Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 76 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridylmethyloxy)benzoic acid (0.100 g, 0.221 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.303 g, 0.552 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=1:2) and then recrystallized from ether to obtain the titled compound (0.071 g, 0.168 mmol, 76%).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].N=[C:20](CCCC)C(OCC)=O>CO>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:6]=1)[CH2:2][CH2:3][CH2:4][CH3:20]
Reactant: CCCCc1nc(CNC(=O)OC(C)(C)C)n[nH]1
Reactant: CCCCC(=N)C(=O)OCC
Solvent: CO
Product: CCCCCc1nc(CNC(=O)OC(C)(C)C)n[nH]1

Procedure:
Under nitrogen, a solution of 18.9 g (100 mmol) of N-Boc glycine hydrazide (from step 2 of Example 3) in 100 mL of methanol is treated with 14.3 g (100 mmol) of ethyl iminocaproate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)]. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-pentyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)=[CH:30][CH:29]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 61 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 4-[(4-methylpiperazin-1-yl)methyl]aniline (260 mg, 1.3 mmol) to afford the desired product (250 mg, 58%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 11.04 (br s, 1H), 9.01 (s, 1H), 8.14 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 3.52 (s, 2H), 2.58 (s, 3H), 2.48 (br s, 8H), 2.30 (s, 3H); ESI MS m/z 410 [M+H]+
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[O:13].[OH-].[K+:18]>CO>[O:13]=[C:12]([CH:14]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([O-:16])=[O:15].[K+:18]
Reactant: CC(=O)C(=O)O
Reactant: O=C/C=C/c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=Cc1ccccc1
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A solution of trans-cinnamaldehyde (26.43 g) and pyruvic acid (11.9 mL) in 10 mL of methanol was stirred and chilled to 0-5° C. in an ice bath. To the chilled solution was added 35 mL of potassium hydroxide (16.83 g in 50 mL of methanol) over a period of 20 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The solution changed from a yellow to a dark orange and the precipitate was formed. The reaction mixture was chilled in the refrigerator overnight and the solid was collected by filtration, washed with 50 mL of methanol three times, 50 mL of ether and then air dried to afford 29.3 g of the desired 2-oxo-6-phenyl-3,5-hexadienoate as a yellow solid (61.0%). 1H NMR (DMSO-d6/D2O, 300 MHz), δ (ppm) 7.48 (d, 2H), 7.28 (m, 4H), 7.12 (d, 2H), 6.27 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[Si:20]([O:27][C@H:28]([C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36](=[O:43])[NH:37]2)[CH2:29][NH:30][CH3:31])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:20]([O:27][C@H:28]([C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36](=[O:43])[NH:37]2)[CH2:29][N:30]([CH3:31])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 55 °C

Procedure:
A mixture of Intermediate 40 (0.30 g, 0.90 mmol) and Intermediate 4 (375 mg, 1.1 mmol) in DMF (5 mL) was treated with N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) and catalytic tetra-n-butylammonium iodide (100 mg). The mixture was heated for 3 days in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 12 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound. ES/MS calcd. for C31H39F3N3O4Si+ 602.3. Found m/z=602.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[OH-].[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:8])[CH:4]=2)[C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][C:3]=1[F:8]
Reactant: Fc1ccccc1F
Reactant: O=Cc1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(C(c2ccncc2)c2ccc(F)c(F)c2)cc1F
Temperature: 70 °C
Yield: 91.1 %

Procedure:
A mechanically stirred mixture of 49.0 g (0.43 mole) of 1,2-difluorobenzene, 20.6 g (0.19 mole) of pyridine-4-carboxaldehyde and 80 ml of concentrated H2SO4 was heated at 70° C. for 21 hours. The reaction mixture was poured over ice, and the icy mixture was made basic with 50% NaOH. The resulting mixture was extracted with CH2Cl2 and the CH2Cl2 solution was dried (MgSO4). The solvent was removed in vacuo to give 54.94 g (89.8%) of a solid. This was recrystallized from a mixture of CH2Cl2 and hexane to give 44.82 g (74.3%) of a crystalline solid, mp 79°-82° C. Proton NMR showed that this sample contained ~5% of the 2,3-difluoro isomer.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1.Cl.[CH3:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26].C(O)(=O)/C=C\C(O)=O>CN(C)C=O.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[O:11][CH2:12][C:13]([O:15][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(O)COC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)COC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
Sodium hydride (1.32 g., 80% w/w dispersion in mineral oil) was added in portions to a solution of di-(4-chlorophenyl)methyloxyacetic acid (6.2 g.) in dry dimethylformamide (30 ml.) cooled below 30°. The mixture was stirred for 15 minutes at ambient temperature after the addition was complete and N,N-dimethyl-2-chloroethylamine hydrochloride (2.88 g.) was then added. The mixture was heated at 100° for 16 hours, cooled and then poured into water (200 ml.). The aqueous mixture was extracted with ether. The extracts were washed with aqueous acetic acid (2×100 ml. of a 10% v/v solution). The acid washings were basified to pH 11-12 with aqueous sodium hydroxide solution and extracted with ether. The ether extracts were dried (MgSO4) and evaporated. The residual oil thus obtained was mixed with an excess of an ethereal solution of maleic acid. The solid thus formed was separated by filtration and crystallised from ethyl acetate to give 2-dimethylamino-ethyl di-(4-chlorophenyl)methyloxyacetate as the maleate salt, m.p. 103°-104°, having the composition C19H21O3NCl2.C4H4O4 by microanalysis, and in 43% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[Si](C)(C)[CH3:14]>CO>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
The mixture of 4-(aminomethyl)benzoic acid (1.0 g, 6.61 mmol) and chlorotrimethylsilane (3.35 mL, 26.44 mmol) was stirred for 30 minutes at room temperature, and anhydrous methanol (20 mL) was added thereto. The reaction mixture was stirred for 48 hours and then vacuum distilled to give methyl 4-(aminomethyl)benzoate (1.25 g, 94%). 1H NMR (500 MHz, D2O) δ 8.02 (d, 2H, J=6.4 Hz), 7.51 (d, 2H, J=8.2 Hz), 4.20 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1nc(-c2cccc(CNS(=O)(=O)c3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (400 mg, 1.0 mmol) and benzenesulfonyl chloride (300 mg, 1.7 mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), and sodium hydrogen carbonate (225 mg, 2.6 mmol) was added thereto. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (162 mg, 38%) as white crystals.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]4[CH2:36][O:35]C(C)(C)[O:33]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:33])[CH2:36][OH:35])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCC(O)CO)c4ccc(OC(F)F)cc34)nc12
Reaction time: 2 h
Yield: 39 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (1 mL) at room temperature and the reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 38% acetonitrile/62% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 46% acetonitrile/54% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3,4-dihydroxybutyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (30 mg, 39% over two steps) as a white solid. MS: (M+H)+=489.1; 1H NMR (300 MHz, DMSO): δ 12.85 (s, 1H), 9.11 (s, 1H), 8.42 (d, 1H, J=3.0 Hz), 8.24 (d, 1H, J=1.2 Hz), 7.92-7.88 (m, 2H), 7.45 (t, 1H, J=9.2 Hz), 7.23 (t, 1H, J=74.4 Hz), 4.67-4.64 (m, 2H), 3.48-3.26 (m, 4H), 2.16-2.10 (m, 4H), 1.86-1.83 (m, 4H), 1.54 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:31])[CH2:8][C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C@H:4]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][C@@H:35]2[C:39]([NH:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:40])=[O:33])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:57](#N)[CH3:58]>C(Cl)(Cl)Cl>[CH:57]1([CH2:58][N:46]2[CH2:45][CH2:44][CH:43]([CH2:42][NH:41][C:39]([C@H:35]3[CH2:36][CH2:37][CH2:38][N:34]3[C:32]([C@@H:4]3[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]3[C:7](=[O:31])[CH2:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:33])=[O:40])[CH2:48][CH2:47]2)[CH2:4][CH2:3][CH2:2][CH2:6]1
Reactant: CC#N
Reactant: O=C(NCC1CCNCC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCN(CC2CCCC2)CC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 19 mg of (2R)-1-((2S,4R)-4-hydroxy-1-{3,3,3-tris(4-fluorophenyl)propanoyl}pyrrolidin-2-yl)carbonyl-N-(4-piperidylmethyl)pyrrolidine-2-carboxamide in 1.5 ml of acetonitrile, 14 mg of methanesulfonic acid-cyclopentylmethyl, 13 mg of potassium carbonate and 5 mg of potassium iodide were added at room temperature, followed by 24 hours' stirring at 80° C. under heating. The reaction liquid was diluted with chloroform, washed successively with water and 1N aqueous sodium hydroxide solution, and drired over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by preparative thin-layer chromatography [Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 16 mg of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16]>CC(N(C)C)=O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1ccncc1F
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccncc1NCc1cccc(F)c1
Temperature: 168 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 3-fluorobenzylamine (308 μL, 2.84 mmol) were combined in DMA (3 mL) and the solution was stirred at 168° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified through a short plug of silica gel chromatography (20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a white precipitate, which was collected by filtration and dried under vacuum to give 58 mg (33%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (br s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247; found 247.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cccc(-c2cccc(C=O)c2)c1

Procedure:
A mixture of (3-bromo-phenyl)-acetic acid methyl ester (5 g), 3-formyl phenyl boronic acid (5 g) and potassium carbonate (9 g) in toluene/methanol [10:1] (33 mL) was degassed with nitrogen for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (1.3 g) was washed with ethanol, under nitrogen, until golden in colour and added to the mixture. The resultant mixture was heated to reflux for 24 hours. On cooling, the reaction was diluted with iso-hexane/diethyl ether [4:1] (100 mL) and filtered through a Celite pad. The filtrate was evaporated and the residue purified on silica, eluting iso-hexane/ethyl acetate [4:1] to give the subtitle product, as an oil (3.7 g).
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].Cl.[OH-].[Na+]>CCOCC.O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]([NH2:5])=[NH:16]
Reactant: N#Cc1cccc(F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N=C(N)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran) was added a solution of 3-fluorobenzonitrile (2.5 g, Aldrich, USA) in 10 mL of anhydrous ether. After standing at room temperature for 2 h, the solution was cooled to 0° C. in an ice bath, and 28 mL of 3 M hydrochloric acid was added slowly. After stirring for 30 min, 100 mL of water was added and the ether layer was discarded. The aqueous layer was made basic with 2 M sodium hydroxide and extracted three times with chloroform. The chloroform layers were combined, dried over magnesium sulfate and concentrated in vacuo to yield 3-fluorobenzamidine (1.27 g) as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[H-].[Na+].Cl.Cl[CH2:19][C:20]1[N:21]([CH3:27])[C:22](=[N:25][CH3:26])[S:23][CH:24]=1>CN(C=O)C>[CH3:27][N:21]1[C:20]([CH2:19][N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[O:1])=[CH:24][S:23]/[C:22]/1=[N:25]\[CH3:26]
Reactant: CN=c1scc(CCl)n1C
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/N=c1\scc(CN2CCNCC2=O)n1C
Yield: 94.4 %

Procedure:
tert-Butyl 3-oxopiperazine-1-carboxylate (1.5 g) was dissolved in DMF (50 mL), and sodium hydride (0.3 g) was added thereto. With ice cooling, N-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine hydrochloride (1.6 g) was added thereto, and the mixture was mixed at 80° C. for 3 hours. The solvent was distilled off, and the residue was poured into water, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-2-piperazinone (1.7 g) as a pale brown oily matter (a crude product). The resulting oily matter was dissolved in concentrated hydrochloric acid (5 mL) and mixed at room temperature for 1 hour. After concentrating the reaction solution, the residue was dissolved in dichloromethane (30 mL), and triethylamine (1.4 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.5 g), HOBt (0.84 g) and WSC (1.0 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.25 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O.CCCCCC>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:27])[CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2N(C)C1C(F)(F)F
Yield: 89.2 %

Procedure:
Ethyl-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 157, Step 2) (1.28 g, 4.21 mmol), tetrabutylammonium iodide (0.36 g, 0.92 mmol) and aqueous NaOH(50%, 2 mL) were stirred vigorously in methylene chloride (40 mL). Dimethyl sulfate (2.12 g, 16.84 mmol) was added to the dark orange mixture via syringe over 2 hours. Hexane (5 mL) was added, and the solution was washed with water (2×20 mL), saturated ammonium chloride solution (2×20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the crude ester as a yellow solid. The solid was purified by flash chromatography (silica gel, 50 g; ethyl acetate-hexanes, 1:19) to yield, upon concentration of the appropriate fractions, ethyl 6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinoline-carboxylate (1.2 g, 90% yield): mp 118–120° C. 1H NMR (CD3OD/300 MHz) 7.71 (s, 1H), 7.30–7.26 (m, 2H), 6.77–6.74 (m, 1H), 5.12 (q, 1H, J=6.8 Hz), 4.44–4.22 (m, 2H), 3.18 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). EIHRMS m/z 320.0701 (M−H, Calc'd 320.0665) Anal. Calc'd for C14H13F3NO2Cl: C, 52.60; H, 4.10; N, 4.38. Found: C, 52.57; H, 4.14; N, 4.32.