Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][O:22][CH2:23][CH2:24][OH:25])[CH3:20])=[CH:15][N:14]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:27]1[CH:59]=[CH:58][C:30]([CH2:31][CH:32]2[S:36][C:35](=[O:37])[N:34]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:57])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][O:22][CH2:23][CH2:24][O:25][C:27]3[CH:59]=[CH:58][C:30]([CH2:31][CH:32]4[S:36][C:35](=[O:37])[N:34]([C:38]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]4=[O:57])=[CH:29][CH:28]=3)[CH3:20])=[CH:15][N:14]=2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=NOCCO)c1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)nc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)nc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 1.22 g of 2-(1-{2-[N-(4-methylphenylsulfonyl)-N-methylamino]pyridin-5-yl}ethylideneaminooxy)ethanol (prepared as described in Preparation 34), 1.52 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 0.97 g of triphenylphosphine and 0.63 g of diethyl azodicarboxylate, 2.33 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH2:53][OH:54].CN1CCOCC1>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([C:9]([N:11]2[CH2:12][CH:13]([C:15]([NH:51][CH2:52][CH2:53][OH:54])=[O:17])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCCO
Reactant: O=C(O)C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCO)C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic acid (15 mg, 0.03 mmol), prepared using procedures similar to those in Example 1, in N,N-dimethylformamide (2.00 mL) was added HBTU (38 mg, 0.10 mmol). The mixture was stirred for 15 minutes at room temperature followed by the addition of 2-aminoethanol (3.6 μL, 0.06 mmol) and N-methylmorpholine (110 μL, 1.00 mmol). The mixture was allowed to stir at room temperature for 3 d, then diluted the mixture with chloroform (20 mL), and washed with water (30 mL). The aqueous phase was back extracted with chloroform (10 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by high pressure liquid chromatography to afford the title compound (9.20 mg, 58%) as the trifluoroacetic acid salt: 1H NMR (400 MHz, CDCl3): 8.54 (s, 1H), 7.41-7.37 (m, 1H), 7.34-7.31 (m, 1H), 7.18-7.14 (m, 1H), 6.85-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.66 (br, 1H), 4.40-4.24 (br, 3H), 3.83-3.23 (br m, 7H), 1.18 (t, 3H); MS (EI) for C19H17F3IN3O3: 542 (MNa+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CCNC1
Agent: [Pd]
Solvent: CO
Product: c1ccc(-c2cc(-c3cnc4cc(C5CCNCC5)ccn34)ccn2)cc1

Procedure:
3-(2-Phenyl-pyridin-4-yl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-imidazo[1,2-a]pyridine (Ex. 1.190) (1.0 eq, 1.15 mmol, 0.51 g) in dissolved in MeOH (20 ml) and Pd/C (10%, 1.15 eq, 1.32 mmol, 140 mg) and the reaction mixture is hydrogenated at rt for 16 h (4 bar pressure). The solid is removed by filtration and the solvent is evaporated to dryness to yield 3-(2-phenyl-pyridin-4-yl)-7-piperidin-4-yl-imidazo[1,2-a]pyridine as a light yellow solid which did not require any further purification; [M+H]+=391
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].O.O[Li].O.Cl>C1COCC1>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:7])[CH:13]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CNC(=O)c1cc(-c2ccc(C)cc2)ccn1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccnc(C(=O)NCC(=O)O)c2)cc1
Reaction time: 16 h
Yield: 12 %

Procedure:
To a solution of [(4-(4-methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 24, (0.092 g, 0.32 mmol) in THF (2 mL) at room temperature is added H2O (1 mL) and LiOH.H2O (0.027 g, 0.64 mmol). The reaction is stirred for 16 hours after which time the solution is acidified using 1M HCl. The solvents are removed under reduced pressure and the solid that remains is suspended in a mixture of THF: MeOH and filtered. The filtrate is concentrated under reduced pressure and the resulting solid is triturated with MeOH and collected by filtration to provide 0.012 g (12% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, MeOD) δ ppm 8.69 (1H, d, J=4.8 Hz), 8.38 (1H, s), 7.86 (1H, d, J=6.2 Hz), 7.72 (2H, d, J=8.1 Hz), 7.38 (1H, d, J=7.9 Hz), 4.21 (1H, s), 2.44 (2H, s). HPLC-MS: m/z 271 [M+H]+.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:75]=[CH:74][CH:73]=[C:72]3[C:68]=2[CH:69]=[CH:70][NH:71]3)[C:56]=1[CH3:76].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:75]=[CH:74][CH:73]=[C:72]5[C:68]=4[CH:69]=[CH:70][NH:71]5)[C:56]=3[CH3:76])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Cc1c(-c2cccc3[nH]ccc23)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccc3[nH]ccc23)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.049 mmol), 2,5-dimorpholinopyridin-3-amine (0.096 g, 0.37 mmol), 4-chloro-5,7-difluoro-2-(1H-indol-4-yl)-3-methylquinoline (0.1 g, 0.30 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) in toluene (3.04 mL) was added sodium t-butoxide (0.073 g, 0.760 mmol). The reaction mixture was heated to 120° C. and stirring continued for 7 h. The reaction was cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-2-(1H-indol-4-yl)-3-methyl-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (1H, br. s.), 7.81 (1H, br. s), 7.66 (2H, br. s.), 7.51 (1H, m), 7.32 (1H, br. s), 7.19-7.26 (2H, m), 7.05 (1H, br. s.), 6.44 (1H, br. s.), 6.31 (1H, br. s.), 3.92 (4H, br. s), 3.80-3.88 (4H, m), 3.27 (4H, br. s), 3.02-3.14 (4H, m), 2.02 (3H, s). Mass Spectrum (ESI) m/e=557.2 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:42]=[C:43]=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([NH:42][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCCCCCCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, octyl isocyanate (0.44 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The slurry mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(octylamino)carboxamide (0.46 g, 56%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.85-7.68 (m, 3H), 6.43 (t, J=6.0 Hz, 1H), 6.13 (t, J=5.6 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.02-2.83 (m, 3H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.36-1.24 (m 12H), 0.85 (t, J=6.2 Hz, 3H); 13C NMR (DMSO-d6) δ 172.75, 169.82, 167.57, 167.03, 157.99, 141.19, 134.57, 133.33, 131.50, 126.95, 121.61, 48.82, 39.32, 38.83, 31.21, 30.93, 29.92, 28.73, 28.69, 26.37, 22.07, 21.98, 13.93; Anal. Calcd. For C23H30N4O5: C, 62.43; H, 6.83; N, 12.66. Found: C, 62.27; H, 6.94; N, 12.54.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.C[S:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17]2>CN(C=O)C>[S:10]1[C:15]2=[C:16]3[C:20](=[CH:21][CH:22]=[C:14]2[O:13][CH2:12][CH2:11]1)[NH:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17]3
Reactant: CCOC(=O)c1cc2cc(OCCSC)ccc2[nH]1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)OCCS3
Temperature: 25 °C
Yield: 71.1 %

Procedure:
NCS (0.048 g, 0.358 mmol) was added to a DMF (2 mL) solution of ethyl 5-{[2-(methylthio)ethyl]oxy}-1H-indole-2-carboxylate (0.100 g, 0.358 mmol) and the reaction mixture stirred over the weekend at room temperature. The reaction mixture was partitioned between water and EtOAc and the organic layer was separated. The organic layer was dried over MgSO4, filtered and evaporated onto silica. Purification was accomplished by silica gel column chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.067 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.38 (br. s., 1H), 7.11 (s, 1H), 7.04 (d, 1H), 6.85 (d, 1H), 4.35-4.47 (m, 4 H), 3.16-3.24 (m, 2H), 1.41 (t, 3H). LCMS: m/z=264 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)[C:6]=1[C:7]([O:9]C)=O.[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:25].Cl.C(O)(=O)C>C(OCC)C>[CH3:23][O:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:5]2[C:6]3[C:7](=[O:9])[NH:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:1][C:2]=3[CH:3]=[N:4]2)=[CH:15][CH:16]=1)=[O:21]
Reactant: COC(=O)c1ccc(OCCn2ncc(N)c2C(=O)OC)cc1
Reactant: CCOC(=O)C#N
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1nc2cnn(CCOc3ccc(C(=O)OC)cc3)c2c(=O)[nH]1
Temperature: 90 °C
Yield: 67.8 %

Procedure:
Methyl 4-amino-1-[2-({4-[(methyloxy)carbonyl]phenyl}oxy)ethyl]-1H-pyrazole-5-carboxylate (2.18 g, 6.83 mmol) and ethyl cyanoformate (811 mg, 8.18 mmol) were added to 1N hydrogen chloride-acetic acid (40 mL), and the mixture was stirred under heating at 90° C. for 4 hr. After the mixture was allowed to cool, diethyl ether was added, and the precipitated crude crystals were collected by filtration, and washed with diethyl ether to give the title compound (1.79 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([Br:19])=[C:16](Br)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][CH:16]=[C:15]([Br:19])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c(Br)[nH]1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c[nH]1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of intermediate 47 (75.93 mmol) in dry tetrahydrofuran (300 mL) at −78° C. under nitrogen was added n-butyllithium 2.5M solution in hexane (275 mmol). After completion of addition, the mixture was stirred under nitrogen between −70° C. and −80° C. for 30 min, and then allowed to warm up to −60° C. The reaction was carefully quenched with methanol (20 mL), maintaining the temperature below −40° C. The reaction mixture was then allowed to reach to 0° C., and water (100 mL) and ethyl acetate (100 mL) were added. The layers were separated and the organic was washed sequentially with a diluted HCl solution and brine. After evaporation in vacuo of the organic layer, the residue was purified by silica gel chromatography (eluent: DCM to DCM/methanol (1%)) to give compound 48 as a white foam in 52% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.16-1.37 (2s, 9H), 1.78-1.94 (m, 3H), 2.08-2.21 (m, 1H), 3.26-3.34 (m, 1H), 3.42-3.50 (m, 1H), 4.63-4.74 (m, 1H), 7.07-7.10 (m, 1H), 12.09-12.13 (m, 1H); MS (ESI, EI+) m/z=316.23-318.24 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[BH3-]C#N.[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CO>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A suspension of glycine ethyl ester hydrochloride (10.0 g, 71.6 mmol) and NaBH3CN (5.00 g, 79.6 mmol) in MeOH (60 mL) was treated dropwise over 15 min with p-anisaldehyde (11.0 mL, 90.4 mmol). After stirring at room temperature overnight, the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 (200 mL) and saturated aqueous NaHCO3 (300 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 90:10 to 50:50) gave the title compound (7.77 g, 49%) as a colorless liquid: MS (ESI) m/e 224 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.[Na+]>OCC(CO)O>[OH:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]2[C:3]=1[CH:19]=[CH:14][CH:15]=[N:1]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: COc1ccc(O)cc1N
Agent: [Na+]
Solvent: OCC(O)CO
Product: COc1ccc(O)c2cccnc12

Procedure:
Following the same procedure as in Example 23-(a), reaction and treatment were carried out using 2.25 g of 3-amino-4-methoxyphenol, 3.7 ml of glycerol and sodium m-nitrobenzene sulfonate to obtain 180 mg of 5-hydroxy-8-methoxyquinoline.
Reaction SMILES: [H-].[Na+].CS(C)=O.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=1.Br[CH2:22][CH2:23][CH2:24]Br>C(OCC)C.C(O)(C)C.O>[F:7][C:8]([F:19])([F:20])[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:17]#[N:18])[CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:15]=1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To sodium hydride (4.4 g, 110 mmol) was slowly added DMSO (100 mL) at 0° C. The mixture was warmed to room temperature and stirred for 10 minutes. A solution of 2-(4-(trifluoromethoxy)phenyl)acetonitrile (10.05 g, 50 mmol) and 1,3-dibromopropane (11.0 g, 55 mmol) in diethyl ether (50 ml) was added over 30 min at ≦30° C. Near the end of the addition, the mixture became very thick purple slurry that could not be stirred. An additional 50 mL of DMSO was added. After stirring for 75 min at room temperature, the reaction was complete according to LCMS. The reaction mixture was diluted with 25 mL of isopropanol and 15 mL of water, and extracted with ether. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give the title compound. (10.85 g yield 90%).
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([S:32]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Oc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 24 mg (0.15 mmol) of butanesulfonyl chloride. 48 mg (72% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH:15]([CH3:17])[CH3:16])[S:5]1(=[O:19])=[O:18].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]=3)=[CH:26][NH:27]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O>[F:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][N:4]4[C:9]5[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=5[CH2:7][N:6]([CH:15]([CH3:17])[CH3:16])[S:5]4(=[O:19])=[O:18])[CH2:32][CH:31]=3)=[CH:26][NH:27]2)=[CH:23][CH:22]=1
Reactant: CC(C)N1Cc2ccc(F)cc2N(CCCl)S1(=O)=O
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)N1Cc2ccc(F)cc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: 100 °C
Reaction time: 64 h

Procedure:
To a 25 ml two-necked flask equipped with a reflux condenser and in Argon atmosphere, were added 1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(678 mg, 2.2 mmol), 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (523 mg, 242 mmol), anhydrous K2CO3 (1.09 g, 11 mmol) and 10 ml of deionised water. The mixture was vigorously stirred under Argon for 64 hours at 100° C., allowed to reach room temperature and extracted with EtOAc (3×25 ml). The combined organic extracts were dried (Na2SO4) and solvent removed at reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:hexane 1:3) affording 3,4-dihydro-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-7-fluoro-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale yellow solid, m.p. 103-105°.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.O>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([CH2:15][OH:16])=[N:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ncc(-c2ccc(F)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ncc(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
NaBH4 (138 mg, 3.6 mmol) was added to a solution of 5-(4-fluorophenyl)-1,3-oxazole-2-carbaldehyde (0.58 g, 3.03 mmol) in methanol (10 ml). The mixture was stirred at room temperature for 2 hours, then poured into water (50 ml), extracted with DCM (30 ml), washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to afford 460 mg (79%) of the title compound: δH (360 MHz, CDCl3) 2.57 (1H, m), 4.79 (2H, d, J 5.5) 7.12 (2H, t, J 8.5), 7.24 (1H, s), 7.60-7.64 (2H, m); m/z (ES+) 194 (MH+).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.[OH:17][CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:23]2[CH:24]=[C:19]([CH2:18][OH:17])[CH:20]=[CH:21][CH:22]=2)=[N:11][CH:12]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cccc(CO)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
92 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium are added to a suspension, kept under nitrogen, of 849 mg (4.0 mmol) of tripotassium phosphate, 344 mg (2.0 mmol) of 2-bromo-5-methylpyridine and 304 mg (2.0 mmol) of 3-hydroxymethylbenzeneboronic acid in 12 ml of dioxane and 1 ml of water, and the mixture is heated at the boil with stirring for 18 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: [3-(5-methylpyridin-2-yl)phenyl]methanol as yellowish oil; LCMS 200.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[NH:4]1)=[CH2:2].[CH2:11]([O:18][C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:20]=1[N:26]1[S:30](=[O:32])(=[O:31])[N:29](CC[Si](C)(C)C)[C:28](=[O:39])[CH2:27]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:11]([O:18][C:19]1[CH:24]=[C:23](/[CH:2]=[CH:1]/[CH:3]2[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[NH:4]2)[CH:22]=[CH:21][C:20]=1[N:26]1[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:39])[CH2:27]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC1CCCS(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccc(/C=C/C3CCCS(=O)(=O)N3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
A mixture of 3-vinyl-[1,2]thiazinane 1,1-dioxide (107 mg, 0.664 mmol) (J. Org. Chem. 69, 6377 (2004)), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (250 mg, 0.563 mmol), Pd(OAc)2 (13 mg, 0.058 mmol) and triethylamine (0.768 mL, 5.51 mmol) in MeCN (4 mL) is heated at 120° C. for 1.5 h in a microwave apparatus. The reaction mixture is concentrated and the residue purified by preparative HPLC to afford the title compound.