Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8](O)[CH3:9].S(Cl)([Cl:13])=O.C(=O)(O)[O-].[Na+]>O>[Cl:13][CH:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccncc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(Cl)c1ccncc1F
Temperature: 80 °C
Yield: 39 %

Procedure:
1-(3-fluoropyridin-4-yl)ethanol (0.8 g, 5.7 mmol) was treated with thionyl chloride (5 mL) and the resulting mixture was heated to 80° C. for 2 h. Water (10 mL) and sat. sodium bicarbonate (aq., 10 mL) was added. The product was extracted with DCM (three times). The combined organic extracts were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent heptane: ethyl acetate gradient) to yield 0.36 g (39% yield) of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=1>C(O)CCC>[NH:2]([C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=1)[NH2:3]
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1nc(NN)c2c(n1)NC(=O)CO2
Temperature: 25 °C
Yield: 56.3 %

Procedure:
12.8 ml of 98% hydrazine hydrate dissolved in 40 ml of n-butanol are dropped to a solution of 20 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one in 320 ml of n-butanol at 117° C. within 30 minutes while stirring. The mixture is stirred for an additional 45 minutes at 117° C., then cooled to room temperature. The precipitate is filtered and washed with water to give 11.66 g (56.3%) of the product, m.p.: 262°-264° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([OH:28])=O.[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH2:40])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][C:26](=[O:28])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc(C(C)(C)C)cc(N)n1
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(C)(C)C)cc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)n1
Yield: 21.9 %

Procedure:
Combine [2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid dihydrochloride (0.66 g, 1.57 mmol), 4-tert-butyl-6-methyl-pyridin-2-yl-amine (0.26 g, 1.57 mmol), HATU (0.72 g, 1.57 mmol), diisopropylethylamine (8.12 g, 11.2 mL, 6.28 mmol) in DMF (10 mL) and stir at ambient temperature for 3 hours. Pour the reaction contents onto a pre-washed (with methanol) Varian SCX column (25 g) and wash the column with portions (30 mL) of dichloromethane (2×) and methanol (3×). Elute the product with 2N methanolic ammonia (75 mL) and concentrate the solution to dryness. Chromatograph the crude product on silica using (0-5%) methanol in dichloromethane. Recrystallization from dichloromethane/ether/hexanes provides N-(4-tert-Butyl-6-methyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide (0.17 g). MS(ES), m/z 494 (M+1).
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6](=O)[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])C.[CH3:15][S:16][CH:17]([CH3:25])/[CH:18]=[CH:19]/[N:20]1CCCC1.C([O-])(=O)C.[NH4+].O>C(OCC)C>[CH3:15][S:16][CH:17]([C:18]1[CH:4]=[CH:5][C:6]([C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[N:20][CH:19]=1)[CH3:25]
Reactant: CSC(C)/C=C/N1CCCC1
Reactant: CCO/C=C/C(=O)C(F)(F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CSC(C)c1ccc(C(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
(E)-1-Ethoxy-4,4,5,5,5-pentafluoropent-1-en-3-one (1.09 g, 5 mmol) in anhydrous ethyl ether (5 mL) was treated with 1-((E)-3-methylthiobut-1-enyl)pyrrolidine (0.85 g, 5 mmol) in 2 mL dry ether at −15° C. over a period of 5 min and the reaction was continued for 20 min Then the temperature was allowed to rise to room temperature and the reaction continued for 3 h. The solvent was removed under reduced pressure and the residue re-dissolved in anhydrous DMF (5 mL). Ammonium acetate (0.58 g, 7.5 mmol) was added and the mixture stirred at room temperature over a weekend. Water was added and mixture extracted with ether three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified on silica gel eluted with 8% EtOAc in hexane (v/v) to give 0.16 g of the desired 5-(1-methylthioethyl)-2-pentafluoroethylpyridine (A) as brownish colored oil in 12% yield. GC-MS: mass calcd for C10H11F2N3S [M]+ 271. Found 271.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([C:9](=C(C)C)[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2].C(Cl)Cl.C[OH:30]>O=[O+][O-].O=O>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[O:30])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)=O
Reactant: CO
Agent: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)C(=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)=O

Procedure:
Into a solution of 910 mg (2.5 mmol) of methyl 2-((3S,4S)-4-acetoxy-3-t-butyloxycarbonylaminoazetidin-2-on-1-yl)-3-methylbut-2-enoate in 40 ml of methanol, for 120 minutes at -10° C. in a mixture of ozone and oxygen is introduced at a rate of 0.1 mmol of ozone per minute. The obtained crystalline residue is dissolved by addition of 160 ml of methylene chloride and the solution is washed subsequently with 60 ml of a 10% aqueous sodium bisulfite solution and 60 ml of saturated sodium chloride solution. The organic layer is dried over sodium sulfate and dried in vacuo, affording 640 mg of a noncrystalline solid. Recrystallisation from cold methanol furnishes 613 mg (74%) of pure title compound of a melting point of 144° to 146° C. IR spectrum in methylene chloride: 3400, 3000, 1840, 1765, 1720, 1500, 1360, 1220, 1160 and 1040 cm-1.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=C)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH2:15]>C(Cl)Cl.C(#N)C>[F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: C=C1CC(C#N)(c2ncccc2F)C1
Solvent: CC#N
Solvent: ClCCl
Product: N#CC1(c2ncccc2F)CC(=O)C1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1.45 mol) and RuCl3.H2O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L), and water (1.5 L) was added solid NaIO4 (1235 g, 5.8 mol) portionwise at 10-30° C. Upon completion of the addition, the reaction was stirred 1 h at 15° C. and overnight at rt. The solid precipitate was filtered off and washed with DCM (1 L×2). The organic layer was washed with water (500 mL×2) and brine (500 mL), dried over Na2SO4, and concentrated to provide the title compound as a crude dark solid (238 g, 86.3%), LRMS (M+H+) m/z 191.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reaction time: 8 h

Procedure:
At room temperature, 22.67 ml (294.3 mmol) of trifluoroacetic acid were added slowly to a solution of 6.6 g (14.7 mmol) of tert-butyl cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetate in 90 ml of dichloromethane, and the mixture was stirred overnight. The solvent was then removed under reduced pressure, and the residue was taken up in 100 ml of ethyl acetate and extracted with 50 ml of water. The organic phase was dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure. This gave 4.8 g (12.23 mmol, 83% of theory) of a colorless solid.
Reaction SMILES: [CH2:1]([C:14]1[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([C:14]1[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Yield: 78.9 %

Procedure:
To 10.01 g (32.6 mmol) of methyl 4-tridecylpyrrole-2-carboxylate prepared in Example 32 were added 200 ml of ethanol, 80 ml of water and 5.5 g (131 mmol) of 95% sodium hydroxide and the resulting mixture was heated under reflux for 1 hour. After cooling, 100 ml of water was added thereto. The resulting mixture was acidified with hydrochloric acid and extracted with a mixed solvent of 400 ml of ethyl ether, 100 ml of ethyl acetate and 300 ml of tetrahydrofuran. An aqueous layer was extracted again with 100 ml of ethyl acetate. Then both extracts were combined, washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After concentrating the resulting solution under reduced pressure, the recrystallization of the product from a mixed solvent of hexane and tetrahydrofuran gave 7.55 g of 4-tridecylpyrrole-2-carboxylic acid as white crystals, m.p. 150°-151° C.
Reaction SMILES: BrC[C:3]1[C:4]([NH:10][C:11](=[O:17])[O:12][C:13](C)(C)C)=[N:5][CH:6]=[CH:7][C:8]=1[F:9].O>CS(C)=O>[F:9][C:8]1[C:3]2[CH2:13][O:12][C:11](=[O:17])[NH:10][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(F)c1CBr
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2nccc(F)c2CO1
Yield: 29.7 %

Procedure:
The solution of the product of Step C (120 mg, 0.4 mmol) in DMSO (1 mL) was stirred at 60° C. for 4 hours under N2. Then water (10 mL) was added and extracted with ethyl acetate (3×15 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc:PE=1:1) to give the title compound (20 mg, 30%) as a solid. 1H-NMR (600 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.21-8.18 (m, 1H), 6.97-6.94 (m, 1H), 5.37 (s, 2H) ppm. MS: M/e 169 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[NH:10][C:9]=2[CH:8]=[CH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2>O.CO>[OH:3][C:4]1[C:14]2[C:9]([NH:10][C:11](=[O:15])[CH2:12][CH:13]=2)=[CH:8][CH:7]=[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=12
Reactant: O=c1ccc2c(=O)c3ccccc3ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CC=C2C(=CC=c3ccccc3=C2O)N1

Procedure:
A solution of 0.30 gram (8 millimoles) of sodium borohydride in 5 milliliters of water is added to a solution of 0.70 gram (3 millimoles) of 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one (prepared as described in Example I) in 50 milliliters of methanol and the resulting mixture heated for about twenty minutes at reflux temperature to obtain the desired 5-hydroxy-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one in the reaction mixture. The product is recovered by evaporating the solvent, and washing and drying the residue.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12>>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([NH:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12)=[O:14]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)C1=CSc2ccccc2S1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSc2ccccc2S1

Procedure:
2-(1,4-Benzodithiin-2-yl)-2-methoxyiminoacetic acid (syn isomer, 0.75 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) in a similar manner to that of Example 1 to give the captioned compound (0.7 g.), yellow powder, mp. 142° to 147° C. (dec.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-].[C]>[N:15]1([CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCOC(CN3CCCC3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C1CCN(CC2CNCCO2)C1
Yield: 95 %

Procedure:
4-Benzyl-2-(pyrrolidin-1-ylmethyl)morpholine (450 mg, 1.73 mmol) prepared according to Process Step 1 was dissolved in ethanol (10 mL), and 20% palladium hydroxide-carbon (200 mg, 0.285 mmol) was suspended therein, followed by stirring under the hydrogen gas atmosphere for two days. Celite (registered trademark: 2.0 g) was suspended in the reaction mixture, the solid was separated by filtration, and the solvent was distilled off under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform:methanol=5:1) and thereby yielded 2-(pyrrolidin-1-ylmethyl)morpholine (280 mg, in a yield of 95%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8]2[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc(-c3ccccc3)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cnc(Nc2ccc(-c3ccccc3)cc2)[nH]c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A mixture of ethyl 2-((1,1′-biphenyl)-4-ylamino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (100 mg, 0.298 mmol), sodium hydroxide (1M, aq), and methanol was stirred at 70° C. for 2 hours and for 40° C. overnight. The ester did not dissolve in 3 mL methanol. The ester was then put in 3 mL dioxane and heated to 103° C. for 4 hours with an additional 1 mL of NaOH added. The reaction mixture was then heated at 40° C. overnight. After the overnight heating, the reaction mixture was cooled and the solvent removed. The reaction mixture was diluted with water, and the pH was adjusted to about 3.0. The reaction mixture was filtered to obtain the end product. 1H-NMR confirmed the product (55 mg, 60.0% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCO)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OCCO)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
4-(2-Hydroxy-ethoxy)-benzoic acid (152 mg, 0.84 mmol), (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (193 mg, 1.25 mmol) and triethylamine (303 mg, 3.0 mmol) are dissolved in dichloromethane (5.0 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (786 mg, 1.5 mmol) is added to the mixture. The mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with dichloromethane, washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified using silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1) to give 177 mg (66%) of the title compound. Observed Mass 319.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:43][C:44]([O:46][CH3:47])=[O:45])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:47][O:46][C:44](=[O:45])[CH:43]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCNc1cc(F)ccc1C(=O)N(C)OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide (0.33 g, 1.37 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.7 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triphenylphosphoranylidene)acetate (0.5 g, 1.5 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.23 g, 69%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][NH:65][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:50]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Reactant: CN(C)CCN
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: CN(C)C=O
Product: Cc1c(C(=O)NCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N,N-Dimethylethylenediamine (137 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.026 g, 22%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OC(C)(C)C)[C:16]3=[O:28])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)[C:16]1=[O:28]
Reactant: CCc1cnc(N2CCC(N3CC[C@H](NC(=O)OC(C)(C)C)C3=O)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Yield: 100 %

Procedure:
A solution of (S)-tert-butyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (1 g, 2.6 mmol) in 50% TFA/CH2Cl2 (10 mL) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and washed with 1N NaOH (100 mL) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.75 g, 2.6 mmol, 100%)
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([N:13]([CH3:43])[C:14]([N:16]([CH3:42])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:46]C(C)([O-])C.[K+].CI>CN(C=O)C>[F:45][C:2]([F:44])([F:1])[C:3]1[CH:4]=[C:5]([N:13]([CH3:43])[C:14]([N:16]([CH3:42])[C@H:17]2[C@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:32][CH2:33][C@H:34]([N:37]([CH3:46])[S:38]([CH3:41])(=[O:39])=[O:40])[CH2:35][CH2:36]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NS(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N(C)S(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the compound (0.23 g) obtained in Example 242 in DMF (7.0 mL) were added potassium tert-butoxide (0.079 g) and methyl iodide (0.055 mL) at 0° C. The mixture was stirred at room temperature for 12 hr, diluted with ice water, and extracted with ethyl acetate. The extract was washed with water, 1N aqueous potassium hydrogen sulfate solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (0.17 g, 70%) as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([C:18]1[C:13]2[O:12][CH2:11][C@@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:37])[CH3:36]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@H](c1ccc(C(C)C)cc1)CO2
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@H]2c1ccc(C(C)C)cc1
Yield: 46 %

Procedure:
Using N-((3S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 71, the title compound was synthesized in the same manner as in Example 38. Yield: 46%. Melting point: 177-178° C. (hexane-ethyl acetate). [α]D20=−6.0° (c=0.510, chloroform).