Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[O:5]([CH2:23][CH2:24][NH:25][CH3:26])[Si:6]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27]([C:29]1[C:34]2[N:35]=[C:36]([C:38](OCC)=[O:39])[O:37][C:33]=2[C:32]([F:43])=[C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:30]=1[CH3:50])#[N:28].Cl>ClCCl>[O:5]([CH2:23][CH2:24][N:25]([CH3:26])[C:38]([C:36]1[O:37][C:33]2[C:32]([F:43])=[C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]([CH3:50])=[C:29]([C:27]#[N:28])[C:34]=2[N:35]=1)=[O:39])[Si:6]([C:19]([CH3:20])([CH3:21])[CH3:22])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2c1C#N
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.05 ml, 1.54 mmol) was dropwise added at room temperature to a dichloromethane (3 ml) solution of [2-(tert-butyldiphenylsiloxy)ethyl]methylamine (I-123) (483 mg, 1.54 mmol), and stirred for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (250 mg, 771 μmol) was dropwise added and stirred for 16 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with n-hexane/ethyl acetate (3:1, v/v) gave the entitled compound (304 mg, 67%) as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of p-bromobenzaldehyde 10 (4 g, 21.6 mmol) in THF (20 mL) was added phenyl magnesium bromide (22.7 mL, 22.7 mmol) and the reaction mixture was stirred at room temperature for 30 minutes, quenched with water and partially concentrated under vacuum. The crude material was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified via prep-HPLC (ISCO) in silica gel column with a gradient of ethyl acetate (5-45%) in hexanes to afford title compound 11 as a colorless oil (3.7 g, 65%). 1H NMR (DMSO-d6) δ (ppm): 7.49-7.45 (m, 2H), 7.36-7.17 (m, 7H), 5.98 (d, J=4.1 Hz, 1H), 5.68 (d, J=3.9 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]([O:19][C:20]([CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:21])[CH3:18].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:17]([O:19][C:20](=[O:21])[CH2:22][N:23]([C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:25]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:16])=[O:26])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:18]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (L)-proline benzyl ester hydrochloride (0.49 g), N-Ethoxycarbonylmethyl-N-tert.-butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid (0.760 g), N-methyl morpholine (0.93 mL) and 0.65 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 16 h at ambient temperature. The volatiles were pumped off and water was added followed by extraction with ethyl acetate and concentration of the organic layer. The remaining residue was purified by silica chromatography (isohexane/ethyl acetate 1/2). Yield: 0.99 g (86%); colorless oil; (+)-APCI-MS: 569 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.I[CH3:32]>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH3:32])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (9.96 mg, 0.25 mmol) in DMF (1.25 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (50 mg, 0.125 mmol) and the mixture was stirred for 20 minutes. Iodomethane (26.6 mg, 0.187 mmol) was then added and the reaction was allowed to warm to room temperature and subsequently heated to 60° C. overnight. The reaction was cooled to ambient temperature, quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: C[NH:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[N:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:7]=[CH:8][N:9]=1)=[O:4].CC1C=CC2N(C(CN3C(C(OC)=O)=NC=N3)=C(C3C=CC(C)=CC=3)N=2)C=1.N>>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([C:11]([CH2:10][N:6]3[C:5]([C:3]([NH2:2])=[O:4])=[N:9][CH:8]=[N:7]3)=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[N:13]=2)[CH:16]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: COC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: N
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ncnc2C(N)=O)cc1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and ammonia. m/e− 347 for C19H19N6O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.87 (d, J=6.9 Hz, 2H), 7.61 (d, J=9.3 Hz, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.30 (d, J=6.9 Hz, 2H), 7.12 (dd, J=1.2, 9.3 Hz, 1H), 6.32 (s, 2H), 6.03 (bs, 2H), 2.43 (s, 3H), 2.34 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O.Cl>C(O)C.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.O1CCCC1>[CH3:12][S:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH2:13])[N:10]2[N:9]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: Nc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CSc1ncc2ccc(-c3ccccc3N)n2n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.00 g, 4.10 mmol), 2-aminophenylboronic acid pinocl ester (1.84 g, 8.40 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.710 g, 0.614 mmol) were dissolved in Ethanol (15 mL) and Tetrahydrofuran (15 mL) followed by addition of 2.00 M of Sodium carbonate in Water (5.0 mL, 10 mmol). The reaction mixture was then heated at 75° C. and was allowed to stir overnight. After cooling to room temperature, the reaction mixture was acidified with ˜2 mL concentrated HCl and then extracted with EtOAc (2×, 30 mL). The organics were then back extracted with 3M HCl (2×, 20 mL) and the aqueous layers combined and washed with EtOAc (2×, 20 mL). The combined HCl was then basified while stirring with 5N NaOH followed by extraction with DCM (3×, 30 mL) and brine, drying with sodium sulfate, and conc. in vacuo. The product was then purified by ISCO column chromatography (50/50 EtOAc/Hex, 40 g column) to afford 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine as a white solid (0.78 g, 74%). LCMS: 257 (M+H). 1H-NMR (CDCl3): 8.74 (s, 1H), 7.44 (d, 1H, J=7.72 Hz), 6.98 (d, 1H, J=4.82 Hz), 6.94 (d, 1H, J=4.82 Hz), 6.88 (d, 1H, J=7.78 Hz), 6.84 (d, 1H, J=7.78 Hz), 4.12 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31]([CH:33]1[CH2:35][CH2:34]1)=O>>[CH:33]1([C:31]2[N:27]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:28][CH:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(CBr)C1CC1
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)cs2)C1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 44 mg (0.273 mmol) of 2-bromo-1-cyclopropylethanone (Tetrahedron, 43, 20 1987, 4609-4619) were reacted according to the General Method 3. Yield: 49 mg (56% of theory).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:14]=[CH:15][C:16]2[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH:27]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C>CN(C)C=O.O>[CH3:28][N:7]1[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][C:4](=[O:12])[N:3]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=3[CH:27]=2)[C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
A mixture of ethyl 5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate (0.643 g, 0.00160 mol) and potassium carbonate (0.243 g, 0.00170 mol) in N,N-dimethylformamide is stirred at room temperature for 90 minutes, treated with iodomethane (0.320 mL, 0.00500 mol), stirred at room temperature overnight, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown oil. Column chromatography of the oil using silica gel and a 10% ethyl acetate in hexanes solution gives the title product as a tan solid (0.362 g, mp 150-152° C.).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:24][CH3:25].[OH-].[Na+]>CCO>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[C:5]([O:24][CH3:25])[CH:6]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester (1.0 g, 2.7 mmol) from Step 2 was refluxed in EtOH (15 mL) containing aqueous NaOH (5.5 mL of a 1.0 N solution). The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50 mL). The organic phase was washed with water (25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxy-benzoic acid as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OC1C=CC(C(OC2C3C(=C(OC(=O)C4C=CC(O)=CC=4)C4C(C=3)=CC=CC=4)C=CC=2OC(=O)C2C=CC(O)=CC=2)=O)=CC=1>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C(Oc1ccc2c(OC(=O)c3ccc(O)cc3)c3ccccc3cc2c1OC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Product: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Yield: 47.6 %

Procedure:
Using 3-hydroxy-4-methylbenzoic acid (20.3 g, 0.13 mole)and benzyl chloride (50.8 g, 0.40 mole), the reaction was carried out in the same manner as described in Example 1, (1). The resulting crude solid was recrystallized from ethanol to give 15.0 g of 3-benzyloxy-4-methylbenzoic acid as white crystals having a m.p. of 159°-161° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][C:83]([C:96]2[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=2)([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[S:64])=[C:57](C(=O)C)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1CCOCC1.[F:108][C:109]([F:122])([F:121])[S:110]([O:113][CH2:114][CH:115]1[CH2:120][CH2:119][O:118][CH2:117][CH2:116]1)(=[O:112])=[O:111]>C(N(CC)CC)C.N1C=CC=CC=1>[F:121][C:109]([F:108])([F:122])[S:110]([O:113][CH2:114][CH:115]1[CH2:116][CH2:117][O:118][CH2:119][CH2:120]1)(=[O:111])=[O:112].[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][C:83]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)([C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=2)[C:90]2[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=2)/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)=[S:64])=[C:57]([CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCC1CCOCC1
Reactant: CC(=O)C1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=S(=O)(OCC1CCOCC1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCN1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCOCC3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 98 %

Procedure:
Tetrahydropyran-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27 (a) from tetrahydropyran-4-yl-methanol (223 mg), pyridine (0.17 ml) and trifluoromethanesulfonic acid anhydride (596 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4 -yl) -2 -trityloxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (700 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27(b), followed by reacting the resulting reaction product with the tetrahydropyran-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27 (b).The reaction solution so obtained was post-treated in the same manner as in Example 27 (b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (722 mg; 98%).
Reaction SMILES: I[C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:11][CH2:12][C:13](N(OC)C)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])=[O:14]
Reactant: Cc1c(I)cccc1C#N
Reactant: CON(C)C(=O)CCl
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1C(=O)CCl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-iodo-2-methylbenzonitrile (7.71 g, 31.7 mmol) and 2-chloro-N-methoxy-N-methylacetamide (6.55 g, 47.6 mmol) in THF (100 mL) at −78° C. was added n-butylithium (2.5 M in hexanes, 14.0 mL, 34.9 mmol) dropwise. After complete addition, the mixture was stirred 15 min. at −78° C., then quenched with the dropwise addition of 1 N HCl. The mixture was partitioned between EtOAc/water and the layers separated. The aqueous was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated. Recrystallization of the resulting residue from hexanes provided 3-(2-chloroacetyl)-2-methylbenzonitrile: 1H NMR (500 MHz, CDCl3), δ 7.76 (m, 2H), 7.41 (m, 1H), 4.55 (s, 2H), 2.68 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].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>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:56])[F:58])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (124 mg, 1.2 equiv), ethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B3) (139 mg, 1 equiv), DMF (1.2 ml) and DIPEA (0.16 ml, 3 equiv) was shaken at room temperature for 30 min, then HATU (176 mg, 1.5 equiv) was added and shaking continued for 4 h. Reverse phase HPLC (Preparative Method B) gave ethyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate as a white solid (174 mg).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]1[CH:10]2[CH:11]3[CH:15]=[CH:14][CH:13]([CH:9]2[CH:8]=[CH:7]1)[CH2:12]3>>[CH2:7]1[CH2:6][C@H:10]2[C@H:9]([C@H:13]3[CH2:12][C@@H:11]2[CH2:15][CH2:14]3)[CH2:8]1.[CH2:2]1[CH:1]2[CH:8]3[CH:7]=[CH:6][CH:10]([CH:5]2[CH:4]=[CH:3]1)[CH2:9]3
Reactant: C1=CCC=C1
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: C1C[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2C1

Procedure:
In the prior art, JP-10 is prepared by first completely hydrogenating extra-high purity cyclopentadiene (CPD) dimer, namely dicyclopentadiene (DCPD, freezing point of 33.6° C.), as a precursor to yield the solid endo-isomer of the hydrogenated derivative, namely endo-THDCPD (freezing point of 77° C.), wherein the hydrogenation of DCPD is carried out in two stages (the first stage and the second stage). In the first stage, the dihydro derivative, namely dihydrodicyclopentadiene (DHDCPD, freezing point of 51° C.) was obtained by selective hydrogenation of DCPD in the presence of nickel or palladium catalyst at the temperature of 50-120° C. In the second stage, the solid endo-THDCPD (freezing point of 77° C.) was obtained by hydrogenation of DHDCPD in the presence of metal catalyst at the temperature of 130-220° C. Finally, the solid endo-THDCPD is isomerized to the liquid exo-THDCPD, namely JP-10 (freezing point <−79° C.), in an amount of more than 98.5% of the total product weight in the presence of an acidic catalyst. JP-10 is very expensive because it is obtained by chemical synthesis from extra-high purity DCPD using a batch reactor (referring to U.S. Pat. Nos. 3,381,046, 4,086,284, 4,107,223, and 4,270,014).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15](=[O:16])[NH:33][CH2:32][C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NCc1ccncc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and pyridin-4-ylmethanamine as a brown solid (43%). MS 437 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][NH:11]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[C:4]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[O:31])[CH:3]=1.N1CCCCC1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][NH2:11])=[C:4]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[O:31])[CH:3]=1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: NCC(=O)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
A round-bottomed flask was charged with 9H-fluoren-9-ylmethyl [2-({4-bromo-2-[(2-fluorophenyl)carbonyl]phenyl}amino)-2-oxoethyl]carbamate (580 mg) and tetrahydrofuran (15 mL). The mixture was treated with piperidine (1.5 mL) then stirred at room temperature for 1.5 h. After concentrating to an oil, the residue was taken up in methylene chloride and purified by silica gel chromatography to yield N1-{4-bromo-2-[(2-fluorophenyl)carbonyl]phenyl}glycinamide (135 mg) as a white powder. H1 NMR (d6-dmso): 8.42 (d, 1H), 7.82 (dd, 1H), 7.65-7.72 (m, 1H), 7.6 (dt, 1H), 7.52 (m, 1H), 7.33-7.40 (m, 2H), 4.0-6.4 (br s, 2H), 3.20 (s, 2H).