Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(Cl)c1
Yield: 55.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-on (3.0 g, 9.7 mmol) was reacted with tert-butyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (5.7 g, 14 mmol) to afford the desired product (2.7 g, 56%) as a brown solid: ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13](=O)[CH2:14]Br)[CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOC(=O)c1cc(F)cc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(F)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-fluoro-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-fluoro-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH2:36][O:37][CH2:38][CH3:39])[CH2:27][O:28][Si](C(C)(C)C)(C)C)[N:12]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][CH2:24]2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:25][C@@H:26]([CH2:27][OH:28])[CH2:36][O:37][CH2:38][CH3:39])[N:12]=1
Reactant: CCOC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC[C@H](CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(ethoxymethyl)ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide, (product from step v) (0.79 g) in THF (10 mL) was added a 1M solution of tetrabutylammoniumfluoride in THF (2.4 mL) with stirring, at ambient temperature, for 72 h. The reaction mixture was diluted with H2O and extracted with EtOAc (×2). The organic layer was washed with H2O then brine and dried (MgSO4), filtered and evaporated. The resulting oil was purified by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with DCM followed by ether/iso-hexane to give the title compound as a white solid. Yield: 0.28 g
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[F:16])[CH3:2].Cl>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[F:16])[CH3:2]
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1ccc(N)cc1F
Yield: 45.2 %

Procedure:
A solution of (2-fluoro-4-nitro-phenoxy)-acetic acid ethyl ester (17.0 g, 55.92 mmol) in EtOH (330 ml) and aqueous 1M HCl (55.92 ml, 55.92 mmol) was hydrogenated in the presence of 10% Pd/C (1.7 g) for 2 days. After removal of the catalyst the reaction was evaporated and treated with water/Et2O (3×), the aqueous phase was treated with NaHCO3 and extracted with Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 5.39 g (45%) of (4-amino-2-fluoro-phenoxy)-acetic acid ethyl ester as a brown crystallin residue, MS: 213 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[Na].[CH3:31][S:32]([OH:34])=[O:33]>CC(C)=O>[Cl:28][C:20]1[CH:19]=[C:18]([C@@H:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Reactant: CS(=O)O
Agent: [Na]
Solvent: CC(C)=O
Product: CS(=O)(=O)Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 30, 102.2 mg, 0.20 mmol) in acetone (1 mL) was cooled to 0° C. and then treated with the sodium salt of methanesulfinic acid (31.8 mg, 0.30 mmol). The reaction stirred at 0° C. for 1 h and then at 25° C. for 4 h 20 min. A second aliquot of the sodium salt of methanesulfinic acid (24.0 mg, 0.24 mmol) was added, and the reaction was stirred at 25° C. overnight. The reaction was then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (2×25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfonylmethyl-pyrazin-2-yl)-propionamide (74.9 mg, 73%) as a white foam: mp 91–95° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O5S2 (M+H)+ 500.1075, found 500.1080.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:13](O)CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]1[O:11][CH2:12][CH2:13][CH2:1][O:2]1
Reactant: OCCCO
Reactant: COC(=O)CCCC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)CCCC1OCCCO1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
Methyl 5,5-dimethoxyvalerate (20.0 g, 0.114 mol), propane-1,3-diol (13 g, 0.17 mol) and para-toluene sulphonic acid (2.17 g, 0.0114 mol) were heated under Dean-Stark conditions in toluene (100 ml) for 4 h. The mixture was cooled to room temperature and diluted with diethyl ether (100 ml) and then neutralized with solid sodium bicarbonate. The solid was filtered and the filtrate evaporated to give a pale yellow oil (22.3 g). A 10 g portion of this was then purified by silica gel chromatography (eluent 30% EtOAc:hexane) which gave the title compound as a colourless oil (6.82 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C[O:10][C:11]([C:13]1[O:14][C:15]([CH2:18]Cl)=[CH:16][CH:17]=1)=[O:12]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:18][C:15]1[O:14][C:13]([C:11]([OH:12])=[O:10])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(COCC(F)(F)F)o1
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 60 mg, 1.50 mmol) was added to 2,2,2-trifluoroethanol (99 μL, 1.38 mmol) in anhydrous DMF (1 mL) and the mixture was stirred under nitrogen for 20 min. 5-Chloromethylfuran-2-carboxylic acid methyl ester (200 mg, 1.15 mmol) was then added and the mixture was stirred at room temperature for 18 h, then at 60 C for 3 h, then at 100 C for 3 h. Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added under nitrogen and the reaction mixture was stirred at room temperature for 18 h. Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (30 mL) then washed with saturated aq. sodium bicarbonate (4×6 mL), saturated aq. ammonium chloride (2×6 mL) and then brine (6 mL). The aqueous extractions were combined and brought to pH 1 by the addition of 2M HCl and then extracted with DCM (5 mL). The combined organic extractions were washed with water (3×6 mL), then brine (6 mL) and then dried over sodium sulfate and evaporated under vacuum to afford the title compound (123 mg, 48%), which was used without further purification. Method C HPLC-MS: (MH+) requires m/z=225. Found: m/z=252, Rt=1.15 min (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2Cl.[N+:16]([C:19]1[CH:20]=[C:21]([OH:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])([O-:18])=[O:17]>CO>[N+:16]([C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[O:28][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CO
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2cc1OC
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 6,7-dimethoxy-4-chloroquinoline (0.35 g, 1.6 mmol) and 3,4-dinitrophenol (0.85 g, 4.6 mmol) was heated to 150° C. for 4 h. The mixture was cooled at RT and MeOH added. The reaction was stirred for 3 h. The precipitate filtered out and was washed with MeOH to afford 4-(3,4-dinitrophenoxy)-6,7-dimethoxyquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[CH:48]=[C:49]([CH:53]2[CH2:67][N:57]3[C:58](=[O:66])[NH:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:65]=4[C:56]3=[N:55][CH2:54]2)[CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH:53]2[CH2:67][N:57]3[C:58](=[O:66])[NH:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:65]=4[C:56]3=[N:55][CH2:54]2)[CH:48]=1)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 3-methyl-furan-2-carboxylic acid (2.4 mg, 0.019 mmol), N,N-diisopropylethylamine (0.017 mL, 0.095 mmol), and BOP (10.1 mg, 0.023 mmol) in 0.6 mL DMF was stirred at rt for 1 hour, then 3-(3-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (5.0 mg, 0.017 mmol) added and the reaction continued at rt. After 2.5 hours, a small spatula tip of 3-methyl-furan-2-carboxylic acid and BOP was added and the reaction heated at 60° C. for 1 hour. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The residue was rinsed with 2 portions of 30% EtOAc/hexane and then chromatographed eluting with 10% MeOH/CHCl3. The resulting solid was chromatographed using a prep plate and eluting with 50% acetone/hexane. The obtained solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and evaporated to give the title compound as a white solid (3.2 mg, 47%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.04 (dd, J=8.2, 1.2 Hz, 1H), 7.68 (t, J=1.8 Hz, 1H), 7.60 (ddd, J=8.1, 2.1, 0.9 Hz, 1H), 7.46-7.53 (m, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.16 (ddd, J=8.1, 7.2, 1.2 Hz, 1H), 7.03-7.10 (m, 2H), 6.45 (dd, J=1.8, 0.6 Hz, 1H), 4.48-4.56 (m, 1H), 3.86-3.95 (m, 1H), 3.61-3.74 (m, 2H), 3.07-3.19 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [N:1]([C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6])=[N+]=[N-].[ClH:23].[H][H]>O1CCCC1.O.[Pd]>[ClH:23].[NH2:1][CH:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6]
Reactant: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
To a solution of (R)-α-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (3.5 g, 1.9 mmol) in tetrahydrofuran (75 mL), water (10 mL), and concentrated hydrochloric acid (1 mL) is added palladium on carbon (0.5 g, 20%). The mixture is shaken under 52 pounds per square inch (psi) of hydrogen at 25° C. for 6 hours. Solid is filtered. The filtrate is concentrated in vacuo to give a light green solid, which is recrystallized in 3N hydrochloric acid (with activated charcoal) to give the title compound as a white solid, 2.84 g; mp 313°-314° C. (dec), [α]D =-47.6° (c=1.0, methanol).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(O[C:10]1[C:15]2=[CH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N+:22]=3[CH:23]=[C:14]2[CH:13]=[CH:12][CH:11]=1)(=O)C>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:15]([C:23]1[N+:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:16]=[C:15]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=12)[CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)Oc1cccc2c[n+]3ccccc3cc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: CCCCc1c2ccccc2cc2cccc[n+]12
Yield: 115.8 %

Procedure:
The above 10-acetoxybenzo[b]quinolizinium perchlorate (3.3 g) was dissolved in 500 mL of water, the solution was boiled, and filtered. To the filtrate was added 100 mL of 30% sodium perchlorate solution and the mixture was chilled. The precipitated solid was isolated by filtration and dried in vacuo to afford 1.9 g of 10-acetoxybenzo[b]quinolizinium perchlorate (Formula II: R1 =R2 =H; R7 =10-OAc; X- =ClO4-). The filtrate was extracted with methylene chloride (3×100 mL), the organic layer was dried and concentrated to yield an additional 0.32 g of the desired acetate perchlorate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])(C)C)=[O:14])[CH2:9][CH2:8]1.Cl.C(OC(Cl)=O)[C:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:19]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC(C2CC2CCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Cis tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (2.0 g, 7.44 mmol) was treated with 4M HCl in dioxane (200 mL) at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue taken up in 200 mL DCM. To this solution was added TEA (10.0 mL, 7.64 mmol) followed by benzylchloroformate (1.30 g, 7.64 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was washed with 1N aqueous HCl (75 mL), followed by saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via Biotage (40M+ silica gel) eluting with a gradient of 0-80% ethyl acetate to afford the title compound (2.06 g, 91%) as a viscous oil.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:28]([S:36]([O-:39])(=[O:38])=[O:37])[C:27]1=[O:40])=O)(C)(C)C.C(Cl)Cl>C(O)=O>[NH2:25][C@H:26]1[C@H:29]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:28]([S:36]([OH:39])(=[O:37])=[O:38])[C:27]1=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=CO
Product: N[C@@H]1C(=O)N(S(=O)(=O)O)[C@H]1C1CCCCC1

Procedure:
(trans)-3-(t-Butoxycarbonylamino)-4-cyclohexyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (3.8 g) is stirred in 20 ml of formic acid for 3 hours, followed by the addition of 20 ml of methylene chloride. The precipitated title compound (1.0 g) is filtered off, melting point 217°-219° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=O)[CH3:35].O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2/[CH:12]=[C:34](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)\[CH3:35])=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C(\C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (450 mg, 1.00 mmol) obtained in Example 321b) in THF (5 ml) was added sodium hydride (50% oil dispersion, 75 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of acetophenone (117 μl) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was stirred at 60° C. for 15 hr and cooled to 0° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/4 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (150 mg, 36%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24](OB(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[CH3:20].ClCCl>C(N(CC)CC)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: CCCOCCOc1ccc(OB(O)O)cc1OCC
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 3-ethoxy-4-(2-propoxyethoxy)phenylboric acid (0.80 g), cupric acetate (0.27 g), MS4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 16 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2→2:3) to obtain methyl 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) as a light yellow, oily substance. 1H-NMR (200 MHz, CDCl3) δ0.95 (3H, t, J=7.4 Hz), 1.44 (3H, t, J=7.0 Hz), 1.56-1.70 (2H, m), 3.04-3.11 (2H, m), 3.53 (2H, t, J=6.8 Hz), 3.58-3.65 (2H, m), 3.80-3.85 (5H, m), 4.03 (2H, q, j=7.0 Hz), 4.17-4.22 (2H, m), 6.56-6.63 (2H, m), 6.94-7.04 (3H, m), 7.70 (1H, s), 8.08 (1H, d, J=8.4 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]2)=[CH:14][C:13]=1[O:26][CH2:27][CH3:28]>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=[C:2]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][C:12]([Cl:11])=[C:13]([O:26][CH2:27][CH3:28])[CH:14]=3)[CH2:18][CH2:19]2)[N:3]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: OCc1cc(Cl)nc(Cl)c1
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3cc(CO)cc(Cl)n3)CC2)ccc1Cl
Yield: 4 %

Procedure:
A solution of (2,6-dichloro-pyridin-4-yl)-methanol (44.5 mg, 0.25 mmol, 1.25 equiv; commercially available) and 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (53.8 mg, 0.20 mmol, 1.2 equiv; intermediate A2) in DMF (2.0 mL) was heated by microwave irradiation to 220° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.2 mg (4%) of the title compound. MS (ISP): 410.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][C:13](Cl)=[O:14])=[CH:6]2.C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH:13]=[O:14])=[CH:6]2
Reactant: COc1ccc2[nH]c(CC(=O)Cl)cc2c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(CC=O)cc2c1

Procedure:
A solution of 5-methoxy-2-indolylacetyl chloride (0.1 mol.) in dry tetrahydrofuran is treated with 0.25 mole of lithium aluminum tri-t-butoxy hydride with ice-cooling and stirring. After the initial reaction, the mixture is stirred at room temperature for 4 hours and poured into ice. Excess of acetic acid is added, and the product is extracted with ether. The ethereal solution is washed with sodium bicarbonate, dried over sodium sulfate, and evaporated to a syrup. Chromatography of the residue on a column of silica gel, using ether-petroleum ether (v./v.) 10-30% as eluent, gives 5-methoxy-2-indolyl acetaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](F)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][NH2:16]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([NH:16][CH3:15])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
2-Fluoro-4-methylamino-5-nitro-benzoic acid (750 mg) was prepared by following General Procedure A starting from 2,4-difluoro-5-nitro-benzoic acid (1.0 g) and methylamine (2 M in THF, 2.46 mL) in THF.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1/[CH:14]=[N:15]/[OH:16]>CN(C)C=O.O>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1/[C:14](=[N:15]/[OH:16])/[Cl:8]
Reactant: O/N=C/c1ccccc1OC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccc1OC(F)(F)F

Procedure:
NCS (22 g, 166.04 mmol, 1.12 equiv) was slowly added to a stirred solution of (E)-2-(trifluoromethoxy)benzaldehyde oxime (30 g, 146.27 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL) keeping the internal temperature below 25°C. The reaction mixture was stirred fo(1 h at room temperature. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed with brine (5×300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give (Z)-2-(trifluoromethoxy)benzoyl chloride oxime as a light yellow crystalline solid.