Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].Br[CH:12]([F:21])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[F:21][CH:12]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: COc1ccc(C)c(O)c1
Reactant: O=C(c1ccccc1)C(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1ccc(C)c(OC(F)C(=O)c2ccccc2)c1

Procedure:
Using the method described in Example 17, equimolar amounts of 2-hydroxy-4-methoxytoluene and α-bromo-2-fluoroacetophenone are refluxed in benzene in the presence of potassium carbonate to provide 2-fluoro-α-(2-methyl-5-methoxyphenoxy)acetophenone. Recrystallization from cyclohexane provides a tan solid, m.p. 57°-58° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[Cl:20][C:17]([F:19])([F:18])[S:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 18.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white solid. HPLC (Condition 4) tR=4.94 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=466.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.88 (m, 2H) 2.86-2.99 (m, 1H) 3.19-3.33 (m, 2H) 3.36-3.51 (m, 1H) 4.13-4.23 (m, 1H) 4.76-4.90 (m, 1H) 6.31-6.42 (m, 1H) 7.65 (d, J=8.21 Hz, 2H) 7.76-7.84 (m, 1H) 7.92 (d, J=8.60 Hz, 2H) 7.98-8.08 (m, 1H) 8.66-8.82 (m, 1H) 10.28 (s, 1H) 12.82-13.14 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:15]#[N:16])=[N:6][CH:7]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2].O[CH2:18][C@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>>[NH2:21][C@H:19]([CH3:20])[CH2:18][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:15]#[N:16])=[N:6][CH:7]=2)=[N:14]1
Reactant: N#Cc1ncc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Product: C[C@@H](N)Cn1ccc(-c2cnc(C#N)c([N+](=O)[O-])c2)n1
Yield: 46.5 %

Procedure:
(R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile was prepared from 3-nitro-5-(1H-pyrazol-5-yl)picolinonitrile (0.88 g, 4.9 mmol) and (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.86 g, 4.9 mmol) using the method of Example 34(d). Thus, 0.62 g (56%) of the title compound was obtained. m/z [273.3+1].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[S:8][C:7]=2[CH:27]=1.CS(C)=[O:30]>>[F:24][C:23]([F:26])([F:25])[C:13]1[CH:12]=[C:11]([C:9]2[S:8][C:7]3[CH:27]=[C:3]([CH:2]=[O:30])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(C)=O
Reactant: FC(F)(F)c1cc(-c2cc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Product: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 100 °C

Procedure:
To a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (180 mg, 0.4 mmol) in 5 mL DMSO, Ag2CO3 (330 mg, 1.2 mmol) is added. The suspension is heated to 100° C. for 3 hours. After work up, the organic layer is dried and concentrated. The residue is applied in column (hexane:EtOAc 9:1) to afford 100 mg of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde as a off white solid. MS m/z 383[M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([O:21]CC)=O)=[CH:17][N:18]=3)[CH:15]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C[NH:58][C:59]1[CH:64]=[C:63]([C:65]2[N:69]=[C:68]([CH:70]3[CH2:73][C:72]([F:75])([F:74])[CH2:71]3)[O:67][N:66]=2)[CH:62]=[CH:61][C:60]=1[CH3:76]>CN1C(=O)CCC1>[F:75][C:72]1([F:74])[CH2:71][CH:70]([C:68]2[O:67][N:66]=[C:65]([C:63]3[CH:62]=[CH:61][C:60]([CH3:76])=[C:59]([NH:58][C:19]([C:16]4[N:14]5[CH:15]=[C:10]([CH2:9][CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[CH:11]=[CH:12][C:13]5=[N:18][CH:17]=4)=[O:21])[CH:64]=3)[N:69]=2)[CH2:73]1
Reactant: CCOC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Reactant: CNc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of ethyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (114) (25 mg, 0.087 mmol) in anhydrous NMP (1 mL) was added HATU (26 mg, 0.104 mmol) and DIEA (23 uL, 0.130 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then, 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (23 mg, 0.087 mmol) was added and the reaction was stirred for two days. The crude product was purified by reverse phase preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (F63). MS m/z 453.14 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[CH2:20])=[C:14]([OH:21])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[CH2:20])=[C:14]([O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: C=CCc1ccc(Oc2ccc(C(=O)OCC)cc2)cc1O
Reactant: CCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCc1ccc(Oc2ccc(C(=O)OCC)cc2)cc1OCCCCCCCCCC
Yield: 48.1 %

Procedure:
Following the general procedure of Example 1H above, 7.11 g of 4-[3-hydroxy-4-(2-propenyl)phenoxy]benzoic acid ethyl ester was allowed to react with 6.38 g of decyl iodide in the presence of 3.3 g of potassium carbonate to provide 5.02 g of the desired subtitle intermediate as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:19])[NH:15]2)=[C:11]([CH3:27])[CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH:21]1([NH:20][C:18]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([CH3:27])[CH:10]=[C:9]([OH:8])[CH:17]=3)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1cc(OCc2ccccc2)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Reaction time: 6 h
Yield: 106.4 %

Procedure:
To a solution of 6-(benzyloxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-a: 1.5 g, 4.14 mmol) in ethanol (30 mL) was added 10% Pd—C (300 mg) and the mixture placed in a Parr hydrogenator (50 psi) at room temperature for 6 h. The reaction mixture was filtered through celite pad and washed with ethanol (30 mL), concentrated under reduced pressure to afford 1.2 g (90%) of N-cyclohexyl-6-hydroxy-4-methyl-1H-indole-2-carboxamide (I-9A-b) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2CC[CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21]CC(O)=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](Cl)(=[O:36])[C:33](Cl)=O.NC1C=CN([CH2:44][C:45](C)([OH:47])[CH3:46])N=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:26][CH:27]2[CH2:33][CH2:32][O:36][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:45]([OH:47])([CH3:46])[CH3:44])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (prepared as in PCT WO 2003/095438 A1, Example 20, 86 mg, 0.25 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylfomamide (three drops) at 25° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 0.14 mL, 0.26 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (3 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 39 mg, 0.25 mmol), 2,6-lutidine (58 μL, 0.49 mmol), and methylene chloride (2 mL) which was cooled to 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (69 mg, 57%) as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:6]([C:23]([F:26])([F:25])[F:24])[CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]2)=[C:6]([C:23]([F:25])([F:26])[F:24])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reaction time: 16 h

Procedure:
To a solution of the product of Example 44A (1 g, 2.7 mmol) in methanol (30 mL) was added Raney Nickel (100 mg) and the mixture stirred under nitrogen for 16 hours. The catalyst was filtered off and the solvent concentrated to give the title compound which was used in the next reaction without further purification. MS: 346 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1/[CH:4]=[CH:5]/[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1/[CH:4]=[CH:5]/[C:6]([Cl:16])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1c(F)cccc1F
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1c(F)cccc1F

Procedure:
To a solution of (E)-2,6-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,6-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,6-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 369.80; mp: 204.5-206.5° C.; 1H-NMR (DMSO) δ: 8.82-8.77 (1H, m), 8.29-8.18 (1H, m), 8.00 (1H, d, J=16.5 Hz), 7.89-7.80 (2H, m), 7.74-7.66 (1H, m), 7.58-7.34 (4H, m), 7.39 (1H, d, J=16.5 Hz), 7.27-7.16 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1ccc(N)cn1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2nc(Cl)ncc2F)cn1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-methoxypyridine gave 2-chloro-5-fluoro-N4-(6-methoxypyridin-3-yl)-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.39 (d, 1H, J=3.0 Hz), 8.10 (d, 1H, J=3.6 Hz), 7.95 (dd, 1H, J=2.4 and 9 Hz), 8.30 (d, 1H, J=9 Hz), 3.91 (s, 3H); 19F NMR (CD3OD): −44737; LCMS: purity: 97%; MS (m/e): 255 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:36][C:37]1[CH:38]=[C:39]([NH:44][CH2:45][C:46](O)=[O:47])[CH:40]=[C:41]([Cl:43])[CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:36][C:37]1[CH:38]=[C:39]([NH:44][CH2:45][C:46]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[O:47])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl(S)-piperidin-3-ylcarbamate (500 mg, 2.5 mmol), in DMF (5 mL) was added EDCI (573 mg, 3.0 mmol), HOBt (405 mg, 3.0 mmol), 2-(3,5-dichlorophenylamino)acetic acid (550 mg, 2.5 mmol) and DIEA (0.5 mL, 3.0 mmol) at 0° C. The reaction mixture was stirred at rt overnight, the reaction mixture was diluted with EtOAc and washed with water. The water layer was extracted with the EtOAc and the combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (900 mg, 98%) of the titled intermediate. LCMS: m/z: [M+1]=402.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[NH:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N(C1CCCCC1)C1CCCCC1.Cl>CCCCCC>[N:5]([P:1]([Cl:4])[Cl:2])([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: ClP(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Product: ClP(Cl)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A mixture of 34.4 g (0.25 moles) of PCl3 in 400 mL of hexane was treated with Cy2NH (90.7 g, 0.50 moles) dropwise at ° C. for 30 min. The resulting white slurry was warmed to room temperature and stirred for 1 h, refluxed overnight before removal of Cy2NH—HCl by filtration. The white solids were washed with hexane (2×100 mL). The combined filtrates were concentrated to give the crude Cy2N—PCl2 (54.0 g, 77% yield). 31P NMR (121 MHz, CD2Cl2): δ171.3 (s) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)[N:3]=1.[OH:36][CH2:37][C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:39][CH2:38][C:37]([N:17]1[CH2:16][CH2:15][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:6]3[C:2]([CH3:1])=[N:3][C:4]([C:20]4[O:24][N:23]=[C:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=5)[N:21]=4)=[N:5]3)[CH:9]=2)[CH2:19][CH2:18]1)=[O:36]
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCNCC2)c1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCN(C(=O)CO)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(5-methyl-1-(3-(piperazin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 81; 110 mg, 0.23 mmol), 2-hydroxyacetic acid (21 mg, 0.28 mmol) and DIPEA (89 mg, 0.69 mmol) in DMF (5 mL) was added HATU (106 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 3 h, diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC (20% to 50% MeCN/H2O containing 0.1% trifluoroacetic acid) to give the title compound as a white solid; MS (ES+) C25H24F3N7O4 requires: 543. found: 544 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.23 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.24 (m, 1H), 6.95 (m, 2H), 6.69 (d, J=7.5 Hz, 1H), 5.49 (s, 2H), 4.12 (s, 2H), 3.56 (m, 2H), 3.15 (m, 4H), 2.58 (s, 3H), 2.50 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:34]([NH:36][CH:37]2[CH2:39][CH2:38]2)=[O:35])[N:22]=[N:21]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:27]([O:26][CH2:25][C:24]1[N:20]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=2[OH:8])[N:21]=[N:22][C:23]=1[C:34]([NH:36][CH:37]1[CH2:38][CH2:39]1)=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCc2ccccc2)c(O)c1
Yield: 77.2 %

Procedure:
1-{2-(Benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-[(benzyloxy)methyl]-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (205 mg, 0.390 mmol) obtained in Example 316 was dissolved in methanol (7.0 ml), and the mixture was stirred at room temperature for 4 hr in the presence of 10% palladium carbon (wet, purity 50%, 41 mg) under a hydrogen atmosphere. The reaction mixture was filtrated to remove the catalyst, and the filtrate was concentrated to dryness to give a colorless oil. This was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-4:1) on silica gel (manufactured by E. Merck, Art.7734, 10 g), and the fraction obtained by elution with ethyl acetate-hexane (2:1-4:1) was concentrated and diluted with ethyl acetate-diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (131 mg, 0.301 mmol, 77.1%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2=[O:16])[CH:2]=[CH2:3].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:40]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].C(O)(C)(C)C.[OH2:88]>C(OCC)(=O)C>[OH:88][CH:2]([CH2:3][OH:40])[CH2:1][C:4]1[C:5]([O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]2=[O:16]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CCc1c(OC)ccc2c1OC(C)(C)CC2=O
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1CC(O)CO)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 8-allyl-7-methoxy-2,2-dimethyl-4-oxochroman was dissolved in 16 ml of t-butanol-water (1:1). Thereafter, 0.85 g of AD-mix-β was added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, 0.91 g of sodium sulfite was added to the reaction solution while cooling on ice, and the obtained mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, so as to obtain 171 mg of 8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxochroman. This compound was used in the following reaction without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.CCCCCCC.CCOC(C)=O>[Pd].C(O)C>[CH2:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC=C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCNCC1
Yield: 33 %

Procedure:
In a 500 mL flask fitted with a stirrer was added a slurry of 2 (13.2 g, 58 mmol) and 10% palladium on charcoal (1.2 g) in ethanol (70 mL), followed by addition of concentrated hydrochloric acid (1.5 mL). The reaction flask was evacuated and hydrogen was added via a reaction flask. A total of 2.5 dm3 of hydrogen was consumed. The reaction mixture was filtered and evaporated and the residue was dissolved in H2O (40 mL) and NaOH (20 mL, 2 M) followed by extraction with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (30 mL) and evaporated to dryness to produce 7.1 g of crude 3. The crude product was subjected to CC [eluent:heptane:EtOAc (4:1)] to give pure 3 (2.7 g, 33%). 1H NMR (CDCl3) δ0.85 (t, 3H), 1.0-1.38 (m, 9H), 1.65 (dd, 2H), 2.38 (s, 1H), 2.55 (dt, 2H), 3.04 (dt, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C.C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-2-piperazinone (600 mg) in DMF (9 ml) was added sodium hydride in oil (120 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise a solution of 4-nitrobenzyl bromide (648 mg) in THF (5 ml) at ° C., and the mixture was stirred for 30 minutes. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and brine, dried and concentrated, and the residue was crystallized from diisopropylether to give colorless crystals of 4-(tert-butoxycarbonyl)-1-(4-nitrobenzyl)-2-piperazinone (755 mg).