Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:31])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:30]=1.[CH3:32][C:33]([OH:37])([C:35]#[CH:36])[CH3:34]>>[C:16]([C:14]1[N:15]=[C:7]2[C:6]3[CH:30]=[C:2]([C:36]#[C:35][C:33]([OH:37])([CH3:34])[CH3:32])[C:3]([F:31])=[CH:4][C:5]=3[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]2[C:13]=1[CH:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20]1)(=[O:18])[NH2:17]
Reactant: CC(C)(C)OC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)C1
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
Similar to as described in General Procedure E, tert-butyl 3-(10-bromo-2-carbamoyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepin-3-yl)azetidine-1-carboxylate was reacted with 2-methylbut-3-yn-2-ol to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Reactant: NCCCO
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(C)cccc3c21
Yield: 50.6 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (1.0 g) and 3-aminopropanol (3.0 g) were heated to 150° C. for 3 hours. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from ethyl acetate/petroleum ether yielded 1-(2-methylphenyl)-4-(3-hydroxypropylamino)-6-methylpyrrolo[3,2-c]quinoline (0.57 g), m.p. 135°-137°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([CH3:11])[CH:13]=1)=[O:6]
Reactant: Cc1cccc(N)c1
Reactant: Nc1ccccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2ccccc2N)c1
Reaction time: 16 h

Procedure:
To a solution of 2-aminobenzoic acid (290 mg) and 3-methylaniline (215 mg) in 10 mL of DMF was added 1-hydroxybenzotriazole (300 mg), EDC (400 mg) and triethylamine (500 μL). The resulting solution was stirred for 16 h. The reaction solution was partitioned with ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 5% citric acid, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13]>C1COCC1>[CH3:11][O:10][C:7]1[CH:6]=[C:4]2[C:3]([CH2:2][NH:1][C:12](=[O:13])[NH:5]2)=[CH:9][CH:8]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc(CN)c(N)c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
2-aminomethyl-5-methoxyaniline (1.2 g. 7.9 mmol) and carbonyl diimidazole (1.53 g, 9.5 mmol) were added to THF (100 ml) and the mixture was stirred at room temperature overnight. The insoluble matter precipitated was obtained by filtration, washed with dichloromethane and water, dried to obtain 7-methoxy-3,4-dihydro-1H-quinazolin-2-one (1.11 g) as white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25]
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)c(Cl)ccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)c(Cl)ccc23)CC1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,8-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 30 min, β-bromophenetole was added (0.31 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (17:3) to give 0.22 g (55%) of a white solid: mp 138.4-139.7° C.; 1H NMR (300 MHz, CDCl3) δ 6.92 (m, 1H), 6.79 (m, 2H), 4.90 (m, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.66 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 2979, 1687, 1467, 1443, 1416, 1365, 1253, 1239, 1223, 1172, 1165, 1156, 923, 808, 760 cm−1; MS (EI) m/z 474 (M+), 420, 418, 332, 86, 84, 57, 56, 55, 51; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.15; H, 6.00; N, 5.89.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:28]=O>COCCOC>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:28]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (1.37 g (9.68 mmol) in anhydrous 1,2-dimethoxyethane (10 ml) is added sodium methoxide (0.575 g, 10.60 mmol) in one portion, followed by stirring at this temperature for 10 minutes. To this slurry is then added a second solution of 4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.60 g, 8.80 mmol) in 1,2-dimethoxyethane (10 ml) dropwise. When addition is complete the reaction mixture is stirred at 0° C. for a further 1 hour, then quenched with 2M hydrochloric acid (50 ml). After stirring for an additional 1 hour the solution is diluted with diethyl ether, the two phases separated, and the aqueous phase further extracted with diethyl ether (×2). The combined organics are further washed with brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to afford 4-[1-(4-bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (3.40 g, 92%) as a yellow gum.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([N:28]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35]([C:37]4[NH:38][C:39]([CH3:44])=[C:40]([Cl:43])[C:41]=4[Cl:42])=[O:36])[C@H:30]([O:45][CH3:46])[CH2:29]3)[S:21][C:22]=2[C:23]([O:25]CC)=[O:24])=[N:16][CH:17]=1.Cl>O1CCCC1.C(#N)C>[Cl:42][C:41]1[C:40]([Cl:43])=[C:39]([CH3:44])[NH:38][C:37]=1[C:35]([NH:34][C@@H:31]1[CH2:32][CH2:33][N:28]([C:20]2[S:21][C:22]([C:23]([OH:25])=[O:24])=[C:18]([C:15]3[CH:14]=[N:13][C:12]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:17][N:16]=3)[N:19]=2)[CH2:29][C@@H:30]1[O:45][CH3:46])=[O:36]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Reactant: OCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CO[C@H]1CN(c2nc(-c3cnc(OCCN4CCCC4)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a stirred solution of 2-(pyrrolidine-1-yl)ethanol (0.102 mL, 0.872 mmol) in dry tetrahydrofuran (20 mL) was added sodium hydride (70 mg, 1.771 mmol) at 0° C. The reaction mixture was heated to 80° C. After 10 min, ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 250 mg, 0.436 mmol) was added to the reaction mixture at 80° C. and further maintained at 80° C. for 10 min. After the completion of the reaction, the reaction mixture was cooled and carefully quenched by adding ice pieces. The aqueous layer was extracted with ethyl acetate (2×50 mL) to get rid of any organic impurities and discarded. The aqueous layer was acidified to pH=2 using 2N HCl solution and was extracted with 10% methanol/dichloromethane (2×100 mL). The organic layer was dried and concentrated under reduced pressure to yield the product. The obtained product was stirred in acetonitrile (10 mL). The solid was filtered and dried to obtain 120 mg (45%) of 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-{5-[2-(pyrrolidin-1-yl)ethoxy]pyrazin-2-yl}-1,3-thiazole-5-carboxylic acid as yellow solid.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].C([O-])(=O)C.[NH4+]>O1CCCC1.O.[Zn]>[OH:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:23]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
Zinc dust (1.3 g, 20.3 mmol) was added to a solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (400 mg, 0.92 mmol) in tetrahydrofuran (20 mL). This suspension was treated with a solution of ammonium acetate (1.1 g, 13.9 mmol) in water (7 mL). After stirring at room temperature for 16 h, the zinc residues were filtered off and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium hydrogen sulfate solution, the aqueous layer was extracted with ethyl acetate (2×), the organic layers were combined and the volatiles were removed in vacuo. The residual acetic acid was azeotroped off with toluene (3×10 mL) to give crude (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (280 mg, 99%) half of which (140 mg, 0.46 mmol) was combined with (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (obtained from ASIBA Pharmatech, Inc.), (194 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.400 mL, 2.3 mmol) in anhydrous acetonitrile (10 mL). This solution was then treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (227 mg, 0.60 mmol). After stirring at room temperature for 3 h, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and subsequently washed with saturated ammonium chloride solution and sodium bicarbonate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (136 mg, 55%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.83 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 1.38 (d, J=6.9 Hz, 3H), 1.60 (d, J=6.9 Hz, 3H), 1.65-1.75 (m, 3H), 1.87-1.96 (m, 1H), 2.02-2.12 (m, 2H), 2.87-3.00 (m, 1H), 3.55-3.62 (m, 1H), 3.81 (d, J=3.4 Hz, 1H), 4.24-4.34 (m, 1H), 5.18-5.28 (m, 1H), 5.31-5.40 (m, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.69 (dd, J=8.7, 1.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.33 (d, J=8.7 Hz, 1H). LCMS (m/z) 534.1, 536.1 [M+H], Tr=2.27 min.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][N:16](C(OCC2C=CC=CC=2)=O)[CH3:17])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][NH:16][CH3:17])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CN(C)C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)CNC)CC1
Reaction time: 12 h

Procedure:
To a solution of 746 mg 4-[2-(Benzyloxycarbonyl-methyl-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester in 10 ml ethanol were added 100 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated. Yield: 570 mg colorless oil
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([OH:9])[CH2:2]2.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([O:9][C:17](=[O:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2]2
Reactant: O=C=Nc1ccccc1
Reactant: O[C@@H]1CN2CCC1CC2
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)O[C@@H]1CN2CCC1CC2
Yield: 90.4 %

Procedure:
A solution of (3S)-(+)-quinuclidin-3-ol (0.50 g, 3.93 mmol) [M. Langlois, C. Meyer, and J. L. Soulier, Synth. Comm., 23, 1895-1911 (1992)], phenyl isocyanate (0.47 mL, 4.32 mmol, 1.1 equivalents), and dibutyltin dilaurate (0.013 mL, 0.08 mmol) in anhydrous toluene (20 mL) was heated at reflux under nitrogen for 1 hour. The resulting reaction mixture was evaporated under reduced pressure, and the resulting solid was placed in 1N HCl (25 mL). The resulting aqueous mixture was extracted with ethyl acetate (2×25 mL), basified to pH 10 with Na2CO3, and extracted with chloroform (3×50 mL). The chloroform extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The resulting solid was recrystallized using toluene (5 mL) to afford the title compound (0.875 g, 90%) as a white solid: mp 129.0-130.0° C.; FAB LRMS m /z (relative intensity, %) 247 (MH+, 39), 110 (100); [α]22D =-7.5° (c=1.0, MeOH).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][C@H:20]1[CH3:34])=[O:18].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:8]([CH:13]=1)[CH2:7][NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)CCNCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CNCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamino)-propionic acid methyl ester (0.035 g, 0.069 mmol) in tetrahydrofuran (0.2 mL), methanol (0.2 mL) and water (0.1 mL) was added lithium hydroxide monohydrate (0.015 g, 0.35 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in dichloromethane and treated with hydrogen chloride gas. The resulting white solid was washed with acetonitrile. The acetonitrile wash was concentrated to give the title compound as its hydrochloride salt (0.010 g, LRMS: 490.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=[C:15]3[S:24][N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:13]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]3[S:24][N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2snc(C)c2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)cnc3snc(C)c23)cc1

Procedure:
Following the procedure of Example 54, a 2.25 g sample of the above ester was hydrolysed with KOH to give 0.46 g of 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylic acid as a white solid, m.p. 234-236° C.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[OH:21][C@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:25]2[CH2:26][C@H:22]([OH:21])[C@H:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:24]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: O=C(N[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Product: O=C(N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@@H]1O)OCc1ccccc1

Procedure:
Prepared as described in Example 9B using (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (1.06 g, 3.08 mmol) and benzyl (3R,4S)-4-hydroxypyrrolidin-3-ylcarbamate (0.802 g, 3.39 mmol) in place of (S)-tert-butyl pyrrolidin-3-ylcarbamate in Step D (1.16 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.I[CH2:21][CH2:22][CH3:23].[H-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:21]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7]1)[CH2:22][CH3:23]
Reactant: CCCI
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1cc(C2CCN(C)CC2)c2cc(OC)cc(C)c21
Yield: 72.2 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmole, 1.50 g), iodopropane (5.81 mmole, 0.987 g, 0.566 mL) in THF (100 mL), potassium hydride (5.81 mmole, 0.665 g), and 18-crown-6 (0.58 mmole, 0.153 g) afforded 1.26 g (72%) of the title compound: mass spectrum (ion spray): m/z=301 (M+1);. Calculated for C19H28N2O-0.3H2O: C, 74.61; H, 9.43; N, 9.16. Found: C, 74.37; H, 9.03; N, 9.01.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 82.9 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (10.68 g, 59.3 mmol; commercial) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound in step H.i.; 12.0 g, 59.3 mmol) in EtOH/H2O (9:1; 320 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure to afford the title intermediate as a brown oil (18.8 g, 83% yield) which was used as such in the next step.
Reaction SMILES: N[C:2]1[C:11](C)=[C:10]2[C:5]([C:6](C)=[CH:7][C:8](C)(C)[NH:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(=O)CC(OCC)=[O:21]>>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:21]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC1=CC(C)(C)Nc2c1ccc(N)c2C
Product: O=c1ccc2ccccc2[nH]1
Yield: 105.4 %

Procedure:
This compound was prepared in a manner similar to that described for Compound 102 (EXAMPLE 2) with 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline (100 mg, 0.49 mmol) and ethyl 4,4,4-trifluoroacetoacetate (107 mL, 0.73 mmol, 1.5 equiv), affording 75 mg (47%) of the desired 2-quinolone as a fluorescent-yellow solid. Data for 1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-f]quinoline: 1H NMR (400 MHz, CDCl3) 9.23 (br s, 1H, CONH), 7.37 (s, 1H, 5-H), 6.67 (s, 1H, 7-H), 5.45 (s, 1H, 3-H), 4.14 [br s, 1H, (CH3)2CNH], 2.12 (s, 3H, 10-CH3), 2.04 (d, 3H, J=1.1 Hz, 4-CH3), 1.37 [s, 6H, 2-(CH3)2 ].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[CH2:34][OH:35])=[O:14])=[CH:8][C:7]=2[CH:36]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:39]([O:35][CH2:34][CH:16]1[CH2:17][N:18]([CH2:21][C:22]2[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:19][CH2:20][N:15]1[C:13]([C:9]1[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:37][CH3:38])[C:3]([O:2][CH3:1])=[CH:36][C:7]=2[CH:8]=1)=[O:14])(=[O:41])[CH3:40]
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1COC(C)=O)=C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
A mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg), acetic anhydride (153 mg), triethylamine (150 mg), 4dimethylaminopyridine (10 mg) and methylene chloride (5 ml) is stirred for 20 hours at room temperature. To the reaction mixture is added methylene chloride, and the organic layer is washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate) to give 2-acetoxymethyl-1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine (420 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless prisms, m.p. 135-139° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[OH:21])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:29][CH2:30][CH2:31][CH3:32]>CC(CC)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:29]([O:21][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC
Reactant: CC(C)Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CCCCOc1cc(-c2ccc(S(C)(=O)=O)cc2)ccc1OC(C)C
Temperature: 40 °C
Yield: 88 %

Procedure:
4-isopropoxy-4′-methanesulfonyl-biphenyl-3-ol (30 mg) and potassium carbonate (20 mg) were dissolved in methylethylketone. Afterward, butane iodide (27 mg) and tetrabutylammoniumiodide (2-3 mg) was added one after another and heated for 24 hours at 40° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (30 mg, productive yield 88%) was obtained.