhydrous hydrogen chloride in dioxane (2 mL of a 2M solution) and stirred at room temperature for 2 h. Concentration gave 134 mg of 4-{2-[(2-aminoethyl)amino]-6-imidazolyl-4-ylpyrimidin-4-yl}benzenecarbonitrile as its (2x) hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O.O>[Si:13]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc2cccc(O)c2n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
8-Hydroxyquinaldine (10 g), t-butyldimethylsilyl chloride (10 g) and imidazole (8.6 g) were dissolved in N,N-dimethylformamide (150 ml) and stirred at ambient temperature overnight. Further t-butyldimethylsilyl chloride (4.7 g) was added and the reaction stirred for another 30 minutes. The reaction was diluted with water (600 ml) and extracted with dichloromethane (3×300 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to afford the title compound as an orange oil (17 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:21](O)=[O:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(Cl)Cl>[CH2:28]([N:30]([CH2:31][CH3:32])[C:21]([C:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][CH:8]=1)=[O:22])[CH3:29]
Reactant: CCNCC
Reactant: COc1ccc(-c2c(OC(C)C)cccc2C(=O)O)c(OC)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(OC(C)C)c1-c1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Prepare a stirred solution of 6-isopropoxy-2',4'-dimethoxy-biphenyl-2-carboxylic acid (8.60 g, 0.0276 mole) in CH2Cl2 (200 mL) at ambient temperature under argon. Dropwise add thionyl chloride (4.6 g, 54 mmol, 2.8 mL). Continue stirring for about 60 minutes. Cool the reaction to 0° C. and dropwise add diethylamine (19.7 g, 28 mL, 0.27 mole), ensuring the temperature does not rise above 25° C. Continue stirring the reaction for about 30 minutes after addition is complete. Wash the organic layer with water, separate, and wash twice with 100 mL 5% sodium bicarbonate. Separate again, wash with brine (sat'd NaCl) and dry over magnesium sulfate. Filter through celite and condense on a rotovap to give a viscous light brown liquid. Dissolve (partially) in methylene chloride (20 mL) and filter. Flash chromatograph, in 30% ethyl acetate/70% hexane, to remove a solid impurity which is discarded. Continue eluting to obtain a mixture of the discardable and desired product. Further chromatography isolates the title compound as a pale yellow liquid (6.80 g, 68%). (EtOAc/hexane 30:70; Rf =0.15).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:5]2[CH:6]=[C:7]([C:14]3[CH:15]=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][CH:19]=3)[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>C1COCC1.O1CCOCC1>[CH3:27][CH:26]([CH3:28])[CH2:25][C:24]([NH:13][NH:12][C:10]([C:9]1[N:4]2[N:3]=[C:2]([NH2:1])[N:23]=[C:5]2[CH:6]=[C:7]([C:14]2[CH:19]=[N:18][C:17]([N:20]([CH3:21])[CH3:22])=[N:16][CH:15]=2)[CH:8]=1)=[O:11])=[O:29]
Reactant: CN(C)c1ncc(-c2cc(C(=O)NN)n3nc(N)nc3c2)cn1
Reactant: CC(C)CC(=O)Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)CC(=O)NNC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(N)nn12

Procedure:
The product of Step 2 (0.11 g, 0.35 mmol) was combined with isovaleryl chloride (0.04 mL, 0.35 mmol) and 5 mL of a 1:1 solution of THF/dioxane in a tube. The mixture was microwaved at 130° C. for five minutes. The reaction mixture was cooled, then the solid was collected by filtration to give 2-amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid N′-(3-methyl-butyryl)-hydrazide. MS (APCI+): m/z 398.1.
Reaction SMILES: O[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3].N1C=CC=CC=1.P(Br)(Br)[Br:20]>CCOCC>[Br:20][CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3]
Reactant: CC(O)C#Cc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(Br)C#Cc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
The product prepared in step (d) above (0.05 mol) and dry pyridine (1 ml) are dissolved in dry ether (20 ml) and cooled to 0° C. Phosphorous tribromide (0.025 mol) in 20 ml dry ether is added dropwise with stirring. The reaction mixture is then refluxed for 3 hours. After cooling the mixture to 0°, the excess PBr3 is destroyed by adding crushed ice. The ether layer is washed and dried. The ether is removed and the title product is obtained by distillation.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[N:8]1.[OH:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[CH2:26][O:27][C:23]=2[C:22]=1[CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.N1CCCCC1>CO>[OH:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])/[C:26](=[CH:16]/[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[N:8]=3)/[O:27][C:23]=2[C:22]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A solution of the positional isomer (2) of N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxaldehyde (0.354 g, 1.28 mmol) obtained in Step 1 in methanol (5 mL) was added with tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.446 g, 1.28 mmol) and piperidine (0.0109 g, 0.128 mmol), and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.419 g, 53%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH2:9][F:10])[C:5]([F:21])=[CH:4][CH:3]=1.[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:16])([CH2:11][C@H:12]([OH:13])[C:23]([F:25])([F:24])[F:22])[CH2:9][F:10])[C:5]([F:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(CC=O)c1nc(Br)ccc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL round-bottomed flask was added (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1-fluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (5.9 g, 15.39 mmol) and THF (130 mL). The mixture was cooled to −78° C. and (trifluoromethyl)trimethylsilane (Apollo Scientific Ltd.; 24.46 mL, 154 mmol) was added. After stirring for 10 min, tetrabutylammonium fluoride (Aldrich; 27.7 mL, 27.7 mmol, 1.0 M in THF) was added over 10 min. The solution was stirred at −78° C. for 2 h. To the solution was added 1 N HCl (10 mL) and the solution was allowed to warm to rt. The solution was carefully diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (100 mL) and brine (50 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 60% EtOAc/hexane, 120 g Silicycle HP) afforded:
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:21]([OH:22])[C:20]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:19]=2[S:18][C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: CN1CCC(Cl)CC1
Reactant: COc1ccc(Sc2cc(F)ccc2F)c(C=O)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Sc2cc(F)ccc2F)c(C(O)C2CCN(C)CC2)c1
Yield: 99.5 %

Procedure:
A solution of a Grignard reagent is prepared by a reaction of 6.7 g of 4-chloro-1-methylpiperidine with 1.25 g of magnesium in 40 ml of tetrahydrofuran and is treated while stirring for 10 minutes with a solution of 9.35 g 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde in 20 ml of tetrahydrofuran, added dropwise. The mixture is refluxed for 3 hours and, after cooling, it is decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 12.6 g (100%) of crude oily α-(1-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-methoxybenzyl alcohol which is used in this state for the next reaction. For characterization the crystalline hydrogen oxalate may be prepared by neutralization of a sample with oxalic acid; it is purified by crystallization from acetone and melts at 160°-163° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](=[O:30])[N:13]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:14][C:15]2[NH:16][C:17](=[O:25])[CH:18]3[CH2:24][O:23][CH2:22][CH2:21][CH:19]3[N:20]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH:27]1([CH2:26][N:13]([CH2:14][C:15]2[NH:16][C:17](=[O:25])[CH:18]3[CH2:24][O:23][CH2:22][CH2:21][CH:19]3[N:20]=2)[C:12]([CH2:11][N:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:30])[CH2:28][CH2:29]1
Reactant: COC(=O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of 1-{[cyclopropylmethyl-(4-oxo-3,4a,5,7,8,8a-hexahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-carbamoyl]-methyl}-piperidine-4-carboxylic acid methyl ester (0.6 g, 1.43 mmol, 1 eq.) in 3 mL of MeOH was added a solution of NaOH (0.13 g, 5.43 mmol, 3.8 eq.) in 3 mL of H2O. The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and treated with 1 N HCl to pH 5. The resulting mixture was freeze dried using lyophilizer to remove H2O. The resulting white solids were washed with dichloromethane/methanol and filtered to remove NaCl. The filtrate was concentrated to give the title compound as a white solid (0.53 g, 92%). Exact mass calculated for C23H31N4O3 407.2. MS (ESI) m/z 407.6 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]([O:29][CH2:30][O:31][CH3:32])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:13][C:12]=2[CH2:33][CH2:34][CH3:35])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[I:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]([O:29][CH2:30][O:31][CH3:32])([C:21]([F:22])([F:23])[F:24])[C:25]([F:27])([F:28])[F:26])=[CH:13][C:12]=2[CH2:33][CH2:34][CH3:35])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccc(I)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccc(I)c(CO)c1
Yield: 107.7 %

Procedure:
To a solution of (2-iodo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy) benzaldehyde (25 mg, 0.0404 mmol) in methanol (2.0 mL), sodium borohydride (1.7 mg, 0.445 mmol) was added under ice-cold conditions, and the resultant mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was added with water under ice-cold conditions and extracted with chloroform. The organic layer was washed with brine and dried over sodium sulfate. (2-Iodo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy) phenyl)methanol (27 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].N1C=CC=CC=1.[CH3:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17]>ClCCl>[C:2](=[O:3])([O:17][CH2:16][CH:15]([CH3:14])[CH2:18][CH3:19])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)COC(=O)OC(C)Cl
Temperature: 0 °C

Procedure:
In 70 ml of dichloromethane are dissolved 13 ml of 2-methyl-1-butanol and 17 g of 1-chloroethyl chloroformate, and the solution is cooled to 0° C. With stirring, a solution of 9.6 ml of pyridine in 30 ml of dichloromethane is added dropwise, and the mixture is stirred for 30 minutes. The salt precipitate is collected by filtration and the filtrate is washed with two 200-ml portions of water and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is further distilled under reduced pressure to give 12.5 g of 1-chloroethyl 2-methylbutyl carbonate.