Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O=P(Cl)(Cl)[Cl:38]>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:38])=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1

Procedure:
6.6 g of 1-benzyl-3-(2-furyl)-4-hydroxypyrazolo[3,4-d]pyrimidine are boiled for 12 h in 100 ml of POCl3. The mixture is evaporated in vacuo, the residue is stirred with aqueous K2HPO4 solution and the mixture is extracted with ethyl acetate. After drying using Na2SO4 and concentrating in a rotary evaporator, 7.47 g of a solid are obtained which can be reacted directly for the next stage (Rf=0.8, SiO2, toluene/ethyl acetate=1:1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44]O)[CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44][NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])[CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4cccc(OCCO)c4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Solvent: NCCO
Product: CC(C)(CO)NCCOc1cccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[3-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-2-methyl-1-propanol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)NC2CCc3ccccc32)c1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.6 g, 12.3 mmole) and m-anisoyl chloride (1.9 g, 13.54 mmole) as in Ex. 46; crystallization from EtOAc:hexane gave 2:0 g (7.2 mmole, 59w) white solid, mp: 140° C.
Reaction SMILES: [H-].[Na+:2].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H][H]>C1COCC1>[CH3:10][O:9][C:3](=[O:8])/[CH:4]=[C:5](/[O-:6])\[CH3:7].[Na+:2]
Reactant: COC(=O)CC(C)=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)[O-]

Procedure:
60 g of a 30% strength sodium hydride suspension in mineral oil (744 mmol of NaH) are suspended in 250 ml of dry THF in an inert gas atmosphere. 86.4 g (744 mmol) of methyl acetoacetate in 200 ml of THF are slowly added dropwise, the resulting hydrogen being led directly into the waste air. After dropwise addition has taken place, the mixture is stirred at reflux for half an hour and then cooled. The solvent is stripped off in vacuo and the residual solid is washed with diethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24](OS(C)(=O)=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C.O.Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1)OS(C)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CCOC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-methanesulfonyloxypropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (3.7 g) in tetrahydrofuran (40 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.1 ml) at ambient temperature and the mixture was stirred for one hour. Removal of the solvent in vacuo gave an oil which was dissolved in a mixture of ethyl acetate (100 ml), water (50 ml) and 1N-hydrochloric acid (10 ml). The organic layer was separated, washed twice with brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[{3-[ethoxycarbonyl)-2-propenyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (2.72 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4]O.[BrH:22].S(=O)(=O)(O)O>O>[Br:22][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: Br
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Temperature: 100 °C
Yield: 84 %

Procedure:
To a mixture of 40.0 g (134 mmol) of 3,7,11,15-tetramethyl-1-hexadecanol and 400 mL of 48% hydrobromic acid was slowly added 40 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 24 h and poured into 1.2 L of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous NaHCO3 and dried over MgSO4. The solution was concentrated to a dark liquid, which was eluted through 3 inches (7.6 cm) of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 40.8 g (84%) of 1-bromo-3,7,11,15-tetramethylhexadecane as a clear, colorless liquid, bp 160-180° C. at 0.06 mm Hg.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:21]([C:31](=[O:40])[NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:51]>C(OCC)(=O)C>[ClH:51].[ClH:51].[ClH:51].[NH2:23][CH2:22][C@H:21]([N:20]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:18]([C:8]1[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][CH:7]=1)=[O:19])[C:31](=[O:40])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)NCc1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CN)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
tert-Butyl {(2S)-2-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-3-oxo-3-[(pyridin-2-ylmethyl)amino]propyl}carbamate (19 mg) was dissolved in ethyl acetate (3 ml), 4 M hydrogen chloride-ethyl acetate solution (1.5 ml) was added, and the mixture was stirred at room temperature for 14 hr. The solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and fractions eluted with water-acetonitrile (9:1) to acetonitrile were collected. The mixture was basified (pH 10) with saturated aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 ml), 4 M hydrogen chloride-ethyl acetate solution (1.5 ml) was added and the mixture was stirred for 1 min and concentrated under reduced pressure to give the object compound (17 mg).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1>CN(C=O)C>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cccc(OCCCCBr)c1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Yield: 55 %

Procedure:
The title compound was synthesized analogously to 83.8, using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-bromobutoxy)-3-nitrobenzene (164 mg, 0.6 mmol) in anhydrous. DMF (1 mL). The crude product obtained after workup was purified by flash column chromatography on silica gel (25% ethyl acetate-petroleum ether) to give 83.9 as a white solid (m p 87-89° C.) in 55% yield (95 mg).
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:15](=[O:20])[CH:16]=[C:17]([CH3:19])[CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:21]>CCOCC>[C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:15](=[O:20])[CH2:16][C:17]([Cl:21])([CH3:19])[CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CC(C)=CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCC2
Solvent: CCOCC
Product: CC(C)(Cl)CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-(8-tert-butyl-2,3-dihydrobenzopyran-6-yl)-3-methyl-2-buten-1-one (0.62 g, 2.26 mmol) in Et2O (10 mL) is bubbled hydrogen chloride gas for about 15 min. The resulting solution is stirred at room temperature for 1 h, and concentrated. The resulting off-white oil is purified by flash column chromatography on silica (hexanes, hexanes/EtOAc; 10/1) to give the title compound (0.425 g. 61 %) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([C:2]2[N:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=[C:4]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:3]=2[N+:15]([O-:17])=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1c(Cl)nc(C2CC2)nc1NC1CC1
Reactant: C1CCCNCC1
Product: O=[N+]([O-])c1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1

Procedure:
6-(1-azepanyl)-N,2-dicyclopropyl-5-nitro-4-pyrimidinamine 197 was synthesized as described in 7.1 using 6-chloro-N,2-dicyclopropyl-5-nitro-4-pyrimidinamine 44 and azepane as starting material.
Reaction SMILES: [Na].[C:2](=O)([O:5]C)[O:3][CH3:4].[CH2:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3([CH3:24])[O:23][CH2:22][CH2:21][O:20]3)=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:25])[CH3:9]>CO>[CH3:4][O:3][C:2]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]3([CH3:24])[O:20][CH2:21][CH2:22][O:23]3)[CH:14]=2)[N:10]([CH2:8][CH3:9])[C:11]1=[O:25])=[O:5]
Reactant: COC(=O)OC
Reactant: CCN1C(=O)Cc2cc(C3(C)OCCO3)ccc21
Agent: [Na]
Solvent: CO
Product: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21

Procedure:
Sodium (2.68 g, 112 mmol) was added to methanol (110 mL) in a 3-neck flask fitted with a reflux condenser, while controlling the temperature with an ice-bath. After dissolution dimethyl carbonate (9.4 mL, 112 mmol) was added followed by 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-1,3-dihydro-indol-2-one (U.S. Pat. No. 4,686,224, 9.2 g, 37 mmol). The mixture was heated to reflux for 70 hours, then cooled, concentrated to about 25 mL, diluted with water, acidified to pH 7 with acetic acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to an oily solid which was triturated in isopropyl ether, collected and dried (7.9 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O>O1CCCC1>[Br:12][C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:9][CH:10]=1
Reactant: COc1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1cnc2[nH]cc(Br)c2c1
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (0.439 g, 2.96 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (0.527 g, 2.96 mmol) at 0° C. After 90 minutes at 0° C., the reaction was quenched with 30% Na2S2O3 and extracted with EtOAc (2×). The combined organic layers were washed with water, dried and concentrated. The residue was triturated with EtOAc/diethyl ether (1:1) to give 0.375 g of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][NH2:48])=[CH:46][C:41]=2[O:40][CH2:39]1>>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][NH:48][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc5c(c4)OCO5)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and C-benzo[1,3]dioxol-5-yl-methylamine, m.p. 167-168° C. MS [(+)ESI, m/z]: 586 [M+H]+ Anal. Calcd for C36H31N3O5: C, 73.83; H, 5.34; N, 7.17. Found: C, 73.41; H, 5.43; N, 7.12.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][NH2:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16](OCC)(OCC)(OCC)[CH3:17]>>[CH3:16][C:17]1[O:13][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2](=[O:1])[NH:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)=[N:14][N:15]=1
Reactant: NNC(=O)c1ccc2c(O)ncnc2c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2ccc3c(=O)[nH]cnc3c2)o1

Procedure:
4-Hydroxy quinazoline-7-hydrazide (0.41 g) was treated with triethyl orthoacetate (10 ml) at reflux under nitrogen for 24 hours. The mixture was cooled, filtered and purified by chromatography to give the title compound (0.09 g); m/z (M+1+) 229.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C1C=CC=CC=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8])[CH3:17]
Reactant: CC(=O)c1cccnc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1cccnc1

Procedure:
1-Pyridin-3-yl-ethanone, ethyl cyanoacetate, benzene, ammonium acetate, and acetic acid were refluxed for 16 hrs in a 250 mL round bottomed flask fitted with a Dean-Stark trap. The solutions were washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography to yield the product as an oil. MS (ESI+) for C12H12N2O2 m/z 217.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.00 g (132.0 mmol) of 3-bromothiophenol, 200 ml of DMF and 18.23 g (138.0 mmol) of potassium carbonate are introduced into a three-necked flask. 18.0 ml (157.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred at room temperature for five hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 33.00 g (97%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=3[O:21][CH3:22])[NH:9][C:5]=2[CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:26]>>[NH2:2][C:1]([C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=3[O:21][CH3:22])[NH:9][C:5]=2[CH:4]=1)=[O:26]
Reactant: O=S(=O)(O)O
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C#N)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C(N)=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
One gram (2.91 mmol) of 5-cyano-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was added batchwise to 15 ml of concentrated sulfuric acid, and the resulting mixture was stirred for 24 hours at ambient temperature. The solution was then poured onto 300 ml of ice water, and the product precipitated was subjeted to suction filtration and recrystallized from methanol.
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[C:15](C(O)=O)[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2].N1C2C(=CC=CC=2)C=CC=1>[Cu]>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: O=Cc1c(OCCCCC(=O)O)ccc(C(=O)O)c1O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: O=Cc1c(O)cccc1OCCCCC(=O)O

Procedure:
5-(2-Formyl-3-hydroxy-4-carboxyphenoxy)pentanoic acid (Example 6) (0.2 g, 0.0007 M), copper (0.05 g) and quinoline (5 ml) were heated at 210° C. for 1/2 hour. The reaction mixture was cooled and filtered. Ether (20 ml) was added to the filtrate and the organic layer was washed with 2 N hydrochloric acid (3×20 ml), water (1×20 ml) and brine (1×20 ml), dried (magnesium sulphate) and the solvent removed in vacuo to give 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid as a pale-yellow oil that solidified on standing and was homogeneous on thin layer chromatography (silicagel plates; chloroform:methanol, 10:1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][S:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][C:11](OC)=[O:12])=[O:4].C[O-].[Na+]>>[CH3:19][C:17]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][C:11](=[O:12])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[S:6][C:7]=2[CH:18]=1
Reactant: COC(=O)COc1ccc(C)cc1SCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Yield: 73.4 %

Procedure:
Methyl 2-methoxycarbonylmethylthio-4-methylphenoxyacetate (8.9 g) is treated with sodium methoxide in the same manner as described in Reference Example 2 to give methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (5.8 g) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[C:10]2=[N+]=[N-])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2].[CH2:24](B(CC)CC)[CH3:25]>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[CH:10]2[CH2:24][CH3:25])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(=[N+]=[N-])C2SC1
Solvent: C1CCOC1
Product: CCC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12
Temperature: -78 °C

Procedure:
A 2 liter, 3-necked round bottom flask fitted with 2 dropping funnels was charged with 200 ml THF and cooled to -78° C. under N2. One dropping funnel was charged with a solution of 6.33 g (15.3 mM]t-butyl 3-acetyloxymethyl-7-diazo-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 300 ml THF. The other funnel was charged with 32 ml 1M-triethylborane in THF, 1.2 ml H20, and 300 ml THF. The funnels were adjusted so their contents were added to the flask at 2.5 ml/min and the temperature of the reaction mixture maintained at -78° . After the addition, the cooling bath was removed and the reaction mixture allowed to warm. When the temperature reached -45° C., 6.67 ml 30% H2O2 was added. At -15°, the reaction mixture was washed with 300 ml brine, the organic layer diluted with 300 ml CH2Cl2, washed with 300 ml brine, dried over MgSO4, filtered and stripped to give 7.46 g of yellow oil which was chromatographed on a flash column with CHCl3 /EtOAc (25:1) to yield 1.289 g (19%) t-butyl-3-acetyl-oxymethyl-7α-ethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate a 4:1 mixture of the α and β isomers NMR(CDCl3): δ 1.08, t (J™8Hz), 3H; 1.50, s, 9H; 1.8, br, qt, 2H; 2.05, s, 3H; 3.1, brm, 1H; 3.4, d, 2H; 4.35, d (J=2Hz), 1H; 4.82, AB qt (J=12, 6Hz) 2H.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)#[N:2].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCN)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[4-(cyanomethyl)phenoxy]-2-methylpropionate (5.50 g, 20.0 mmol) was dissolved in tetrahydrofuran (90 mL). Subsequently, in a nitrogen atmosphere, borane-tetrahydrofuran complex in tetrahydrofuran solution [1.08M BH3-THF in THF (92.6 mL, 100 mmol)] was added thereto, and the mixture was stirred for three hours at 50° C. Subsequently, 1M hydrochloric acid was gradually added at 0° C., and the resultant mixture was stirred for one hour at room temperature. Thereafter, the reaction mixture was made basic with sodium carbonate. Tetrahydrofuran was evaporated, and then chloroform was added. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained (5.16 g, 13.02 mmol, 65.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[O:38][C:39](=[O:70])[CH:40]([NH2:69])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH:51]([CH2:54][N:55](C(OC(C)(C)C)=O)[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[N:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[NH:55][CH2:54][CH:51]1[CH2:52][CH2:53][N:48]([C:45]2[CH:44]=[CH:43][C:42]([CH2:41][CH:40]([NH:69][C:4](=[O:6])[C:3]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])[C:39]([OH:70])=[O:38])=[CH:47][CH:46]=2)[CH2:49][CH2:50]1
Reactant: COC(=O)C(N)Cc1ccc(N2CCC(CN(C(=O)OC(C)(C)C)c3ccccn3)CC2)cc1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(N3CCC(CNc4ccccn4)CC3)cc2)C(=O)O)c(C)c1

Procedure:
A solution of 202 mg (1.23 mmol) of 2,4,6-trimethylbenzoic acid, 467 mg (1.23 mmol) HATU, 300 mg (0.64 mmol) of (4) and 660 μl (3.85 mmol) DIPEA in 5 ml DMF were stirred at room temperature over night. The reaction mixture was diluted with 100 ml ethyl acetate, washed 3 times with 2 N NaOH/brine (2:1) and once with brine and dried over Na2SO4. The solvent was then removed under reduced pressure.