Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:18])[CH3:17].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reaction time: 6 h

Procedure:
A mixture of 2-phenylindole (193.3 mg, 1.0 mmol) and acetyl chloride (92 μL, 1.3 mmol) in CH2Cl2 is treated with tin tetrachloride (97.4 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the 3-acetyl-2-phenylindole intermediate. A suspension of the thus-obtained 3-acetyl-2-phenylindole (47 mg, 0.2 mmol) in isopropanol and concentrated HCl (5 μL) is treated with aminoguanidine bicarbonate, heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 21.0 mg (36% yield), identified by HPLC1 and mass spectral analyses, (M+H) 292, retention time 3.9 min.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([OH:26])(=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[C:19]([OH:26])(=[O:25])[CH:20]([CH2:21][C:22]([OH:24])=[O:23])[OH:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CC(O)C(=O)O
Temperature: 33 °C

Procedure:
The coryneform bacterium cells prepared after culturing were added to 500 ml of the reaction stock solution in a reaction container under the nitrogen gas atmosphere. Glucose 200 mM and sodium carbonate 200 mM were added, and the reaction temperature was maintained at 33° C. to perform a reaction producing an organic compound. An oxidation-reduction potential was initially −200 mV, but was reduced immediately after the initiation of the reaction, and the reaction was continued by maintaining the oxidation-reduction potential at −400 mV. After the reaction for 3 hours, the reaction medium solution was analyzed by liquid chromatography, indicating that succinic acid 163 mM (19.2 g/L) and malic acid 5 mM (0.67 g/L) were produced. Lactic acid was not detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCOCC1>[CH:32]1([NH:37][C:38]([NH:16][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:28]([F:31])([F:29])[F:30])[CH:4]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C=NC1CCCC1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Solvent: C1COCCO1
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Yield: 67 %

Procedure:
1-(4-Fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (300 mg, 0.67 mmol) and cyclopentyl isocyanate (0.4 mL, 5.3 eq) were stirred in 1,4-dioxane (2 mL) at room temperature overnight. The reaction mixture was concentrated, and purified by flash chromatography (silica gel, hexanes/EtOAc) to give the racemic mixture of 1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (250 mg, yield: 67%). The racemate (250 mg) was dissolved in 10% isopropanol in heptane, and was resolved by chiral prep HPLC using an AD column (10% isopropanol/heptane/0.1% DEA, isocratic) to give the fast eluting enantiomer 1 (110 mg) corresponding to (S)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, (analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA, isocratic), retention time=4.85 min) and the slow eluting enantiomer 2 (105 mg) corresponding to (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, (analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA, isocratic), retention time=14.11 min) LCMS (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=4.33 min, 557.32 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.44 (m, 2H), 7.23-7.29 (m, 3H), 7.13-7.21 (m, 4H), 6.68-6.74 (m, 2H), 4.84 (s, 1H), 4.40 (s, br, 1H), 3.84-3.95 (m, 3H), 1.88-1.98 (m, 2H), 1.56-1.68 (m, 4H), 1.34 (d, J=6.36 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[C:21]([CH2:26][OH:27])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCCl
Reactant: Cc1c(C(=O)Nc2ccc(O)c(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCCN(C)C)c(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
To a solution of 1-[(3,4-dichlorophenyl)methyl]-N-[4-hydroxy-3-(hydroxymethyl)phenyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 26) (0.1 g, 0.245 mmol) in DMF (10 mL), were added potassium carbonate (0.07 g, 2 eq) and (2-chloroethyl)dimethylamine hydrochloride (0.07 g, 2 eq). The reaction was heated at 40° C. for 3 days. After evaporation, the residue was diluted with DCM, washed with water and dried over sodium sulphate. After purification by flash chromatography eluting with DCM/MeOH (90/10) and recrystallisation from methanol, the title compound was obtained as a white solid (18 mg, 16%). HRMS calculated for C22H25Cl2N5O3 (M+H)+ 478.1413, found: 478.1435, Rt: 2.47 min. MP: 163.1° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][O:27][CH2:28]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH:25]12[N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:21])([F:23])[F:22])[N:17]=[CH:18][C:13]=34)[CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A suspension of 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.59 g, 1.4 mmol) in tetrahydrofuran (40 mL) and ethyl acetate (10 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (100 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen-filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a white solid (0.51 g, 89%). MS (ES+): 405.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(-c2ccc(N)cc2)no1
Reactant: O=C=Nc1ccc(F)cc1F
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)no1
Yield: 62 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 2,4-difluoro-1-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-phenylpropanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 62% of title compound. MS (ESI): m/z 521.2 (M+H)+; 1HNMR (DMSO-d6, 300 MHz) δ: 9.43(d, 1H), 9.28 (s, 1H), 8.58(s, 1H), 8.10 (m, 1H), 7.84 (d, 2H), 7.60 (d, 2H), 7.55 (s, 1H), 7.34 (m, 5H), 7.20 (m, 1H), 7.07 (m, 1H), 4.74 (m. 1H), 3.64 (s, 3H), 3.23 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:11][Cl:12])[O:10][CH2:9][CH2:8][O:7]1)(=[O:3])[CH3:2].C[Si]([C:17]#[N:18])(C)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:1]([O:4][CH2:5][C:6]([C:17]#[N:18])([O:10][CH2:9][CH2:8][OH:7])[CH2:11][Cl:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1(CCl)OCCO1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)OCC(C#N)(CCl)OCCO
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of (2-(chloromethyl)-1,3-dioxolan-2-yl)methyl acetate (67.8 mmol), trimethylsilyl cyanide (20.29 g, 204 mmol, TCI America) and zinc iodide (3.65 g, 11.4 mmol) was heated (40° C., oil bath) for 6 hrs, then at ambient temperature for 16 hrs. The mixture was diluted with CH2Cl2 (100 mL) and stirred with silica gel (50 g) for several hours. The mixture was loaded onto a flash silica gel column (350 g silica) and eluted with CH2Cl2 then increasing amounts of Et2O to a final eluent of 30% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo to give the title compound as an amber oil: 1H NMR (500 MHz, CDCl3) δ ppm 4.44 (1H, d, J=-11.90 Hz), 4.35 (1H, d, J=11.90 Hz), 3.83-3.88 (2H, m), 3.79-3.84 (4H, m), 2.13-2.16 (3H, m); LC/MS m/z 222.16 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.[CH3:29][NH:30][CH3:31]>CN(C)C(=O)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:30]([CH3:31])[CH3:29])=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: CNC
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(CN(C)C)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 4b, 1000 mg, 1.98 mmol) in N,N-dimethylacetamide (5 mL) is added dimethylamine (3.0 mL of 2M solution in THF, 6.0 mmol). The reaction mixture is stirred 2 h at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [C:1]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([OH:30])[CH3:29])([OH:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:38]O>>[CH3:38][O:2][C:1]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([OH:30])[CH3:29])=[O:3]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 40 °C

Procedure:
To a solution of (3S,4S)-4-carboxy-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (34 g) in methanol (310 ml), there was added 98% sulfuric acid (2.9 g). The resultant mixture was heated at 65° C. for 3 hours, cooled down to 40° C., neutralized with 8% aqueous sodium hydroxide solution (15 ml) and concentrated to make a one third volume. The concentrate was diluted with 1,2-di-chloroethane (105 ml) and washed with water. The aqueous layer was separated from the organic layer and extracted with 1,2-dichloroethane (105 ml). The extract was combined with the organic layer, washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-methoxycarbonyl-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 102°-104° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)=[CH:3][CH:2]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][N:12]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccncc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (5.9 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (4.3 g) was heated at 145°-150° for 5 hours and allowed to cool to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. This residue was triturated with water, and treated with ethanolic hydrogen chloride to give the title compound m.p. 228°-233°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.N[CH2:10][C@@H:11]1CC[CH2:13][N:12]1CC.C(=O)C>>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][NH:12][CH3:13]
Reactant: CCN1CCC[C@H]1CN
Reactant: COC[C@H]1CCCN1
Agent: CC=O
Product: CNCCN1CCC[C@@H]1COC

Procedure:
By using O-methyl-D-prolinol (500 mg) as a starting material, the title compound (0.45 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2.[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[C:16]([N:7]1[C:8]2[C:3](=[C:2]([Br:1])[C:11]([F:12])=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH:6]1[CH3:13])(=[O:18])[CH3:17]
Reactant: CC1CCc2c(ccc(F)c2Br)N1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1c2ccc(F)c(Br)c2CCC1C
Temperature: 20 °C

Procedure:
To 6.0 g of 5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine was added 50 ml of acetic anhydride and one drop of concentrated sulfuric acid. The solution was heated on a steam bath for two hours, then cooled to about 20° C. The solution was basified with 10% sodium hydroxide solution. The solution was extracted with chloroform, and the chloroform extracts were evaporated to provide an oil which was distilled in vacuo to provide N-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine. The structural assignment was supported by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (35 mg, 45%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)[N:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:18]=3)=[CH:13][C:12]2=[O:31])=[CH:6][C:5]=1[F:37].[CH3:38]I>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[CH:36]=[N:35][N:34]([CH3:38])[CH:33]=2)[N:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:18]=3)=[CH:13][C:12]2=[O:31])=[CH:6][C:5]=1[F:37]
Reactant: O=c1cc(-c2nc(NC3CCOCC3)ncc2F)ccn1C(c1cn[nH]c1)c1ccc(Cl)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C(c2ccc(Cl)c(F)c2)n2ccc(-c3nc(NC4CCOCC4)ncc3F)cc2=O)cn1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
NaH (3.05 mg, 0.0762 mmol; 60% oil dispersion) neat as a solid was added to a stirred solution of 1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (38 mg, 0.0762 mmol) in DMF (1 mL) at room temperature under nitrogen. After 15 minutes, a red solution had formed. Methyl iodide (4.75 μL, 0.0762 mmol) was then added neat by syringe. After stirring overnight, the reaction was quenched by addition of saturated ammonium chloride solution (1 mL). The mixture was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate (15 mL). The organics were isolated and washed with water (3×15 mL) and with brine (15 mL). TLC in 95/5 ethyl acetate/methanol showed complete consumption of starting material with two new major spots of higher rf. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a 20 cm×20 cm×0.5 mm prep plate and eluted with 95/5 ethyl acetate/methanol. Three bands were scraped off the plate. Compound was freed from the silica gel by stirring for 15 minutes with ethyl acetate (50 mL) and filtration. The high rf material shows two methyl signals by 1H-NMR and is presumed to be dimethylated byproduct. The lower rf material was isolated as a clear oil, 1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (9 mg, 23%) and appears to be the desired product by comparison to the non-fluoro analog (see Example 35). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 1H), 7.36 (m, 3H), 7.30 (br s, 1H), 7.23 (s, 1H), 7.01 (m, 2H), 6.80 (d, 1H), 5.09 (d, 1H), 4.00 (m, 3H), 3.91 (s, 3H), 3.54 (m, 2H), 2.04 (m, 2H), 1.57 (m, 2H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1.O>C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:31]([NH:30][OH:29])=[O:32])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=C(NO)Oc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCN(C(=O)NO)C1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 5 h
Yield: 54.3 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (39.1 mg, 92.3 μmol) obtained in Step 1 of Example 2 was dissolved in ethanol (2 mL), and phenyl N-hydroxycarbamate (56.0 mg, 366 μmol) was then added to the obtained solution. The obtained mixture was stirred for 5 hours at reflux. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→20%) to obtain the captioned compound (24.2 mg, 54%) in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]2[C:26]1=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3n(CCCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 59.5 %

Procedure:
To a suspension of 5.20 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 60 ml of DMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 8.89 g (30 mmol) of N-(5-bromopentyl)phthalimide in DMF (20 ml). The mixture was stirred for 1.5 hour at 110° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 6.93 g of the desired compound (59.4%, pale brown solid).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2cccc3cncn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2cccc3cncn23)cc1

Procedure:
A solution of 5-(p-ethoxycarbonylphenyl)-imidazo[1,5-a]pyridine (1.0 g) in 10 ml of ethanol and 10 ml of 1N sodium hydroxide is refluxed for 3 hours. The ethanol is evaporated. The aqueous phase is washed with ether, adjusted to pH=6 and the solid collected to yield 5-(p-carboxyphenyl)imidazo[1,5-a]pyridine.