Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a suspension of 5-bromo-1H-indazole (2.5 g, 12.69 mmol, 1.0 eq) in DCM (10 ml) was added dihydropyran (3.2 g, 38 mmol, 3.0 eq) and a catalytic amount of PTSA (12% in AcOH, 1.8 ml, 0.1 eq). The mixture was stirred overnight and neutralized by addition of sodium bicarbonate. Then the organic layer was sequentially washed with 10% citric acid and brine, dried on Na2SO4 and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel, eluting with DCM to give the expected compound as a colorless liquid (3.57 g, 82%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCOCCO.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CS(C)=O
Solvent: OCCOCCOCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.8 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of triethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.2 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCOCCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: OCCOCCOCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 82.7 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of triethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 g of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.4 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: Cc1ccc(C)cc1
Solvent: CS(C)=O
Solvent: OCCOCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 85.6 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of diethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.0 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.OCC(CO)O.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCC(O)CO
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 87.9 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of glycerol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.5 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CS(C)=O
Solvent: OCCOCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of diethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 g of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.1 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCO.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccc(C)cc1
Solvent: OCCOCCO
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 86.5 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of diethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.2 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCOCCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: O
Solvent: OCCOCCOCCO
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 80.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of triethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 16.9 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3ncnn23)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3ncnn23)nc1
Temperature: 150 °C

Procedure:
60 mg (0.19 mmol) of 6-({2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}amino)nicotinonitrile (Example 54A), 35.6 mg (0.19 mmol) of (2,4-dichlorophenyl)boronic acid and 21.6 mg (0.019 mmol) of tetrakis(triphenyl-phosphine)palladium(0) are introduced into a mixture of 4 ml of dioxane and 1.3 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min. Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 15.3 mg (19% of theory) of the product as a solid.
Reaction SMILES: CO.[NH:3]1[C:7](=[O:8])[CH2:6][CH2:5][C@H:4]1[C:9]([OH:11])=[O:10].OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[C:24]([O-])(O)=O.[Na+]>>[CH3:24][O:10][C:9](=[O:11])[C@@H:4]1[CH2:5][CH2:6][C:7](=[O:8])[NH:3]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Methanol (62 L, 1.155 mol), L-pyroglutamic acid (20 kg, 154.9 mol) and H2SO4 (97%, 0.87 L, 15.5 mol) were introduced into a reactor. The suspension was warmed to 60° C. and stirred until the pyroglutamic acid concentration dropped below 10%. The temperature of the reactor jacket was lowered to 0° C., and when the internal temperature reached 30° C., 9.7 kg (68.1 mol) of Na2SO4 was added and stirred for 15 min, then 8.1 kg (96.4 mol) of NaHCO3 was added. When pH 7 was reached (about 10 min), the suspension was filtered over a pad of celite. The filtrate was reintroduced into the reactor, and the methanol was distilled off at a pressure of 90-160 mbar and a jacket temperature of 50° C. Ethyl acetate (53 L) was then added with stirring, the mixture cooled to 0° C., and the mixture stirred for 16 hr. Unreacted pyroglutamic acid crystallized out and was removed by filtration. Removal of the ethyl acetate by evaporation under reduced pressure provided the title product as a viscous yellow oil, which was taken to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:14][C@@H:15]([C@@H:22]1[C@@:26]2([CH3:44])[CH2:27][CH2:28][CH:29]3[C@@:34]4([CH3:43])[CH2:35][CH2:36][CH:37]([O:39][C:40](Cl)=[O:41])[CH2:38][C:33]4=[CH:32][CH2:31][CH:30]3[CH:25]2[CH2:24][CH2:23]1)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>ClCCl.O1CCOCC1>[CH3:14][C@@H:15]([C@@H:22]1[C@@:26]2([CH3:44])[CH2:27][CH2:28][C@@H:29]3[C@@:34]4([CH3:43])[CH2:35][CH2:36][C@H:37]([O:39][C:40]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:41])[CH2:38][C:33]4=[CH:32][CH2:31][C@H:30]3[C@@H:25]2[CH2:24][CH2:23]1)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of 2-dimethylaminoethylamine (19.40 mg, 24:1, 0.22 mmol) and triethylamine (310 μl, 2.23 mmol) in dichloromethane (3 ml) at room temperature was slowly added a solution of cholesteryl chloroformate (100 mg, 0.22 mmol) in 1,4-dioxane. When the reaction was completed, the mixture was evaporated to dryness and the residue was purified by flash chromatography (CHCl3/MeOH, 4:1). A white solid was obtained, yield 105 mg (95%). The structure was verified by NMR and MALDI.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-chloro-pyrimidine (3.0 g, 15.51 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.42 g, 17.06 mmol, 1.1 equiv; commercially available) in DMAc (50 mL) was added anhydrous K2CO3 (5.36 g, 38.78 mmol, 2.5 equiv) and the reaction mixture stirred at rt for 18 h. The reaction mixture was heated for an additional time period of 2 h to 60° C. and then extracted with ethyl acetate (3×100 mL) and the combined organic phases washed with a sat. solution of sodium chloride (2×50 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 2.22 g (40%) of the title compound. MS (ISP): 357.0 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8](O)[C:9]([CH3:11])=[CH2:10])[CH2:3][CH2:4][OH:5].C1(PCCCCPC2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C@@H:2]([CH2:6][CH:7]=[CH:8][C:9]([CH3:11])=[CH2:10])[CH2:3][CH2:4][OH:5]
Reactant: C=C(C)C(O)CC[C@H](C)CCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(PCCCCPc2ccccc2)cc1
Product: C=C(C)C=CC[C@H](C)CCO
Temperature: 150 °C
Yield: 81.5 %

Procedure:
(S)-3,7-dimethyl-6-hydroxy-7-octene-1-ol (I) (10.0 g, 58.1 mmol), bis(triphenylphosphine) palladium chloride (40.8 mg, 0.058 mmol), and 1,4-bisphenylphosphinobutane (1.24 g, 2.91 mmol) were placed in a 50 ml three neck distillation flask provided with a thermometer and a vacuum distilling apparatus having a side arm. The mixture was then heated for 6 hours with stirring at a reaction temperature of 150° C. under a reduced pressure of 25 mmHg while distilling dienes which is to be produced. 7.3 g (115° to 120° C./25 mmHg) of (S)-3,7-dimethyl-5,7-octadiene-1-ol (II) was obtained in 82% yield.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:12]2[C@H:8]([O:9][CH2:10][CH2:11]2)[O:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[O:7]1[C@H:8]2[O:9][CH2:10][CH2:11][C@H:12]2[C@@H:5]([OH:4])[CH2:6]1
Reactant: CC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 30 °C

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate (8.0 g) was dissolved in dichloromethane (24 ml) and Methanol (24 ml). Potassium carbonate (0.1 g) was added and reaction mass was stirred at 25-35° C. till the completion of reaction. Reaction mass was filtered & concentrated under vacuum at 40-45° C. to residue of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol (Yield 6.5 g).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14](=[NH:18])OCC)[CH2:13][CH2:12]2)[CH:10]=1.[S].C(N(CC)CC)C.Cl.Cl.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]2)=[N:34][C:35]=1N>C(O)C>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14]3[NH:18][C:35]4=[N:34][C:33]([N:37]5[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]5)=[CH:32][CH:31]=[C:30]4[N:29]=3)[CH2:12][CH2:13]2)[CH:10]=1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Agent: Cl
Agent: [S]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Yield: 48.9 %

Procedure:
Acetic acid (0.5 mL, 8.88 mmol), ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (445 mg, 1.78 mmol), a catalytic amount of sulfur, and triethylamine (0.8 mL, 5.92 mmol) were added to a suspension of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate dihydrochloride (500 mg, 1.48 mmol) in ethanol (25 mL) at room temperature. The reaction mixture was heated at reflux for 18 h, then was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 25-70% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (300 mg). MS (ES+) (M+H) 415.2.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@@H:13]1Br)(=[O:10])[CH3:9]>>[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@H:13]1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Sc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2)SC[C@H]1OC(C)=O
Yield: 52.3 %

Procedure:
If the procedure described in Preparation I is followed starting from 4 g (36.3.10-3 mol) of benzenethiol, 14 g (39.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-xylopyranosyl bromide and 10 g (39.10-3 mol) of mercuric cyanide (Hg(CN)2), 7.3 g of the expected product are obtained after crystallization from ether.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[N:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
In a 250 mL four-necked flask, sodiumhydride (60% in mineral oil, 4.16 g) was combined with DMF (60 mL). The suspension was cooled to 0° C. and 2,2,2-trifluoroethanol (10.4 g, [CAS Reg. No. 75-89-8]) was added dropwise over a period of 20 minutes to the cold suspension. The mixture was stirred for 1 hour at 0° C. Then, a solution of 2-chloro-5-nitropyridine (15 g, [CAS Reg. No. 4548-45-2]) in DMF (70 mL) was added dropwise over a period of 20 minutes to the cold reaction mixture. Stirring was continued for 10 minutes at 0° C. and for 2 hours at r.t. The reaction mixture was poured into ice/water and was then extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow solid (20.52 g, 93%). MS (EI, m/e): 222.0 [M+].
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@:3]([CH3:23])([OH:22])[CH:4](O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.OC(C)(C(F)(F)F)C(=O)CC1C=CC(S(C2C=CC=CC=2)(=O)=O)=CC=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[F:25][C:2]([F:1])([F:24])[C@:3]([OH:22])([CH3:23])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: C[C@](O)(C(O)Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: CC(O)(C(=O)Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: C[C@](O)(/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
(2S)-1,1,1-Trifluoro-2-methyl-4-(4-phenylsulfonylphenyl)-2,3-butanediol. To a stirred, cooled 0° C. solution of 3-hydroxy-3-methyl-1-(4-phenylsulfonylphenyl)-4,4,4-trifluoro-2-butanone (3.7 g, 10 mmol) in 135 mL methanol was added NaBH4 (1.7 g, 44 mmol). The mixture was stirred for 15 minutes. 100 mL of saturated aqueous NH4Cl was added. The mixture was extracted with dichloromethane and the combined organic layers were dried and evaporated. The resulting solid was pre-absorbed onto silica gel and purified by chromatography, with ether:hexane as the eluent (75:25), to give the title compound as a mixture of isomers (3.13 g, 83%); NMR (CDCl3): 7.96-7.89 (m,4, Ar), 7.58-7.49 (m,3, Ar), 7.48-7.39 (d,2, Ar), 3.91-3.86 (m,2), 3.13 (s,1), 3.08 (s,1), 2.80 (s,1), 2.76-2.75 (d,1), 2.68 (s,1), 1.47 (s,3, CH3); MS: m/z=375(M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](I)([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8]>>[CH:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:23])([F:24])[F:25])([F:20])[F:21])([F:17])[F:18])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a distillation apparatus-equipped reflux condenser, a dropping funnel and a thermometer, 400 cc of isopropyl alcohol (the water content in the isopropyl alcohol being not higher than 50 ppm, the same is true in the following Examples), and 84.2 g (0.75 mol) of potassium tert-butoxide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 223 g (0.5 mol) of C6F13I was dropwise added thereto over a period of two hours. After completion of the dropwise addition, heating and refluxing were continued for one hour. The conversion at that time was 100%. A fraction with a boiling point of up to 75° C. was recovered by distillation from the reactor and further washed five times with 200 g of water, to obtain 151 g of C6F13H having a purity of 99.8%. In the reactor, no formation of tar was observed.