Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].O.CO[C:39]1C=CC=C(OC)[C:44]=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:9]1[CH:10]=[C:2]([CH:39]=[CH2:44])[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8]=1[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a suspension of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (2.1 g, 4.8 mmol), vinylboronic anhydride pyridine complex (3.5 g, 14.5 mmol) and K2CO3 (6.7 g, 48.4 mmol) in toluene (10 mL)/H2O (4 mL) were added Pd(OAc)2 (0.22 g, 0.97 mmol) and S-Phos (CAS; 657408-07-6) (0.80 g, 1.9 mmol), and then the mixture was stirred at 90° C. under N2 atmosphere for 4 h. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and partitioned. The organic phase was washed with H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by SiO2 column chromatography (heptane/EtOAc=95/5 to 7/3) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.78 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.59 Hz, 2H), 7.26-7.38 (m, 3H), 7.13 (dd, J=11.12, 17.43 Hz, 1H), 6.95 (d, J=3.79 Hz, 1H), 5.70 (dd, J=1.26, 17.43 Hz, 1H), 5.31 (dd, J=1.26, 11.12 Hz, 1H), 4.93 (d, J=11.37 Hz, 1H), 4.72 (d, J=11.37 Hz, 1H), 4.56-4.66 (m, 1H), 3.78-3.92 (m, 1H), 3.35-3.57 (m, 1H), 2.57 (s, 3H), 2.35 (s, 3H), 1.56-1.75 (m, 2H), 1.38-1.56 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1ccnc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To (S)-tert-butyl 1-(1H-imidazol-2-yl)-2-phenylethylcarbamate (120 mg, 0.42 mmol) in DMF (1 mL) was added 1-(bromomethyl)-2-methoxybenzene (58 μL, 0.42 mmol), K2CO3 (70 mg, 0.5 mmol) and TBAI (5 mg) and heated to 90° C. After stirring for 1 hr and cooling to ambient temperature, the reaction was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 408.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]#[N:9])[N:6]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[CH:26][C:19]=23)O1.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CCOC(C)=O>[C:27]([N:24]1[C:20]2=[N:21][CH:22]=[CH:23][C:18]([C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]#[N:9])[N:6]=3)=[C:19]2[CH:26]=[N:25]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)OB(c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Reactant: N#CCc1csc(Br)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1csc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 150 °C
Yield: 60.4 %

Procedure:
A mixture of 2-(2-bromothiazol-4-yl)acetonitrile (575 mg, 2.832 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine (1.840 g, 3.398 mmol), Na2CO3 (4.248 mL of 2 M, 8.496 mmol) and tetrakis(triphenylphosphine) Palladium(0) (130.9 mg, 0.1133 mmol) was heated in the microwave at 150° C. for 20 minutes. The reaction mixture was treated with water/EtOAc and extracted twice. The organics were dried (MgSO4), filtered, concentrated and purified (1:1 Petroleum ether/EtOAc,). The mixture was recolumned (Petroleum ether) to give the desired pure product (827 mg, 60% Yield). 1H NMR (CDCl3, 400 MHz) δ 4.04 (2H, s), 7.47 (2H, m), 8.34 (1H, m), 8.75 (1H, m); MS (ES+) 484.12
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (prepared as in Example 89, 1.73 g, 5 mmol) in tetrahydrofuran/water (20 mL, 3:1) was treated with lithium hydroxide (419 mg, 10 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with water (50 mL) and extracted with ether (1×50 mL). The aqueous layer was acidified to pH=2 with a 2N aqueous hydrochloric acid solution. The product was extracted into methylene chloride (3×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (3×100 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with 90/10 hexanes/ether to afford 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (1.05 g, 63.65%) as a white solid: mp 105–106° C.; EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1055.
Reaction SMILES: [C:1]([Si:5]([CH3:43])([CH3:42])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([CH:17]([OH:33])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3O)[CH2:14][CH2:13][O:12][C:11]=2[CH:41]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:43])([CH3:42])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]3[CH:17]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:23]=4)[O:33][C:35]4[C:34](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:15]=3[CH2:14][CH2:13][O:12][C:11]=2[CH:41]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC(c1ccccc1O)=C2C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC1=C2C(c2ccc(OCCN3CCCCC3)cc2)Oc2ccccc21

Procedure:
Following the procedure described in Examples 76, 2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol, the compound prepared as in Example 105 above, was reacted with 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine to yield 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol as a crude oil. The crude 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol was then further treated with HCl (12N, 4 eq., 0.67 mL) in toluene (100 mL) to generate yield 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine as a crude oil. The crude 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine was then further treated with HF•Pyridine (70% HF, 30% Pyridine, 0.5 mL) in CH3CN (20 mL) at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate:THF (1:1) and then washed with 5% NaHCO3 and brine. The reaction mixture was dried, concentrated and purified by flash chromatograph eluted with 5% MeOH in DCM to yield the title compound as a slightly yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([N:33]([CH:35]([CH3:37])[CH3:36])[CH3:34])=[O:32])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl.CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([N:33]([CH:35]([CH3:37])[CH3:36])[CH3:34])=[O:32])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-isopropyl-N-methylpropionamide (0.114 g, 0.2 mmol) in THF (2 mL) is added a 0.5M solution of TBAF (0.84 mL) in THF. The mixture is refluxed for 1 h, then allowed to cool to RT. To the mixture is added 1N HCl and EtOAc. The organic phase is washed with 1N HCl and sat. NaCl. The solution is dried over sodium sulfate and the solvent removed under reduced pressure to afford the title compound. This is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(Cc2ccccn2)CC1

Procedure:
Using General Procedure B, reaction of COMPOUND 249, pyridine-2-carboxaldehyde and NaBH(OAc)3 in CH2Cl2 gave COMPOUND 252 as an amber solid. 1H NMR (CDCl3) δ 1.84-1.87 (m, 4H), 1.92-2.00 (m, 2H), 2.09 (s, 6H), 2.45-2.50 (m, 1H), 2.95 (d, 2H, J=10.2 Hz), 3.60 (s, 2H), 3.84 (s, 4H), 7.04-7.09 (m, 2H), 7.12-7.17 (m, 1H), 7.33-7.39 (m, 2H), 7.61-7.67 (m, 1H), 8.34 (d, 2H, J=3.0 Hz), 8.55 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.39, 27.28, 54.32, 55.20, 57.77, 64.99, 122.26, 122.61, 123.50, 133.78, 136.69, 138.26, 146.19, 149.60, 157.92, 159.31. ES-MS m/z 402 (M+H). Anal. Calcd. for C25H31N5.1.0H2O: C, 71.57; H, 7.93; N, 16.69. Found: C, 71.73; H, 7.99; N, 16.54.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[CH3:23][N:20]1[C:19]([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[N:18][C:17]2[C:21]1=[N:22][C:14]([N:13]1[C:12]3[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=3[N:10]=[C:9]1[NH:8][CH3:1])=[N:15][C:16]=2[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: CN(Cc1ccccc1)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 16.6 %

Procedure:
A mixture of 2-(1-((2-(2-(benzyl(methyl)amino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol 205 (0.2 g, 0.33 mmol) and palladium on carbon (10 wt %, 0.1 g) and acetic acid (0.1 mL) in ethanol (10 mL) was stirred under a hydrogen atmosphere at 60 degrees for 18 hours. The reaction mixture was then filtered though celite and concentrated. The crude product was purified by RP-HPLC to give 206 (28.5 mg, 17%). LCMS m/z: 520.3 (MH+)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.[P:30]([O-:35])([O:33][CH3:34])[O:31][CH3:32].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:32][O:31][P:30]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:9][CH:8]=1)(=[O:35])[O:33][CH3:34]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(OS(=O)(=O)C(F)(F)F)cc4)c3c2)o1
Reactant: COP([O-])OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COP(=O)(OC)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Yield: 54.9 %

Procedure:
A solution of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenyl trifluoromethanesulfonate (391 mg, 0.900 mmol), dimethyl phosphite (0.165 mL, 1.80 mmol), tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.0900 mmol) and N,N-diisopropylethylamine (0.314 mL, 1.80 mmol) in toluene (5 mL) was stirred at 100° C. for 2 hr under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (190 mg, yield 55%) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[O:12][CH2:13][CH3:14])[NH2:8])(=[O:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([NH:8][C:30](=[O:31])[O:32][CH:33]([CH3:35])[CH3:34])[CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[O:12][CH2:13][CH3:14])(=[O:3])[CH3:2]
Reactant: CCOc1cc(N)cc(OC(C)=O)c1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(NC(=O)OC(C)C)cc(OC(C)=O)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
3-Acetyloxy-4,5-diethoxyaniline (1.0 g) and N,N-diethylaniline (0.70 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.70 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-acetyloxy-4,5-diethoxyphenyl)carbamate (Compound No. 4) (1.21 g) in a yield of 88.9%. M.P., 108°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6]>CO.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[C@H:5]([OH:7])[CH3:6]
Reactant: COC(=O)C(C)(C)C(C)=O
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: COC(=O)C(C)(C)[C@@H](C)O
Temperature: 30 °C
Reaction time: 40 h
Yield: 93.5 %

Procedure:
The reaction is carried out in a 100-mL autoclave. 2,2-Dimethyl-3-oxo-butyric acid methyl ester (4.0 g, 27.8 mmol) is dissolved in 35 mL of degassed methanol under Argon atomosphere. Dichloro[(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium (II) (230.0 mg, 0.28 mmol) is added and the reaction mixture is purged with nitrogen twice and once with hydrogen. The autoclave is pressurized with hydrogen to 500 psi and stirred at 30° C. for 40 h. After this time, the reaction mixture is filtered through celite and concentrated under reduced pressure to provide 3.8 g of the title compound as a green oil with ee of 96%. Yield: 95%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (3H, d, J=6.4 Hz), 1.2 (6H, d, J=5.2 Hz), 2.6 (1H, br. s), 3.7 (3H, s), 3.9 (1H, q, J=6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:5][CH:6]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:12]([C:9]1[S:8][C:7]([C:4]2[O:3][C:2]([CH3:1])=[CH:6][CH:5]=2)=[CH:11][CH:10]=1)(=[O:14])=[O:13]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)o1
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)o1
Yield: 53.1 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methylisoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10% MeOH/CHCl3, gave 45 mg of the pure sulfonamide as a brown semisolid (54% yield, m.p. 123-124° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH2:12][OH:13].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]=[O:13]
Reactant: Cn1cc2c(CO)c(Br)ccc2n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1cc2c(C=O)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
(5-Bromo-2-methyl-2H-indazol-4-yl)methanol (324 mg, 1.34 mmol) and o-iodoxybenzoic acid (414 mg, 1.48 mmol) were dissolved in dimethyl sulfoxide (6.7 mL), and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (311 mg, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[N:13][CH:14]=1.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>N1C=CC=CC=1.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH:12]=[N:13][CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NCCc1cncc(-c2cccc(Cl)c2Cl)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)NCCc1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a solution of 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)ethanamine (35 mg, 0.131 mmol) in pyridine (3 ml) at 0° C. was added ethanesulfonyl chloride (0.037 ml, 0.393 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via PTLC (eluent; 60% EtOAc/Heptane, v/v) gave N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)ethyl)ethanesulfonamide (8.1 mg, 0.023 mmol, 17% yield).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C=O)C>[C:31]([N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:19]([CH:16]2[CH2:17][CH2:18][N:13]([C@H:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH:6]=[CH:5][CH:4]=[C:3]5[CH2:2]3)[CH2:14][CH2:15]2)[C:20]1=[O:28])(=[O:33])[CH3:32]
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)n1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (6.2 g, 16.8 mmol) was dissolved in DMF (60 ml). Sodium hydride (0.9 g, 60%) was added and the suspension was stirred at 50° C. for 30 min. It was cooled to room temperature and acetyl chloride (1.5 g, 19 mmol) was added and the mixture was stirred for 3 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (6.3 g) as pale-yellow crystals
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:16]([O:19][C:20](Cl)=[O:21])[CH:17]=[CH2:18]>O>[CH2:16]([O:19][C:20]([NH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:21])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: NCc1ccc(OCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)NCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.97 g of 4-aminomethylphenoxyacetic acid is suspended in 15 ml of water, 2.4 ml of 5N NaOH solution are added thereto and, after cooling with ice, 0.63 ml of chloroformic acid allyl ester is added thereto over a period of 5 minutes After removing the cooling bath, the reaction mixture is stirred at room temperature for 20 minutes. The reaction mixture is then washed twice with ethyl acetate, and the aqueous phase is adjusted to pH 2 with 4N HC1 and extracted with ethyl acetate. The organic solution is washed with brine and dried over sodium sulphate. The title compound is obtained after evaporating off the solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH:26]([NH:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1)=[O:27]>>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:32]3[CH2:33][CH2:34][O:35][CH:30]([CH2:29][NH:28][CH:26]=[O:27])[CH2:31]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=CNCC1CNCCO1
Product: O=CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(formylaminomethyl)morpholine, the reaction is similarly carried out as Example 26 to give 1-(2,4-difluorophenyl)-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid, melting at 230°-233° C. with decomposition.