Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12]([CH2:21]Cl)=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:23][S:24]C.[Na].C(N(CC)CC)C.O>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12]([CH2:21][S:24][CH3:23])=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CSC
Reactant: Fc1cccc(-c2nc(-c3cccnc3)c(CCl)[nH]2)c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSCc1[nH]c(-c2cccc(F)c2)nc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of a crude product of 2-(3-fluorophenyl)-5-chloromethyl-4-(3-pyridyl)imidazole dihydrochloride (268 mg) in tetrahydrofuran (10 ml) were added 15% aqueous sodium methyl sulfide solution (0.95 ml) and triethylamine (206 mg), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=19:1) to obtain 2-(3-fluorophenyl)-5-methylthiomethyl-4-(3-pyridyl)imidazole (198 mg) as colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of the compound of Example 46, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of CH2Cl2 was stirred vigorously and treated with phenyl isocyanate (0.290 mL, 2.67 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 559 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea as a white solid.
Reaction SMILES: [C:1](=[O:6])([O-])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)(O)[O-].[Na+]>CCOCC.O.C(O)(=O)C.C(O)C>[O:15]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:1]([O:2][CH2:3][CH3:4])=[O:6]
Reactant: CCOC(=O)[O-]
Reactant: CCCCC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 193.9 %

Procedure:
70.8 g of ethyl carbonate in solution in 50 ml of ether were added to a suspension of 27.3 g of sodium hydride (50% in oil, washed 3 times with hexane) in 250 ml of ether and the mixture was stirred for 10 minutes and 30 g of hexanone were added. The mixture was refluxed for 2 hours and then a solution of 35 ml of ether containing 12 ml of ethanol was added. The solution was cooled to 0° C. and a solution of 36 ml of acetic acid in 300 ml of water was added. 12 ml of a saturated sodium bicarbonate solution were added and extraction was carried out with ether. The extracts were washed with water, dried, filtered and evaporated to dryness under reduced pressure to obtain 100 g of an oil which was distilled under a pressure of 3 mbar at 70° C. to obtain 32.5 g of the desired product.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc(C#CCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.7 %

Procedure:
A mixture of 1-(but-3-yn-1-yl)-4-benzylpiperidine (227 mg, 1.00 mmol), 4-iodoaniline (263 mg, 1.20 mmol), copper (I) iodide (15 mg), PdCl2(PPh3)2 (28 mg) in 10 mL of Et3N is stirred at room temperature under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a pale yellow oil (50 mg, 16%): 1H NMR (CDCl3) 1.29 (m, 2 H) , 1.51 (m, 1 H), 1.66 (m, 2 H), 1.99 (m, 2 H), 2.58 (m, 6 H), 2.91 (m, 2 H), 3.73 (m, 2 H), 6.55 (d, J=7.8 Hz, 2 H), 7.13-7.28 (m, 7 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH:30]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[C:6]=2[N:7]=1
Reactant: OC1CCCC1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), cyclopentanol (1.1 equiv), and sodium tert-butoxide (1 equiv) in 1,4-dioxane (0.22 M) was taken in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed and the mixture was stirred at 70° C. for 3 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and loaded onto a silica column (packed with hexanes). The column was eluted with 0-30% ethyl acetate in hexanes. The fractions containing product were combined and concentrated to dryness to give the target product as a light yellow oil (Yield: 88%) that solidified upon standing. MS (ESI) m/z 499.4 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C(N(C(C)C)CCC(C1C=CC=CC=1)C#N)(C)C.ClCCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:9]#[N:10]
Reactant: CN(C)CCCl
Reactant: CC(C)N(CCC(C#N)c1ccccc1Cl)C(C)C
Agent: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: CC(C)N(CCCl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C)C)c1ccccc1Cl)C(C)C

Procedure:
Substitution of equivalent quantities of α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 2-chloro-N,N-dimethylethylamine for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 2-chloro-N,N-diisopropylethylamine called for respectively in the procedure of Example 2, Method B, there is obtained α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(dimethylamino)ethyl]acetonitrile, as an oil boiling at about 160°-165° C. at 0.5 mm. pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([NH:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:22](=[O:28])[N:16]([CH3:17])[CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNC(c1ccccn1)c1cc(Br)ccc1N
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 4-Bromo-2-(methylamino-pyridin-2-yl-methyl)-phenylamine (500 mg) in THF (20 mL) is added triphosgene (493 mg, 1.87 mmol), then the mixture is stirred at room temperature for 2 h. TLC showed the reaction is completed. Water (20 mL) is added and the mixture is extracted with EtOAc, the organic layer is dried over Na2SO4 and concentrated to give the desired compound as a crude mixture. This is used in next step with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:13]3=[N:14][NH:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH3:18])[C:9]2=[O:19])=[CH:5][CH:4]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:15]2[CH:16]=[C:12]3[C:13]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[C:9](=[O:19])[N:10]([CH3:18])[C:11]3=[O:17])=[N:14]2)=[CH:25][CH:24]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c[nH]nc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(Br)cc4)nc32)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A suspension of 7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (161 g, 562 mmol), 1-bromo-4-(bromomethyl)benzene (157 g, 628 mmol) and K2CO3 (93.2 g, 674 mmol) in DMF (800 mL) is stirred at room temperature until the reaction is complete. The reaction mixture is poured into water (5 L). After filtration, the filter cake is washed with water and ethanol successively, and then dried under vacuum to give 226 g of product (yield: 88%). MS (ESI) m/z 455.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[N:17]=[C:16]2[OH:32]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:17]1[C:16](=[O:32])[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[N:18]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)=[O:10]
Reactant: COc1ccc2c(c1)c(O)nn2Cc1cccc([N+](=O)[O-])c1
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(=O)n(C(=O)Nc1ccccc1F)n2Cc1cccc([N+](=O)[O-])c1

Procedure:
1.8 g (0.013 mol) of 2-fluorophenyl isocyanate are added to a solution of 3.0 g (0.01 mol) of 5-methoxy-1-(3-nitrobenzyl)-1H-indazol-3-ol in 100 ml of tetrahydrofuran and the mixture is heated under reflux for 4 hours. It is then concentrated to 20 ml, and the precipitate deposited is filtered off with suction and recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+]([O-])=O)[CH:12]=2)[C:7]1=[O:19])[CH3:2].[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:33][C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:34]=[CH:35][C:22]([F:21])=[CH:23][CH:24]=4)=[CH:32][CH:31]=3)[CH:12]=2)[C:7]1=[O:19])[CH3:2]
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Product: CCOC(=O)CN1C(=O)c2ccc(Oc3ccc(Oc4ccc(F)cc4)cc3)cc2C1=O

Procedure:
Prepared in analogy to Example D-137 a) by reacting (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester with 4-(4-fluoro-phenoxy)-phenol. 1H NMR (200 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 1H), 7.31 (m, 2H), 7.06-7.01 (m, 8H), 4.39 (s, 2H), 4.21 (q, J=7.2, 2H), 1.30 (t, J=7.3, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([NH:21]C(=O)C)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:7]=1.[OH-].[Na+]>CO>[CH3:2][C:3]1[N:4]([NH2:21])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:7]=1
Reactant: CC(=O)Nn1cc(-c2cnn(C)c2-c2ccc(C)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(-c3cn(N)c(C)n3)cnn2C)cc1
Reaction time: 0.5 h

Procedure:
Aqueous hydrochloric acid (1 N, 7.0 mL) was added to a solution of N-{2-methyl-4-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H-imidazol-1-yl}acetamide (236 mg, 0.763 mmol) in methanol (1.0 mL), and the mixture was heated at reflux for 30 minutes. Additional 1 N aqueous hydrochloric acid (2.0 mL) was added, and heating was continued for an additional 30 minutes. After cooling, the solution was basified with 1 N aqueous sodium hydroxide solution, and the mixture was extracted twice with ethyl acetate containing 1% methanol. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow solid. Yield: 148.5 mg, 0.5555 mmol, 73%. LCMS m/z 268.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 2.45 (br s, 3H), 3.70 (s, 3H), 4.45 (br s, 2H), 6.26 (s, 1H), 7.24-7.32 (m, 4H, assumed; partially obscured by solvent peak), 7.97 (s, 1H).
Reaction SMILES: B1C2CCCC1CCC2.[CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)=[CH2:11].[Si:22]([O:29][C@@H:30]1[CH2:34][C:33](=[O:35])[C:32](I)=[CH:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:22]([O:29][C@@H:30]1[CH2:34][C:33](=[O:35])[C:32]([CH2:11][CH2:10][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C(I)C(=O)C1
Reactant: C=Cc1ccc(C(=O)OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC2=C[C@H](O[Si](C)(C)C(C)(C)C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
A solution of 9-BBN (6.95 g, 28.5 mmol) in 110 mL THF was cannula transferred to a solution of methyl 4-vinylbenzoate (4.65 g, 28.7 mmol) in 22 mL THF, rinsing with 10 mL THF. The reaction was stirred at room temperature for 4 h, was cooled to 0° C. and 5.4 mL H2O was added. After 45 minutes at room temperature, the solution was cannula transferred to a mixture of the (R)-4-((tert-butyldimethylsilyl)oxy)-2-iodocyclopent-2-enone (8 g, 24 mmol) and PdCl2(dppf).CH2Cl2 (1.76 g, 2.41 mmol) in DMF (70 mL). The reaction was stirred for 5 minutes and then a solution of K3PO4 (9.6 mL, 28.8 mmol, 3 M) was added. The resulting dark mixture was allowed to stir overnight and then was partitioned between ethyl acetate/H2O. The organic solution was washed further with H2O (2×) and brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (6.81 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:25][C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)=[N:15][N:14]=2)[C@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(F)c2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(F)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 34.4 %

Procedure:
The crude material of N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3,4-difluorobenzohydrazide (1.0 g, 2.37 mmol) was added to THF (120 mL) and stirred at room temperature. PS-BEMP (3.22 g, 7.10 mmol base) was added to the solution followed by slow addition of p-TSCl (496 mg, 2.60 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the product (330 mg). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.81 (m, 2H), 7.37 (d, J=9 Hz, 1H), 7.23 (m, 1H), 6.59 (d, J=9 Hz, 1H), 5.28 (d, J=8 Hz, 1H), 4.8 (m, 1H), 4.39 (m, 1H), 2.39 (s, 3H), 1.38 (d, J=6 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])[NH:7][C:6](=[O:30])[CH:5]=1)([CH3:3])[CH3:2].[I:31]I>[N+]([O-])([O-])=O.[Ag+].CO>[I:31][C:5]1[C:6](=[O:30])[NH:7][C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])=[N:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: II
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)cc(=O)[nH]1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)c(I)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
The compound (1.69 g, 3.9 mmol) of example 1 was added into methanol (15 ml), and added with silver nitrate (0.66 g, 3.9 mol), and then with I2 grain (0.98 g, 3.9 mmol) under stirring. The reaction mixture was stirred at room temperature for 0.5 h, and TLC showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated. The concentrate was washed with water, extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated. The residue was recrystallized from ethyl acetate to give a yellowish solid (1.52 g, yield: 70%). 1H NMR (CDCl3) δ: 8.90 (1H, d), 7.89 (1H, dd), 7.16 (1H, d), 4.27 (2H, t), 3.46 (1H, m), 3.08 (4H, t), 2.49 (4H, t), 2.27 (3H, s), 2.03 (2H, m), 1.25 (6H, d), 1.16 (3H, t).
Reaction SMILES: [H-].[Na+].[P:3]([O-:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Cl[CH:12]([F:14])[F:13]>C1COCC1.CCCCCC>[F:13][CH:12]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[F:14]
Reactant: CCOP([O-])OCC
Reactant: FC(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(OCC)C(F)F
Yield: 16.2 %

Procedure:
A sample of 6.82 g (171 mmol) of 60% NaH in mineral oil was washed twice with 30 ml of petroleum ether and was suspended in 130 ml of THF under argon. A solution of 22 ml (171 mmol) of diethyl phosphite was added dropwise over 45 minutes and the exotherm was controlled with a water bath. After stirring for an additional hour, 42 g (490 mmol) of chlorodifluoromethane was bubbled through the solution over 4.5 hours, while the internal temperature was maintained between 25° and 35° C. with a cool water bath. The white suspension was allowed to stir overnight, was diluted with hexane and filtered through Celite. The filtrate was evaporated to provide 27.6 g of a crude, pale yellow liquid. The crude material was fractionally distilled at 10 mm to provide 5.21 g (16%) of impure title compound (b.p. 82°-84° C.), followed by 20.66 g (64%) of title compound (b.p. 84°-86° C.) as a colorless liquid which contains a trace of impurity.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH3:42][N:43]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[N:44]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH3:42][N:43]1[CH:47]=[CH:46][C:45]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:16])=[O:13])=[CH:10][C:5]=3[N:4]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=2)=[N:44]1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1ccn(C)n1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
(R)-1-(3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (36 mg, 0.060 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.6 mg, 0.090 mmol), PdCl2(dppf)-CH2Cl2 adduct (7.3 mg, 8.96 μmol), 1,4-dioxane (0.6 mL) and Na2CO3 (0.08 mL, 0.160 mmol, 2M) were charged in a vial. The mixture was evacuated and purged with nitrogen six times and heated at 80° C. for 1 h. The mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford crude (R)-1-(3-(1-methyl-1H-pyrazol-3-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea, which was used as such in the next step. MS ESI calcd. For C38H34N7O [M+H]+ 604, found 604.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=[O:21])=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+].O>CO>[F:1][C:2]([F:30])([F:31])[C:3]([C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH2:20][OH:21])[CH:22]=[CH:23][CH:24]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CO)c1
Yield: 99.7 %

Procedure:
To a solution of 3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)benz aldehyde (1.79 g, 3.97 mmol) in methanol, sodium borohydride (0.16 g) was added at 0° C. After completion of the reaction, the reaction solution was added with water, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using thin-layer silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.79 g, yield 100%) was obtained as a colorless oil.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C@@H:7]([C:11]([OH:13])=[O:12])[C@H:8]([CH3:10])[OH:9].[C:14](Cl)(=[O:25])[O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:9][C@@H:8]([CH3:10])[C@@H:7]([NH:6][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])[C:11]([OH:13])=[O:12]
Reactant: O=C(Cl)OCCCc1ccccc1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)OCCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.2 %

Procedure:
In a round bottom flask, NaHCO3 (5.94 g, 70.7 mmol) was suspended in THF (15 mL) and water (30 mL), then D-threonine (3.34 g, 28.0 mmol) was added. 3-phenylpropyl chlorocarbonate (6.2 g, 31.2 mmol) was slowly added, followed by a catalytic amount (0.3 g) of tetrabutylamonium bromide. After stirring 18 h at rt., the mixture was diluted with water (100 mL), washed twice with Et2O (2×100 mL) and pH adjusted to 2 with 2M HCl solution. The aqueous phase was extracted with AcOEt (3×150 mL), the collected organic phases were dried over Na2SO4, filtered and the solvent removed under vacuum to give the title compound (1.43 g, 18%), as colorless oil, which was used in the next step without further purification. Rf=0.38 (Cy/AcOEt 2:8+1% CH3COOH). FTIR (cm−1): 3340 (br), 3064, 3030, 2982, 2939, 1730 (br), 1528, 1374, 1241, 1094, 1072, 1048, 781, 749, 703.