Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5]I.I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>>[CH3:1][O:2][C:3](=[O:14])[C@@H:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1
Reactant: FC(F)(F)c1cc(I)ccn1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1ccnc(C(F)(F)F)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to previously reported procedure (U.S. patent application Ser. No. 11/575,187) from (R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-iodo-2-(trifluoromethyl)pyridine (this starting material was prepared according to a procedure described in Eur. J. Org. Chem. 2003, 1559-1568).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:13](Cl)[N:14]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.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.CCOC(C)=O>[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:13]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[N:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccn2)ccc1=O
Yield: 28.1 %

Procedure:
A toluene solution of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (200 mg), 2-(tributylstannyl)pyridine (311 mg), and Pd(PPh3)4 (22.5 mg) was refluxed for 5 hours. Water (20 ml) and EtOAc (15 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and eluted with CHCl3—MeOH (97:3). The eluent was evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-pyridyl)-2-pyrazinecarboxamide (64 mg) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](Br)=[CH:5][CH:6]=1.[CH:8]1C=C[CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=[O:15].[Na+].[Na+]>CO.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>[Br:1][C:2]1[O:3][C:4]([C:8]2[O:15][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccccc1
Reactant: Brc1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: Brc1ccc(-c2ccco2)o1

Procedure:
In a 2-neck flask was placed 2,5-dibromofuran (18.1 g, 80 mmol) with catalyst Pd(PPh3)4 (5 mol %) and added 30 mL of benzene and 6 mL of 2 M Na2CO3 aqueous solution. The mixture was added 2.2 g (20 mmol) of dihydroxy-2-(furyl) borane dissolved in 6 mL of methanol and heated at reflux for 12 hrs. Thin layer chromatography ("TLC") showed 2 fluorescent spots. The less polar spot was identified as the desired dimer product. The mixture was extracted with ether. The combined ether extracts were dried with anhydrous MgSO4 and concentrated. The crude product was then used for the next reaction.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(C(F)(F)C(F)C(F)(F)F)CC)C.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:11]([C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:13])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: NC1CCCCC1
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Product: O=C(NC1CCCCC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
1-Adamantanecarboxylic acid (10.8 g, 0.06 mole) was dissolved in N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) as described in example 1. After the reaction mixture cooled to room temperature, cyclohexylamine (14.88 g, 17.2 ml, 0.15 mole) was added slowly and a heavy precipitate of the amide appeared almost immediately. The N-cyclohexyl-1-adamantanecarboxamide was isolated as described in example 1 to give 14.8 g, 94.4%; mp 199.3-200.4° C. The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C17H27NO: C, 78.18; H. 10.34; N, 5.36. Found: C, 77.97; H, 10.46; N, 5.32.
Reaction SMILES: [F:1][C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH3:19])[CH:6](C)[CH2:5]2)[CH:11]=1.C=[O:27]>C(O)(=O)C>[F:1][C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH2:19][OH:27])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: CC1Cc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Reactant: C=O
Solvent: CC(=O)O
Product: O=C(O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2CO
Temperature: 80 °C

Procedure:
200 mg of the compound (160) obtained in Example 38 was added to a mixture solvent of 8 ml of acetic acid and 4 ml of formalin, and the solution was heated at 80° C. for 2 hours. The deposited solid matter was filtered off and washed with ether to obtain 50 mg of the subject compound (179).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:35]=[C:36]=[O:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>O1CCCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3,4-dimethoxyphenyl isocyanate (0.182 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from tetrahydrofuran to give 64.6 mg (18.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][NH:48][CH3:49].[C:50](=[O:52])=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:47][N:48]([CH3:49])[C:50]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[CH:12]=1)=[O:52]
Reactant: CNC
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2n1COCC[Si](C)(C)C
Reactant: O=C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1COCC[Si](C)(C)C
Yield: 65 %

Procedure:
5.8 g (13 mmol) 4-Benzyloxy-6-bromo-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole, 1.3 g (5.2 mmol) triphenylphosphine, 0.4 g (1.9 mmol) palladium(II) acetate and 80 ml (160 mmol) dimethylamine (2M in THF) were transferred to an autoclave and carbonylated (6 bar CO2) at 120° C. for 16 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The crystallization of the residue from diisopropyl ether afforded 3.7 g (65%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][C:12](=[O:19])[N:13]3[CH2:16][CH:17]=O)=[N:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[C:29]2[CH:28]=[C:27]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:26]=[CH:25][C:24]=2[O:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:20]1[C:29]2[CH:28]=[C:27]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][N:42]([CH2:17][CH2:16][N:13]4[C:14]5[C:9](=[N:8][CH:7]=[C:6]([N:1]6[CH:5]=[CH:4][N:3]=[CH:2]6)[CH:15]=5)[CH:10]=[CH:11][C:12]4=[O:19])[CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:26]=[CH:25][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: O=CCn1c(=O)ccc2ncc(-n3ccnc3)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(-n4ccnc4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 51 %

Procedure:
To a solution of 0.12 g of (7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 1 mL of dichloromethane, a solution of 0.14 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 1.4 mL of dichloromethane, and 23 μL of acetic acid and 0.13 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour 40 minutes. The reaction mixture was charged with chloroform, and a saturated aqueous sodium hydrogen carbonate solution and adjusted to pH 8.6, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=19:1 to 93:7 to obtain 0.12 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:20][CH2:21][CH:22]1[CH2:25][C:24](=[O:26])[CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.CC(C)=O.[CH3:34][Si:35](Cl)([CH3:37])[CH3:36]>C1COCC1>[CH2:13]([O:20][CH2:21][CH:22]1[CH2:25][C:24]([O:26][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CC(COCc2ccccc2)C1
Reactant: C[Si](C)(C)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)OC1=CC(COCc2ccccc2)C1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
In a 1 L flask charged with argon, dry THF 300 ml was added. This was cooled to −5° C., then n-BuLi (83 ml, 1.6M in hexane, 0.132 mol) was added. After mixing 5 min, diisopropylamine (18 ml, 0.132 mol) was added drop by drop. After stirring for 10 min, this solution was cooled to −78° C. Then a THF solution of 3-(benzyloxymethyl)-cyclobutanone (20 g, 0.11 mol) was added drop by drop at −78° C. After addition, replace the dry ice-acetone bath with ice-water bath. After stirring at 0° C. for 30 min, TMSCl (16 ml, 0.132 mol) was added dropwise, this was stirred at 0° C. for 1 hr and room temperature for 10 min. Then the solvents were removed and the residue was washed with dry pentane and filtered. The filtrate was concentrated to give crude product without further purification. 1H NMR (CDCl3, 600 MHz): δ 0.23 (s, 9H), 2.20 (dd, J=12.6, 1.2, 1H), 2.65 (m, 1H), 2.74 (dd, J=13.2, 4.2, 1H), 3.41 (m, 1H), 3.48 (m, 1H), 4.54 (s, 2H), 4.67 (s, 1H), 7.26-7.35 (m, 5H). 13C NMR (CDCl3, 150 MHz): δ 0.09, 32.70, 38.18, 73.26, 75.41, 93.69, 104.27, 127.70, 127.86, 128.55, 138.20.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH2:16][N:1]=[C:2]1[NH:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[S:3]1)[CH3:15]
Reactant: Nc1nc2cnccc2s1
Reactant: COC(OC)N(C)C
Product: CN(C)CN=c1[nH]c2cnccc2s1
Yield: 80.9 %

Procedure:
A stirred mixture of 2-aminothiazolo[4,5-c]pyridine [prepared according to the procedure of H. W. Altland and G. A. Molander, J. Heterocyclic Chem., 14, 129 (1977)] (0.5 g, 3.3 mmole) and N,N-dimethylformamide dimethyl acetal (5 ml) was stirred at an oil bath temperature of 80° C. for two hours under an atmosphere of argon. The solution was concentrated to dryness to leave the crystalline product. The solid was triturated with cold petroleum ether and dried to afford 0.55 g (80.9%) of the title compound, mp. 125°-127° C.
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pt]>[Cl:3][C:4]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1Cl
Yield: 99.9 %

Procedure:
Hydrogen gas was passed through a solution of methyl 2-chloro-3-nitrobenzoate (10.0 g, 46.4 mM) and 1.0 g of 3% sulfided platinum on carbon in 150 mL ethyl acetate for 48 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 8.6 g (100%) of methyl 2-chloro-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) δ7.25 (dd, 1H, J=1 and 8 Hz), 7.2 (t, 1H, J=8 Hz), 6.95 (dd, 1H, J=1 and 8 Hz), and 3.9 (s, 3H). IR (CHCl3, cm−1) 3450, 3380, 2980, 2900, 1729, 1615, 1456, 1434, 1322, 1290, and 1268. MS (ES) m/e 186, 188.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[C:12]([C:13](=[O:15])[C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=2)=[CH:16][CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2ccc(C)nc2Cl)c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
Magnesium (4.82 g, 200 mmol) was added to a tetrahydrofuran (300 ml) solution of 3-bromotoluene (35.1 g, 200 mmol), and the mixture was stirred at room temperature. Since spontaneous exothermic reaction occurred, the stirring was continued until the exothermicity was ceased. The reaction solution was cooled to -40° C., mixed with 2-chloro-6-methylnicotinic acid (11.6 g, 68 mmol) and then stirred for 16 hours at room temperature. The reaction solution was mixed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-6-methyl-3-(3-methylbenzoyl)pyridine (8.70 g, 52%) as a pale yellow oily material.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]1[N:28]=[C:27]([CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[O:26][N:25]=1)(=[O:17])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[NH3:1].[NH:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]=[C:7]1[S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]1[N:28]=[C:27]([CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:33][CH:32]=2)[O:26][N:25]=1)(=[O:16])=[O:17]
Reactant: C1CCNC1
Reactant: O=Cc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N
Product: O=S(=O)(c1nc2ccccc2[nH]1)N1CCCCC1c1noc(COc2ccc(CN3CCCC3)cc2)n1
Reaction time: 6 h

Procedure:
Pyrrolidine (19 μl) was added to a solution of 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzaldehyde (85 mg) [see Preparation 22] in tetrahydrofuran (10 ml). Sodium triacetoxyborohydride (64 mg) was added followed by glacial acetic acid (11.5 μl). The reaction mixture was stirred under an atmosphere of nitrogen for 6 hours. Sodium triacetoxyborohydride (21 mg) was added and the mixture was stirred for 56 hours after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 97.5:2.5:0.25 changing to 95:5:0.5, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution to afford 3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-5-[4-(1-pyrrolidylmethyl)phenoxy]methyl-1,2,4-oxadiazole (90 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:23])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CCOCC>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:23])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(c2cn(C)c3c(N)cccc23)CCc2cc(F)ccc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC1(c2cn(C)c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 84.8 %

Procedure:
Dissolve 3-(1-ethyl-5-fluoro-indan-1-yl)-1-methyl-1H-indol-7-ylamine (0.18 g, 0.58 mmol) in pyridine (3 ml). Add methanesulfonyl chloride (0.05 ml, 0.70 mmol, 1.20 equivalents) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate solution in vacuo. Purify the residue on silica eluting with 0 to 100% ethyl acetate/hexanes over 25 minutes to provide the title compound as a white solid (0.19 g, 86%). LC-MS m/z 387.1 (M++1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:36])=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:27]=2)OC1>>[F:36][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(C#N)cc3)c2)OC1
Product: N#Cc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)cc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-4-carbonitrile as described in Example 65 to give 2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-4-carbonitrile as a yellow solid: δH (360 MHz, CDCl3) 7.26 (1H, d, J 7), 7.44 (1H, dd, J 8 and 8), 7.55-7.63 (2H, m), 7.70 (2H, dd, J 7 and 1), 7.79 (2H, dd, J 7 and 1), 8.11 (1H, s), 8.74 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:38][CH:39]([F:41])[F:40])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH:31]=3)[N:10]=2)[CH:8]=1.[O:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(#N)C.O>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:38][CH:39]([F:41])[F:40])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH:32]4[CH2:33][CH2:34][N:35]([CH:45]5[CH2:46][CH2:47][O:42][CH2:43][CH2:44]5)[CH2:36][CH2:37]4)[CH:31]=3)[N:10]=2)[CH:8]=1
Reactant: O=C(Nc1cn(Cc2cn(C3CCNCC3)nn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=C(Nc1cn(Cc2cn(C3CCN(C4CCOCC4)CC3)nn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (200 mg, 0.330 mmol) in dichloromethane (30 mL) was added oxan-4-one (264.9 mg, 2.646 mmol). The resulting solution was stirred at room temperature overnight. Then NaBH(OAc)3 (280.8 mg, 1.325 mmol) was added. The resulting solution was stirred at room temperature for 6 h and concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM/MeOH (80:20). The crude product (150 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O (10 mmol NH4HCO3)=20% increasing to ACN/H2O (10 mmol NH4HCO3)=49% within 8 min; Detector, UV 254 nm. 56.9 mg product was obtained. This resulted in 56.9 mg (26%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-([1-[1-(oxan-4-yl)piperidin-4-yl]-1H-1,2,3-triazol-4-yl]methyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=653.3, RT=1.74 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.67-8.66 (m, 2H), 8.39 (s, 1H), 8.26 (s, 1H), 7.65-7.62 (m, 2H), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.4 Hz), 5.48 (s, 2H), 4.58-4.45 (m, 1H), 3.90-3.87 (m, 2H), 3.32-3.25 (m, 2H), 3.04-2.98 (m, 2H), 2.51-2.33 (m, 1H), 2.30-2.24 (m, 2H), 2.09-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.70-1.67 ((m, 2H), 1.49-1.40 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[CH3:28][S:29][C:30]([CH3:37])([CH:32]([NH2:36])[CH:33]([CH3:35])[CH3:34])[CH3:31]>C(OCC)(=O)C.O1CCCC1>[CH3:28][S:29][C:30]([CH3:37])([CH:32]([NH:36][C:12](=[O:14])[C@@H:9]([CH2:10][OH:11])[NH2:8])[CH:33]([CH3:35])[CH3:34])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: CSC(C)(C)C(N)C(C)C
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(C)(C)C(NC(=O)[C@H](N)CO)C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 3.47 g. (0.017 mole) of N-t-butoxycarbonyl-D-serine and 2.5 g. (0.017 mole) triethylamine in 100 ml. of tetrahydrofuran at -15° C. is added 1.63 ml. of ethyl chloroformate. After stirring for 15 minutes, 2.49 g. (0.017 mole) 2-methylthio-2,4-dimethyl-3-aminopentane is added and the mixture stirred for one hour. The reaction mixture is diluted with ethyl acetate, washed with water, 5% aqueous citric acid (w/v), sodium bicarbonate solution and brine. The organic phase is evaporated to dryness. The residue is taken up in 100 ml. methanol, 60 ml. of concentrated hydrochloric acid added and the mixture refluxed for one hour. After evaporation of methanol, the residue is taken up in water, washed with ether, the aqueous phase adjusted to pH 12 with sodium hydroxide and extracted with ethyl ether. Evaporation of the extracts affords the desired D-serine amide.