Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[NH:4][N:3]=1.[CH2:22](Cl)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:3]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[N:4]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)[nH]n1
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)nn1CC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
3-Amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole (180 mg, 0.633 mmol), phenacyl chloride (150 mg, 0.94 mmol) and potassium carbonate (180 mg, 1.27 mmol) were stirred overnight at room temperature in N,N-dimethylformamide (10 mL). The mixture was stirred for further 1 hour at 80° C. The reaction solution was cooled down to room temperature and ethyl acetate was added thereto. The reaction solution was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to remove the solvent. The residue was separated and purified by a silica gel column chromatography (C-300, methanol:chloroform=1:50 to 1:30) to obtain the title compound (26.5 mg, 10.4%) as a cis and trans mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21].BrC1C=[C:27]2[C:32](=CC=1)[NH:31][C:30](=O)[C:29](OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:31]([CH2:32][CH3:27])[CH2:30][CH3:29])[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)c1c(Oc2ccccc2)c(Cl)nc2ccc(Br)cc12
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Product: CCN(CC)c1nc2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccccc1
Temperature: 100 °C

Procedure:
The title compound was prepared using 6-bromo-2-chloro-3-phenoxy-4-(trifluoromethyl)quinoline (Intermediate 8, step b) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d except the reaction mixture was heated at 100° C. under reflux condenser for 2.5 hours.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ncn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)ncn3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-6-(4-amino-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylate obtained in Example (174d) (53.5 mg, 0.2 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (32 mg, 0.18 mmol), WSC hydrochloride (105 mg, 0.55 mmol) and HOBt (24.7 mg, 0.18 mmol), to obtain 62.2 mg of the title compound as a yellow oily substance (81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:19])[F:18])[CH:7]=1.C(N(CC)CC)C.C[O:30][C:31](=O)[C:32]1[C:37]([NH:38][C:39]([CH:41]2[CH2:43][CH2:42]2)=[O:40])=[CH:36][CH:35]=[C:34]([Cl:44])[C:33]=1[CH2:45]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:18])[F:19])[CH:7]=1)[N:20]1[CH2:45][C:33]2[C:32](=[C:37]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[CH:36]=[CH:35][C:34]=2[Cl:44])[C:31]1=[O:30]
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OC(F)F)c1
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2c(Cl)ccc(NC(=O)C3CC3)c2C1=O
Temperature: 90 °C
Yield: 17.2 %

Procedure:
To a solution of 3-amino-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid methyl ester (50 mg, 0.16 mmol) and triethyl amine (0.09 ml, 3.1 mmol) in DMF (2 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (67 mg, 0.19 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester as a off-white solid (15 mg, 17%). mp, 175-177° C.; 1H NMR (CDCl3): δ 0.88-0.94 (m, 2H, cyclopropyl ring CH2), 1.07-1.13 (m, 2H, cyclopropyl ring CH2), 1.65-1.68 (m, 1H, cyclopropyl ring CH), 3.14 (dd, J=6, 15 Hz, 1H, CHHCO), 3.28 (dd, J=10, 15 Hz, 1H, CHHCO), 3.70 (s, 3H, OCH3), 4.13 (d, J=17 Hz, 1H, CHHN), 4.36 (d, J=17 Hz, 1H, CHHN), 5.79-5.85 (m, 1H, CHN), 6.23 (t, JH-F=75 Hz, 1H, OCF2H), 6.26 (t, JH-F=75 Hz, 1H, OCF2H), 7.28-7.41 (m, 4H, Ar), 8.45 (d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO); 13C NMR (CDCl3): 8.45, 15.25, 16.16, 36.46, 46.34, 51.62, 52.31, 65.38, 111.38, 111.42, 115.57, 115.61, 118.64, 119.76, 119.80, 121.76, 121.81, 122.77, 125.45, 133.14, 136.89, 137.03, 138.86, 142.29, 142.21, 168.79, 170.20, 172.73; Anal. Calcd. for C24H21ClF4N2O6: C, 52.90; H, 3.88; N, 5.14; Found: C, 52.78; H, 3.80; N, 5.01;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cl-].[CH3:14][O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=1[O:15][CH3:14])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(O)ccc2cc(Br)ccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-bromo-2-naphthol and 1-(2-methoxy-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([CH2:43][NH2:44])[CH:41]=[CH2:42]>>[CH2:40]([CH2:43][NH:44][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1)[CH:41]=[CH2:42]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: C=CCCN
Product: C=CCCNCCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 15.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and allylmethylamine (13 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:36])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2c(C)noc2C)c1
Yield: 53 %

Procedure:
By carrying out the operation analogously to example 13, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected product is obtained in the form of a pink powder with a yield of 53%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[CH3:23])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Cn1ncc2c(CCl)cccc21
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCc2cccc3c2cnn3C)c(C=O)c1
Yield: 64.8 %

Procedure:
A mixture of 2-hydroxy-5-methoxybenzaldehyde (170 mg, 1.12 mmol), 4-(chloromethyl)-1-methyl-1H-indazole (1.12 mmol), and K2CO3 (618 mg, 4.48 mmol) was reflux in CH3CN (20 mL) for 2 h. The mixture was filtered and the solid was washed with DCM. The filtrate was concentrated and purified on silica gel using a mixture of EtOAc and MeOH as eluent to give 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde (215 mg, 81% for three steps) as a white solid. 1H NMR (400 MHz; DMSO) δ=10.39 (s, 1H), 8.20 (d, 1H), 7.63 (d, 1H) 7.36-7.64 (m, 2H), 7.23-7.29 (m, 2H), 7.18 (d, 1H), 5.58 (s, 2H), 4.06 (s, 3H), 3.34 (s, 3H). LRMS (M+H+) m/z 297.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S@:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:7]1[C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=[C:8]1[S@:10]([CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1)=[O:11])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OCCN(C)C(=O)n1c([S@@](=O)Cc2ncc(C)c(OC)c2C)nc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution (10 mL) of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.34 g) synthesized by the method described in Synthetic Example 1 of Japanese Patent Application under PCT laid-open under kohyo No. 10-504290 in tetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at 60° C. for 6 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a 3:2 mixture (0.92 g) of the title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.Cl.[N+](C([N+]([O-])=O)=O)([O-])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)CCI)cc1
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Agent: Cl
Agent: O=C([N+](=O)[O-])[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CCC(Cc2ccc(OC)c(OC)c2)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.23 h

Procedure:
To a solution of 15 g. (0.071 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 200 ml. of dry tetrahydrofuran was added 33.45 g. (0.08 mole) of 40% Triton B at room temperature. The solution was stirred at room temperature for 14 minutes under N2. 22.6 g. (0.071 mole) of 1-iodo-5-(4-methoxyphenyl)-3-pentanone was then added in portions. The mixture was heated at 50°-55° for 2 hours under N2 until no more starting material was detected on TLC, and then cooled to room temperature. The resulting reaction solution was poured into cold dil. HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4. The crude material was chromatographed on Florisil to provide 22 g. of desired nitro ketone derivative. Recrystallization from 80% ethanol gave a white solid which has m.p. 87°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][CH3:12])=[C:6]([CH:8]=1)[NH2:7].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][CH3:12])=[C:6]2[C:8]=1[C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[NH:7]2
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCOc1ccc(F)cc1N
Solvent: c1ccccc1
Product: CCCOc1ccc(F)c2c(=O)cc(C)[nH]c12
Temperature: 25 °C
Yield: 43.2 %

Procedure:
Amberlyst 15 (1.0 g, a product of Sigma Aldrich Corp.) was added to a benzene solution (200 ml) of 5-fluoro-2-propoxyaniline (10 g, 59 mmol) and ethyl acetoacetate (7.7 g, 59 mmol). The mixture was stirred while heating under reflux for 6 hours and using a Dean-Stark trap. The reaction mixture was cooled to room temperature, the resin was removed by filtration, and the filtrate was concentrated under reduced pressure. Diphenyl ether (20 ml) was added to the residue. The mixture was heated using a mantle heater and stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter obtained by the addition of n-hexane-ethyl acetate (2:1) was collected by filtration. The substance remaining on the filter was washed with n-hexane-ethyl acetate (2:1), and dried to thereby obtain 6.0 g of powdery pale yellow 5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one (yield: 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH2:22])=O)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.[Si]([N:36]=[N+:37]=[N-:38])(C)(C)C>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]4[NH:22][N:38]=[N:37][N:36]=4)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[S:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(N)=O)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: COCCOC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnn[nH]3)cc2)cc1
Temperature: 180 °C
Yield: 88.2 %

Procedure:
To a microwave vial, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (75 mg, 0.174 mmol) and Bu2SnO (4.33 mg, 0.02 mmol) were suspended in DME (3 mL). The vial was charged with TMSN3 (0.023 mL, 0.17 mmol) and the reaction was heated for 60 min at 180° C. under microwave irradiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO2, 1-20% MeOH/DCM) to afford (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole (66 mg, 0.15 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.45-7.61 (m, 5H), 7.32 (d, J=2.02 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 6.98 (d, J=16.67 Hz, 1H), 6.86-6.93 (m, 2H), 6.78-6.86 (m, 3H), 3.78 (s, 3H), 3.69 (s, 3H). LC/MS (m/z, MH+): 457.4.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH:12]([N:15]1[C:19]([C:20]2[CH:21]=[C:22]3[N:28]([N:29]=2)[C:27]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:26]=2[O:25][CH2:24][CH2:23]3)=[N:18][CH:17]=[N:16]1)([CH3:14])[CH3:13]>C(OCC)C>[OH:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:34][C:31]2[CH:32]=[CH:33][C:26]3[O:25][CH2:24][CH2:23][C:22]4[N:28]([N:29]=[C:20]([C:19]5[N:15]([CH:12]([CH3:14])[CH3:13])[N:16]=[CH:17][N:18]=5)[CH:21]=4)[C:27]=3[CH:30]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C=O)ccc1OCC2
Reactant: O=C(CO)N1CCNCC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(CN3CCN(C(=O)CO)CC3)ccc1OCC2

Procedure:
Following the procedure for 128 without the use of HCl in diethyl ether, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde was reacted with 2-hydroxy-1-piperazin-1-yl-ethanone to give 132 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.95 (s, 1 H); 7.86 (d, J=2.0 Hz, 1 H); 7.28-7.23 (m, 1 H); 7.17 (d, J=8.2 Hz, 1 H); 6.86 (s, 1 H); 5.73-5.60 (m, 1 H); 4.55 (t, J=6.0 Hz, 2 H); 4.15 (s, 2 H); 3.69 (t, J=4.8 Hz, 2 H); 3.64-3.55 (m, 3 H); 3.29 (t, J=4.8 Hz, 2 H); 3.16 (t, J=6.0 Hz, 2 H); 2.55-2.46 (m, 4 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS: RT=5.70 min, M+H+=452
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:19]2=[O:43])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC=CCCCC.ClC1C=CC=C(C(OO)=[O:60])C=1>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:60])[CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:19]2=[O:43])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)Sc1nnc(C)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCC=CCCCC
Solvent: ClCCl
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2S(=O)C1)Sc1nnc(C)s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene (0.22 g) in methylene chloride (10 cc) is cooled to 0° C. A solution of 85% pure m-chloroperbenzoic acid (0.07 g) in methylene chloride (5 cc) is added dropwise in the course of 20 minutes. The solution is then stirred for 5 minutes at 0° C., washed with a saturated solution of sodium bicarbonate (20 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column: 1 cm; height: 10 cm). Elution is carried out with a 60/40 (by volume) ethyl acetate/cyclohexane mixture (100 cc) and and 3 cc fractions are collected. Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (0.12 g) in the form of a hard white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:13](=[O:20])(=[O:19])[NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]2[OH:12].N1C=CC=CC=1.[O:27]1[CH2:32][CH2:31][N:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:29][CH2:28]1.Cl>O>[C:15]([NH:14][S:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:33]([N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)(=[O:35])=[O:34])[C:7]=1[OH:12])(=[O:20])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(N)cccc2c1O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(NS(=O)(=O)N3CCOCC3)cccc2c1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a mixture of 9 g. of 5-amino-2-tert-butylsulfamoyl-1-naphthol with 90 ml. of pyridine were added portionwise under ice-cooling and stirring 11 g. of morpholinosulfonyl chloride and stirring was continued at room temperature for 20 hours. Thereafter, 10 ml. of water were added and stirring was carried out for further 1 hour. Into a mixture of 115 ml. of conc. hydrochloric acid with 400 ml. of ice-water was poured the above reaction mixture to separate a solid precipitate, which was then collected on a filter funnel and washed with water. The product was dissolved in an alkaline solution of 6 g. of sodium hydroxide in 150 ml. of water, insolubles were filtered off, the filtrate was poured into a mixture of 15 ml. of conc. hydrochloric acid with 150 ml. of ice-water to separate a solid precipitate. The precipitate was collected on a filter funnel, washed well with water and then dried to afford 9.6 g. of the desired product in a yield of 72%. mp. 105°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:6][C:7]=1[Br:23]
Reactant: Nc1ccc(CC(=O)NCCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1ccc(CC(=O)NCCCO)cc1Br

Procedure:
The title compound was prepared from 2-(4-amino-phenyl)-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step) and NBS according to the procedure in Example 7, step (c). Mass spectrum (ESI, m/z): Calcd. for C1H15BrN2O2, 287.0 (M+H). found 287.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]2I)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:21]1[N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: OCc1c(F)cccc1Cl
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-6-fluorophenyl)methanol (160.5 mg, 0.99 mmol) in THF (8 mL) was added sodium hydride (40 mg, 0.99 mmol) and the reaction was stirred at room temperature. After 25 minutes ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (300 mg, 0.83 mmol) was added and the reaction was refluxed overnight. Water was added slowly and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 2-((2-chloro-6-fluorobenzyl)oxy)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (39).