Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:24][N:2]([CH3:1])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: C1COCCN1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), morpholine (317 μl, 3.64 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (239 μl, 1.37 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide (152 mg, 83.8%) as an off-white solid. Mp.: 196-8° C. MS: m/z=399.0 (M+H+).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37]>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([NH:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 71 %

Procedure:
2.49 g (10 mmol) N-carbobenzoxy-D-proline, 1.37 g (10 mmol) isobutyl chloroformate, 1.01 g (10 mmol) N-methylmorpholine, and 1.03 g (10 mmol) L-valinol were contacted and reacted in THF substantially according to the procedure described in Example 1. Crude product (2.82 g) was recrystallized from a mixture of 20 mL ethyl acetate and 15 mL n-hexane, to give 2.37 g (7.1 mmol, 71%) of colorless crystalline N-carbobenzoxy-D-prolyl-L-valinol; m.p. 117.5°-118.6°, α25D=+26.7° (C=1.02 g/100 mL in acetone).
Reaction SMILES: [Si:1]([CH:18]([OH:28])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@H:21]([OH:26])[C@@H:20]1[OH:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)Cl>C(Cl)Cl.N1C=CC=CC=1>[Si:1]([CH:18]([OH:28])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@:21]([C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:26])[C@:20]1([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:27])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 14.5 h

Procedure:
To a solution of 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside (579 mg, 1.44 mmol) in methylene chloride-pyridine (4:1, 12.5 ml) was added dropwise benzoyl chloride (0.367 ml, 3.16 mmol) at 0° C. The reaction mixture was stirred for 2.5 h at 0° C. and for 14.5 h at room temperature. Ice was added to quench the reaction and the mixture was stirred for 1 h. Methylene chloride (100 ml) was added and two phases were separated. Organic layer was washed with water, saturated ammonium chloride, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside in crude form, which was then purified by silica gel column chromatography (Hx-EtOAc, 5:1→1:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside in more pure form [Rf =0.75 (CHCl3 --MeOH, 10:1), 869 mg, 99%] as a thick syrup. 1H NMR (CDCl3) d 1.05 (s, 9H, t-Bu), 3.42 (s, 3H, --OCH3), 3.86 (dd, J=11.1 and 4.8 Hz, 1H, H-5a), 3.92 (dd, J=11.1 and 4.7 Hz, 1H, H-5b), 4.48 (dd, J=10.6 and 4.6 Hz, 1H), 5.15 (s, 1H), 5.63 (d, J=5.0 Hz, 1H), 5.82 (pseudo t, J=5.8 and 5.4 Hz, 1H), 7,29-8.18 (m, 20H, Ar). Anal. Calcd for C36H38O7Si1 : C, 70.79; H, 6.27; Found: C, 71.01; H, 6.20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH2:32][C:33]([C:36]([O:38]CC)=[O:37])([CH3:35])[CH3:34])=[C:26]2[S:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH2:32][C:33]([C:36]([OH:38])=[O:37])([CH3:34])[CH3:35])=[C:26]2[S:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)(C)Cc1[nH]c2ccc(OC(Cc3ccc(Cl)cc3)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2c1SC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(Cc1ccc(Cl)cc1)Oc1ccc2[nH]c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c2c1

Procedure:
The ester from Step 4 (0.16 g, 0.26 mmol) was dissolved in MeOH (1 mL), THF (1 mL), and water (1 mL). Lithium hydroxide (0.6 g, 1.43 mmol) was added, and the reaction was heated for 12 hours until no starting material was seen by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (0 to 40% EtOAc in hexanes) to give the desired product (C-5; X═Cl).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1
Yield: 78 %

Procedure:
(S)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.051 mol) and 5-chloro-1H-indole-2-carboxylic acid (0.051 mol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 50%, 75%, 80% and 100% ethyl acetate-hexanes giving a foam (yield 78%), HPLC (60/40) 4.21 minutes (99%). A portion of this material was recrystallized by dissolving in hot ethyl acetate (approximately 5-7 mL/g), and adding an approximately equal volume of hexanes at reflux, followed by slow cooling of the solution to 25° C. The solid was filtered and washed with 1:4 ethyl acetate-hexanes and dried (70-90% recovery): mp 175-177° C.;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:13]([O:19]C)=[N:14][CH:15]=[CH:16][C:17]=2I)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Cl.C(N(CC)CC)C.[NH2:29][CH2:30][C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[OH:32]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=2[NH:29][CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[OH:32])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(-c2c(I)ccnc2OC)nc1C
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)nc1C
Temperature: 65 °C
Yield: 13.8 %

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (0.020 g, 0.052 mmol) was dissolved in acetic acid (1 mL) and concentrated hydrochloric acid (1 mL) and this mixture was stirred at reflux for 2 hours. The mixture was then evaporated and the residue was dissolved in N,N-dimethylformamide (2 mL) and treated with triethylamine (˜22 μL, 0.155 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.020 g, 0.096 mmol). The mixture was heated at 65° C. overnight, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.003 g, 14%) as a white solid. HPLC 100% (220 nm), LCMS (+ESI, M+H+) m/z 417; 1H NMR (400 MHz, methanol-d4) δ (ppm) (mixture of tautomers): 1.40 and 1.43 (3H, 2t, J=7.1 Hz), 2.49 and 2.61 (3H, 2s), 3.61-3.72 (2H, m), 4.35 and 4.39 (2H, q, J=7.1 Hz), 4.95-4.97 (1H, m), 6.21 and 6.23 (1H, 2d, J=7.6 Hz), 7.19-7.55 (5H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Sc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
2-Fluoronitrobenzene (1.5 g) and 4-chlorothio phenol (1.5 g) were dissolved in ethanol (30 ml) and potassium carbonate (1.4 g) was added thereto, followed by stirring at 60° C. for five hours. Subsequently, the solvent was removed under reduced pressure and the residue was dissolved in water (50 ml). The resultant solution was subjected to extraction with ethyl acetate (30 ml×2). The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was re-crystallized from diethyl ether, to thereby produce the target compound (2.1 g) as pale-brown crystals.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1.[N:14](OCCC(C)C)=[O:15]>C(O)C>[N:14]([C:11]1[CH:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[C:12]=1[NH2:13])=[O:15]
Reactant: CC(C)CCON=O
Reactant: Nc1ccnn1-c1ccccn1
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1-c1ccccn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
HCl (37%, 11 μl) was added to a heterogeneous solution of 2-pyridin-2-yl-2H-pyrazol-3-ylamine (2.2 g, 13.7 mmol) in absolute ethanol (15 ml). The reaction mixture was subsequently cooled to 0° C. and isopentyl nitrite (2.02 ml, 15 mmol) was slowly added. The reaction mixture became dark. After the isopentyl nitrite had been completely added, the reaction mixture was allowed to return to ambient temperature. After 2.5 h at ambient temperature, the reaction mixture was cooled to 5° C. and filtered. The solid was washed with absolute MeOH (10 ml) and was then triturated twice from heptane. The solid was dried under vacuum at 35° C. to give 4-nitroso-2-pyridin-2-yl-2H-pyrazol-3-ylamine (2.1 g, 81%) in the form of a green solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cccnc1Cl
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1

Procedure:
2-Chloro-3-trifluoromethyl-pyridine (7.26, 40 mmol, TCI-US) and (R)-(−)-2-methyl-piperazine (4.45 g, 44 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as a gum. MS (ESI, pos. ion) m/e: 246 (M+1).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:7]2[N:8]([C:9](=[O:14])[NH:10][C:11]3[CH2:12][CH2:13][N:4]([CH2:3][C:1]4[NH:27][N:26]=[N:25][N:2]=4)[CH2:5][C:6]=32)[N:15]=1
Reactant: N#CCN1CCc2[nH]c(=O)n3nc(-c4ccccc4F)nc3c2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)nn13)CN(Cc1nnn[nH]1)CC2
Reaction time: 3 h

Procedure:
A mixture of the product of Example 50 (640 mg), sodium azide (1.41 g), ammonium chloride (120 mg) and dimethylformamide (10 mL) is stirred at 90° over 3 hours under nitrogen. The mixture is cooled and quenched in ice-water (40 mL), stirred 1/2 hour, and cautiously acidified with glacial acetic acid to afford the solid product 2-(2-fluorophenyl)-9-tetrazolylmethyl-7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine-5(6H)one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=2[N:16]=1)=[O:6].[C:28](=[O:31])([O-])[O-].[Cs+].[Cs+]>N1CCOCC1>[CH3:18][O:17][C:14]1[C:15]2[N:16]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:7]4[CH2:8][CH2:28][O:31][CH2:4][CH2:5]4)[CH:3]=3)[S:9][C:10]=2[C:11]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [Cs+]
Solvent: C1COCCN1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide with cesium carbonate in morpholine. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1(C)C(C)=CC=CC=1.[Fe:21]>O>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10].[Fe+2:21].[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CCCCCC(=O)O
Reactant: [Fe]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)CCCCCC(=O)[O-]
Product: [Fe+2]

Procedure:
Iron neodecanoate was prepared by a procedure based on U.S. Pat. No. 2,584,041 Example 14. 86 g (0.5 moles) of neodecanoic acid, 125 g of xylene, 25 g of water, and 12.7 g of iron powder (100 mesh) were charged to a 500 ml round bottom flask equipped with a stirrer, condenser, air inlet tube, and heating. The mixture was heated to reflux and refluxed for 7 hours, cooled and the organic phase separated from the water phase and unreacted Fe. The organic phase contained 65.2 g iron neodecanoate which on removal of the xylene by evaporation was a dark amber viscous liquid, with viscosity 10,000 cps.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][N:27]=1>>[F:32][C:31]1[C:26]([C:18]2[CH:19]=[C:20]([C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]4)[CH:21]=[CH:22][C:17]=2[F:16])=[N:27][CH:28]=[C:29]([F:33])[CH:30]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Product: Fc1cnc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c(F)c1
Yield: 66.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid (71 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-2-trifluoromethyl[1,8]-naphthyridine (59 mg, 68%). δH (360 MHz, CDCl3) 7.36-7.44 (2H, m), 7.55-7.62 (2H, m), 7.75 (1H, dd, J 2.3 and 6.5), 7.85 (1H, d, J 8.8), 8.48 (1H, d, J 2.1), 8.57 (1H, d, J 8.8), 9.28 (1H, d, J 4.2). m/z (ES+) 406 [MH]+.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([CH2:19]O)[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(Cl)Cl>C=CCCC>[C:5]1([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([CH2:19][NH:11][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCc1c(CO)c(-c2ccccc2)nn1-c1ccccc1
Solvent: C=CCCC
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCCNCc1c(-c2ccccc2)nn(-c2ccccc2)c1CCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (1 mL) is added to a solution of 165 (289 mg) in pentene stabilized chloroform (8 mL) and the mixture heated to 60° C. for 2 hours. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (Na2SO4), and concentrated. The resulting crude chloride is taken up in dimethylformamide (3 mL) and added dropwise to a solution of butylamine (1.0 g) in dimethylformamide (10 mL) containing 2g of powdered potassium carbonate. After the addition is complete, the resulting mixture is stirred for an additional 3 h and partitioned between water (20 mL) and ether (10 mL). The ether layer is washed 2 times with water, dried (Na2SO4), and concentrated. The resulting material is purified by chromatography on silica eluting with 10% CH3OH/CHCl3 to give the desired secondary amine 166. LC-MS (M+1): 348.3; 1H NMR (δ, CDCl3), 7.87 (dd, J=8.0, 1.6 Hz, 2H), 7.32-7.48 (m, 1H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 (m, 2H), 0.91 (t, J=7.6 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H) ppm.
Reaction SMILES: O=C1N(C[C:9]([OH:11])=[O:10])C(C2C=CC(F)=CC=2)=NC=C1.[ClH:19].[CH3:20][C:21]([C:29]1[O:30][C:31]([CH:34]([OH:40])[C@@H:35]([NH2:39])[CH:36]([CH3:38])[CH3:37])=[N:32][N:33]=1)([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:19].[CH3:20][C:21]([C:29]1[O:30][C:31]([CH:34]([OH:40])[C@@H:35]([NH2:39])[CH:36]([CH3:37])[CH3:38])=[N:32][N:33]=1)([CH3:28])[C:22]1[CH:23]=[CH:24][C:25]2[O:10][CH2:9][O:11][C:26]=2[CH:27]=1
Reactant: CC(C)[C@H](N)C(O)c1nnc(C(C)(C)c2ccccc2)o1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nccc1=O
Agent: Cl
Product: CC(C)[C@H](N)C(O)c1nnc(C(C)(C)c2ccc3c(c2)OCO3)o1

Procedure:
The intermediate 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared in an analoguous manner as described in Example 1 E using [6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]acetic acid. and 1-[2-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride. The intermediate 1-[2-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride was prepared using a similar procedure as described in Example 1 D. The heterocyclic intermediate 2-(α,α-dimethylbenzyl)-1,3,4-oxadiazole gave the following physical data.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[CH:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:16][C:17]([CH3:19])=[O:18]>COC(C)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[C:10][C:17]([CH3:19])([OH:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)nc1C
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: Cc1nc(Cl)ccc1C#CC(C)(C)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
6-Chloro-3-ethynyl-2-methylpyridine (Example 432, Step 1) (200 mg, 1.32 mmol) was taken up in 4 ml tert-butyl methyl ether and added to a dry flask under argon. The flask was cooled to −78° C. and allowed to stir for 20 min. Butyllithium (0.99 ml of 1.6 M in hexanes, 1.58 mmol) was added to the reaction mixture dropwise over 30 minutes, and the mixture was allowed to stir as such for 30 min. Acetone (0.13 ml, 1.72 mmol) was taken up in 1 ml tert-butyl methyl ether and added dropwise over 30 min. The reaction mixture was allowed to warm to 0° C. and was stirred as such for 90 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted twice with diethyl ether. All organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[OH:15]/[N:14]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)/C(=N/O)c1ccccc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 12.9 %

Procedure:
A mixture of methyl phenylglyoxylate (25.5 g), hydroxylamine hydrochloride (11.3 g), triethylamine (22.8 ml) and methanol (300 ml) was stirred for 17 hours at 60° C. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, (MgSO4), and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain methyl E-2-hydroxyimino-2-phenylacetate (3.58 g, yield 13%) as colorless crystals. m.p. 151-153° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:12]([CH3:25])[CH:11]=1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:12]([CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
By adding tert-butyl(dimethyl)silyl chloride to a DMF solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde and imidazole, and stirring at room temperature for 10 hours, 4′-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-carbaldehyde was obtained.