Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C(C1C=CC(OC2N=CC(N[C:33]([C@H:35]([NH:38][C:39](=O)[O:40]C(C)(C)C)[CH2:36][CH3:37])=[O:34])=CC=2)=CC=1C(C)C)#N.Cl>ClCCl.CN(C1C=CN=CC=1)C.CCOCC>[CH2:36]([C@H:35]1[NH:38][C:39](=[O:40])[N:14]([C:13]2[CH:15]=[CH:16][C:10]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:11][CH:12]=2)[C:33]1=[O:34])[CH3:37]
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(OC)c3)cc2)C1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To Boc-anhydride (138 mg, 0.631 mmol) in dichloromethane (1 mL) was added DMAP (55.1 mg, 0.451 mmol) followed by a solution of 4-{[3-(methyloxy)phenyl]oxy}aniline (97 mg, 0.451 mmol) in dichloromethane (1 mL). The mixture was stirred for 10 min. The brown solution thus obtained was added to Solution 1 via syringe with shaking at 35° C. and shaking was continued at this temperature for 2 hours. The solution was then kept at room temperature for ca. 64 hours. Conc. aq. HCl (ca. 0.8 mL) was added and the heterogenous mixture was heated at 100° C. for 2 hours with shaking, allowing the DCM to distill off through a glass capillary. After cooling to room temperature, the residue was diluted with water (ca. 3 mL) and extracted with dichloromethane (2 times ca. 2 mL). The dichloromethane extracts were concentrated under vacuum. The residue was purified by silica gel chromatography (Biotage system, 10 g column) eluting with a gradient cHex/EtOAc from 95/5 to 0/100 to give a brown viscous oil that was dissolved in Et2O (ca. 0.7 mL) and cHex (ca. 0.1 mL) and kept over night. The overstanding faint brown solution was decanted from a small quantity of a brown oil that had separated out. As the solvent was allowed to evaporate from this solution crystallisation initiated. The material thus obtained was allowed to dry and then triturated with Et2O (2 times ca. 0.5 mL) to afford, after drying, the title compound as a solid (28 mg).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[NH:20][N:21]=[CH:22][C:14]=12.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.C(Cl)Cl>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[N:20]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:21]=[CH:22][C:14]=12
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
pTsOH (30.2 mg, 0.159 mmol) was added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.587 mmol) and 3,4-dihydro-2H-pyran (200 mg, 2.381 mmol) in a mixture of tetrahydrofuran (ratio: 1.000, volume: 5 ml) and CH2Cl2 (ratio: 1.000, volume: 5 ml). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was taken in CH2Cl2 (20 mL) and poured into water (20 ml). The organic phase was separated, the aqueous phase was extracted with CH2Cl2 (20 mL), and the organic phases were combined. The combined organic phases were washed with water (40 mL), washed with brine (40 mL), dried over Na2SO4 and then concentrated. The resulting crude material was purified by flash chromatography (CH2Cl2/MeOH 99/1 increasing) to yield the title compound (397 mg, 1.454 mmol, 92% yield) as a pale white oil. 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 5.99 (dd, 1H, J=2.4 & 10.4 Hz), 4.12 (m, 1H), 3.79 (m, 1H), 2.53 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H), 1.76 (m, 2H), 1.64 (m, 1H). ESI-MS: 273.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:35])[C:8]([CH2:33][CH3:34])=[C:9]([C:31]#[N:32])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21](CC3C=CC(OC)=CC=3)[N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:35])[C:8]([CH2:33][CH3:34])=[C:9]([C:31]#[N:32])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnnn3Cc3ccc(OC)cc3)cc2)c(C#N)c(CC)n1C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Yield: 90.8 %

Procedure:
Into a round bottom flask containing 4-cyano-5-ethyl-3-{4-[1-(4-methoxybenzyl)-1H-tetrazol-5-yl]-phenyl}-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.15 g, 0.33 mmol, prepared in example E-241) add TFA (2 mL) and stir over night. Concentrate the mixture and azeotrope the residue with a mixture of methylene chloride/hexanes. Dilute the mixture with 0.500 N HCl (20 mL) and extract with ethyl acetate (3×30 mL). Combine the organic extracts, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: 0 to 5% MeOH/ethyl acetate). Concentrate the purified fractions under reduced pressure and place under vacuum to provide the title compound as a tan solid (0.105 g); mass spectrum (m/e): 351.05 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:18])[S:12][C:13]=2[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>>[CH2:14]([C:13]1[S:12][C:11]([NH:18][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=2)=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1sc(N)nc1-c1ccc(OC)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: CCCCc1sc(NC(=O)c2cc(OC)c(OC)c(OC)c2)nc1-c1ccc(OC)cc1
Yield: 51.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-n-butyl-thiazol-2-ylamine prepared in Example 62 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a glassy crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 51.8%, mp: 197-198 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.93 (3H, t, J=7.2 Hz, CH3), 1.43 (2H, sextuple, J=7.20 Hz, CH2), 1.72 (2H, quintuple, J=7.20 Hz, CH2), 2.88 (2H, t, J=7.2 Hz, CH3), 3.75 (6H, s, 2×OCH3), 3.78 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.74 (2H, d, J=8.80 Hz, ArH), 6.91 (2H, s, ArH), 7.28 (2H, d, J=8.80 Hz, ArH), 11.96 (1H, br, CONH); EI-MS m/e (%): 456.1 (M+, 49), 413.1 (7), 195.1 (100); HREI-MS Calcd. for C24H28N2O5S: 456.1719. found: 456.1718. Anal. Calcd. for C24H28N2O5S: C, 63.14; H, 6.18; N, 6.14. found: C, 63.24; H, 6.20; N, 6.25.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1C=CC=C[CH:3]=1.[N+](C1C(C2C=CC=CC=2)=C(OCC#C)C=C(C=1)C(O)=O)([O-])=O>>[NH2:24][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([O:8][CH2:1][C:2]#[CH:3])[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: C#CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: C#CCOc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 5-nitro-4-phenyl-3-propargyloxybenzoic acid, and following the procedure described, 5-amino-4-phenyl-3-propargyloxybenzoic acid is obtained with a melting point of 172°-173° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.O=[C:26]1[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27]1.O>C1(C)C=CC=CC=1>[C:31]([CH:28]1[CH2:29][CH2:30][C:26]2([O:6][CH2:5][C:2]([CH3:7])([CH3:1])[CH2:3][O:4]2)[CH2:27]1)([OH:33])=[O:32]
Reactant: COC(=O)C1CCC(=O)C1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC2(CCC(C(=O)O)C2)OC1

Procedure:
72.8 g (0.70 mole) of 2,2-dimethylpropane-1,3-diol and 12.2 g (0.05 mole) of pyridinium-4-toluenesulphonate are added one after another to 40.0 g (0.28 mole) of methyl 3-oxocyclopentane carboxylate OCCME in 560 ml of absolute toluene. The mixture is boiled for 1.5 hours in a water separator; after 30 minutes the solid is dissolved. Approximately 8 ml of H2O in total are separated out. After cooling, the solution is washed three times using 100 ml of H2O each time, the toluene phase is dried over MgSO4 and evaporated in vacuo. The oily residue is fractionally distilled in vacuo at 0.6 mbar over a metallised pin tube column 20 cm long.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:24][CH2:23][CH2:22][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCOCC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 2.9 %

Procedure:
The reaction was carried out in the similar procedure to Example 75a using 5.00 g (20.1 mmol) of benzyl 4-(hydroxymethyl)piperidine-1-carboxylate, 0.88 g (20.1 mmol) of sodium hydride (55% or more, oily) and 5.28 g (22.1 mmol) of (2-bromoethoxy)-tert-butyldimethylsilane to obtain 237 mg (yield: 3%) of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)O)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C)c(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
(3-Fluoro-4-methylphenyl)acetic acid (105.3 g) was dissolved in methanol (740 ml). Concentrated sulfuric acid (9.9 ml) was added and the mixture was stirred at 85° C. for 1 hr. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. Water was added to the obtained residue and the mixture was extracted with ethyl acetate (1 L). The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (114.2 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(OCC)(=O)C.C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
0.34 g of t-butyl α-(6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g)] was N-alkylated with 0.50 g of benzyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH2:1]([NH:11][C:12]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@H:19]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]([OH:22])=O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:89][CH2:90][CH2:91][O:92][CH2:93][CH2:94][O:95][CH2:96][CH2:97][O:98][CH2:99][CH2:100][P:101](=[O:108])([O:105][CH2:106][CH3:107])[O:102][CH2:103][CH3:104]>C(Cl)Cl>[CH2:106]([O:105][P:101]([CH2:100][CH2:99][O:98][CH2:97][CH2:96][O:95][CH2:94][CH2:93][O:92][CH2:91][CH2:90][NH:89][C:20](=[O:22])[C@@H:19]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][S:17][CH2:16][C@H:15]([O:14][C:12](=[O:13])[NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:41][O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])(=[O:108])[O:102][CH2:103][CH3:104])[CH3:107]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)O
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)-2-palmitamidopropanoic acid and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an off-white oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(-c2ccco2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(Cl)c(/C=C/C(=O)O)n1Cc1ccc(-c2ccco2)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a suspension of methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-methylimidazol-5-yl)-2-propenate (319 mg) in 1,4-dioxane (1.6 ml) was added 1N aqueous sodium hydroxide solution (1.2 ml) and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was ice-cooled and 1N hydrochloric acid (1.2 ml) was added dropwise to neutralize the mixture. The resulting product was extracted 3 times with chloroform-methanol (4/1). The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated to give (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-methylimidazol-5-yl)-2-propenic acid (310 mg) as a gray white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(N)c3)c2cc1OC
Solvent: CC(=O)O
Product: COc1cc2ncc(C#N)c(Nc3cccc(NC(C)=O)c3)c2cc1OC
Yield: 46 %

Procedure:
To a stirred solution of 4-(3-aminophenylamino)-6,7-dimethoxy-3-quinolinecarbonitrile (0.96 g, 3.0 mmol) in 9.0 ml of acetic acid at 25° C. was added 0.85 ml (9.0 mmol) of acetic anhydride. After 2 h the solution was evaporated to dryness, and the residue was stirred with methanol. This solution was evaporated, and the residue was recrystallized from ethanol to give 0.50 g of amber solid, mp 147-150° C.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C@H:17]([CH3:18])[O:16]1>CCCCCC.CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:16])([C@H:17]([S:3][CH2:4][CH2:5][OH:6])[CH3:18])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](SCCO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 74 %

Procedure:
70 mg (1.60 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were washed with hexane, and then suspended in 3 ml of dimethylformamide. 187 mg (2.4 mmole) of 2-mercaptoethanol were added to the resulting suspension under an atmosphere of nitrogen, whilst ice-cooling, and the mixture was stirred for 10 minutes. At the end of this time, 200 mg (0.80 mmole) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (prepared as described in European Patent Publication 332 387, the disclosure of which is incorporated herein by reference) were added to the mixture, and the resulting mixture was stirred at 50°-60° C. for 30 minutes. The mixture was then cooled after which it was diluted with ethyl acetate. It was then washed with a saturated aqueous solution of sodium chloride; and the solvent was then removed by distillation under reduced pressure. The crude product thus obtained was purified by column chromatography through 10 g of silica gel, using a 4:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford 195 mg of the title compound. A pure specimen melting at 89°-90° C. was then obtained by recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 27 (0.5 g, 1.05 mml) in methanol (30 mL) was added 5% Pd/C (0.5 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 4-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 28 (0.395 g, 98%) as a colorless foam.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[CH:32]([CH3:34])[CH3:33]>O1CCOCC1>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)c1cccc(C(C)C)c1Nc1ccccc1F
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)c1cccc(C(C)C)c1Nc1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
A 250-mL Schlenk flask equipped with a condenser was flashed with nitrogen thoroughly. To this flask was added KPPh2 (73 mL, 0.5 M in THF solution, Aldrich, 36.9 mmol). THF was removed in vacuo and a solution of N-(2-fluorophenyl)-2,6-diisopropylaniline (10 g, 36.9 mmol) in 1,4-dioxane (40 mL) was added with a syringe. The transparent, ruby reaction solution was heated to reflux for 5 d, during which time the reaction condition was monitored by 31P {1H} NMR spectroscopy. All volatiles were removed from the resulting orange solution under reduced pressure and degassed deionized water (100 mL) was added. The product was extracted with deoxygenated dichloromethane (100 mL). The dichloromethane solution was separated from the aqueous layer, from which the product was further extracted with dichloromethane (20 mL×2). The combined organic solution was dried over MgSO4 and filtered. All volatiles were removed in vacuo to yield the product as pale yellow oil. The product was purified by washing it with boiling EtOH (10 mL×4) until it became white powder; yield 15.2 g (94%). 1H NMR (CDCl3, 200 MHz) δ 7.39 (m, 10, PC6H5), 7.0-7.22 (m, 4, Ar), 6.82 (m, 1, Ar), 6.65 (t, 1, Ar), 6.15 (m, 1, Ar), 5.95 (d, 1, JHP=8, NH), 2.90 (septet, 2, CHMe2), 1.06 (d, 6, CHMe2), 0.94 (d, 6, CHMe2). 1H NMR (C6D6, 200 MHz) δ 7.48 (m, 4, Ar), 6.60-7.15 (m, 10, Ar), 6.92 (m, 1, Ar), 6.59 (t, 1, Ar), 6.34 (m, 1, Ar), 6.26 (d, 1, JHP=8, NH), 3.13 (septet, 2, CHMe2), 1.09 (d, 6, CHMe2), 0.97 (d, 6, CHMe2). 31P{1H} NMR (C6D6, 202 MHz) δ−20.11. 31P{1H} NMR (Et2O, 121.5 MHz) δ−19.87. 31P{1H} NMR (CDCl3, 121.5 MHz) δ−20.17. 13C NMR (CDCl3, 75.3 MHz) δ 150.57 (J=17.1), 147.41, 135.35, 135.26, 135.24, 133.93 (JCP=19.6), 130.28, 128.92, 128.47 (JCP=7.5), 127.14, 123.70, 118.71, 117.63, 111.60, 28.18 (CHMe2), 24.40 (CHMe2), 23.03 (CHMe2). Anal. Calcd. for C30H32NP: C, 82.35; H, 7.37; N, 3.20. Found: C, 82.32; H, 7.36; N, 3.28.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC(c1ccc(F)cc1)c1cccs1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-fluorobenzoyl)thiophene (5.09 g, 24.7 mmol) in Et2O (100 mL) was added a solution of LiAlH4 (1M in THF, 30 mL, 30 mmol) and the reaction mixture was stirred overnight. The resulting mixture was cooled to 0° C., poured onto ice, extracted with Et2O, dried (Na2SO4) and concentrated under reduced pressure to give (4-fluorophenyl)-2-thienylmethan-1-ol as a yellow oil. The crude product was used without further purification.