Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:43])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:42])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>>[CH3:8][O:9][C:10](=[O:43])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:42])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
TFA (4 ml) was added to 2-(2-(4-(4-(t-butoxycarbonylmethoxy)-phenoxy)phenyl)acetylamino)benzoic acid methyl ester produced by the Example 27 and the mixture was stirred for 2 hours at room temperature. After the reaction, TFA was distilled out under reduced pressure and the product was dissolved in ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to quantitatively obtain the subject compound (164 mg). The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-methoxynicotinate (Avacado), 0.1 g (0.6 mmol) in 5 mL of tetrahydrofuran was added a solution of 1.2 mL of 5 N sodium hydroxide in 5 mL of water. The mixture was stirred for four hours at ambient temperature, acidified to pH=3 with 5 N HCl and concentrated to dryness to yield the crude desired compound. MS (ion spray) 154.0 (M+1). The crude product was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:12][CH:13]=[CH:14][N:15]=1
Reactant: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(COc2ncccc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a mixture of 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde (620 mg), tetrahydrofuran (10 ml) and ethanol (10 mL) was added sodium borohydride (54 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (615 mg, 99%) of [2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. The crystals were recrystallized from ethyl acetate-hexane. melting point: 143-144° C.
Reaction SMILES: [CH:1]([O:11][C:12]1[N:17]=[CH:16][C:15](Br)=[CH:14][N:13]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:19]1([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:11][C:12]1[N:17]=[CH:16][C:15]([C:28]2[CH:29]=[CH:30][C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:26][CH:27]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC=COc1ncc(Br)cn1
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Product: CCCCCCCCCCOc1ncc(-c2ccc(-c3ccccc3)nc2)cn1

Procedure:
The synthesis was carried out analogously to Example 27 from 2-decenyloxy-5-bromopyrimidine and 2-phenylpyridine-5-boronic acid.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:26][CH:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:32][C:29]1([CH3:33])[O:28][CH:27]([CH2:26][N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=3[C:2]([I:1])=[CH:3]2)[CH2:31][O:30]1
Reactant: COc1nccc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 73.0 mg), and the mixture was stirred at room temperature for 1 hr, (2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (523 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (122 mg).
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22]/[C:23](=[CH:25]/[CH2:26][OH:27])/[CH3:24])[CH3:19]>[Cl-].[Zn+2].[Cl-]>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([O:27][CH2:26]/[CH:25]=[C:23](/[CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])\[CH3:24])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Agent: [Cl-]
Agent: [Zn+2]
Product: C=CC(=O)N1Cc2ccccc2SC(OC/C=C(\C)CCC=C(C)C)C1
Yield: 68.3 %

Procedure:
The above-mentioned 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g), geraniol (0.9 g) and zinc chloride (0.8 g) were reacted in the same manner as in Experimental Example 9 to give 4-acryloyl-2-geranyloxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:17])=[C:6]([S:9][CH2:10][C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.Cl.C(OCC)(=O)C.CC(C)=O>C(O)=O>[NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([S:9][CH2:10][C:11]3[CH:15]=[N:14][NH:13][CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CC(C)=O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cn[nH]c3)CS[C@H]12
Temperature: 25 °C
Yield: 68.1 %

Procedure:
Diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (810 mg) was dissolved in formic acid (3.2 ml) below 5° C. and herein concentrated hydrochloric acid (0.71 ml) was added thereto at the same temperature. After the reaction mixture was stirred at the room temperature for an hour, it was poured into a mixture of ethyl acetate (50 ml) and acetone (25 ml), resulting precipitate was collected by filtration, and dried under reduced pressure. The precipitate was suspended in a mixture of water (6.0 ml) and acetone (2.5 ml). After the suspension was dissolved at pH 7.0 with saturated sodium bicarbonate solution, and adjusted to pH 4.5 with 1N-hydrochloric acid. The mixture was stirred at the room temperature for 30 minutes, and then resulting precipitate was collected, washed with acetone (5.0 ml), and dried under reduced pressure to give 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (0.36 g) was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][N:69]([CH3:74])[CH2:70][C:71](O)=[O:72].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O.O>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:71](=[O:72])[CH2:70][N:69]([CH3:74])[CH3:68])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: CN(C)CC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), N,N-dimethylglycine (0.011 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at RT for 1 hr. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was triturated with methanol and dried under vacuum to give the title compound (0.016 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (br. s., 1H), 9.52 (br. s., 1H), 8.96 (t, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.41-7.54 (m, 2H), 7.36 (t, 1H), 7.30 (s, 2H), 7.07 (s, 1H), 4.53 (d, 2H), 2.22 (s, 6H). ES MS: m/z 553 (M).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH2:12][OH:13])=[C:4]([CH2:8][CH2:9][OH:10])[S:5][C:6]=1[Cl:7].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:4]([CH2:8][CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[S:5][C:6]=1[Cl:7]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1sc(Cl)c(Cl)c1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1sc(Cl)c(Cl)c1CCOS(C)(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of the product from step (e) (1.99 g, 8.25 mmol) in CH2Cl2 (41 ml) was cooled to 0° C. and treated with triethylamine (3.4 ml, 24.7 mmol) followed by dropwise addition of methanesulfonyl chloride (1.4 ml, 18.1 mmol) over 10 min. After 45 minutes, the crude reaction was diluted with CH2Cl2 (100 ml) and washed with ice water (25 ml), 10% citric acid (2×25 ml), sat. NaHCO3 (2×25 ml) and brine (1×25 ml). The organic layer was dried (MgSO4), concentrated to 20 ml and diluted with anhydrous dioxane (76 ml). This mixture was concentrated to remove remaining CH2Cl2 and the resulting dioxane solution was carried forward to the next reaction.
Reaction SMILES: C1(C)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:22][S:23]([CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH:30]=[CH:29]1)([F:27])([F:26])([F:25])[F:24]>CCCCC>[F:22][S:23]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)([F:27])([F:26])([F:25])[F:24]
Reactant: FS(F)(F)(F)(F)C1C=CCc2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: FS(F)(F)(F)(F)c1cccc2ccccc12
Temperature: 65 °C

Procedure:
Toluene and dichlorodicyanobenzoquinone (2 equivalents) were added to the product of step 2 and heated to 65° C. The reaction was monitored by GC. When the reaction was complete pentane was added. Resulting solids were removed by filtration. Color was removed by filtering through silica. The crude product was isolated by removing the solvent using rotary evaporation.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:18][O:19][CH:20]=[O:21].O>O1CCCC1>[CH3:18][O:19][C:20]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: O=COCCl
Reactant: NCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NCCc1ccccc1
Yield: 97.6 %

Procedure:
To a cold solution consisting of phenethylamine (20g,0.16mol) in tetrahydrofuran (900 mL) was added triethylamine (23 mL, 0.16 mol). To this solution was added dropwise chloromethylformate (64 mL, 0.8 mol). The reaction mixture was then stirred overnight water (450 mL) was added and the layers were separated. The organic layer was washed successively with water (1×200mL) and brine (1×200mL). The organic solvent was dried (anhydrous magnesium sulfate), filtered and concentrated to give the title compound (28 g, 94% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:36])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CO)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 88.2 %

Procedure:
To a solution of 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone (3.80 g, 8 mmol) in toluene (30 mL) was added thionyl chloride (1.2 mL, 16 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone (3.4 g, 88.8%) as an oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[C:36](=[O:44])[O:37][CH:38]([CH2:41][CH2:42]O)[C:39]=1[OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC#N.CCOCC>[CH2:27]([O:34][C:35]1[C:36](=[O:44])[O:37][CH:38]([CH2:41][CH2:42][I:25])[C:39]=1[OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=C1OC(CCI)C(O)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To an oven dried 250 mL round bottom flask flushed with argon was added 5.8 g (22 mmol) of PPh3, 1.5 g (22 mmol) of imidazole and 80 mL of ether/CH3CN (3/1). The mixture was cooled in an ice water bath with magnetic stirring and 5.6 g (22 mmol) of iodine was added in 4 equal portions with vigorous stirring. The resulting slurry was warmed at room temperature for 20 minutes, cooled to 0° C., and 5.0 g (20 mmol) of 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone dissolved in 20 mL of CH3CN/ether (1/1) was added in one portion and the remainder was rinsed in with 5 mL of ether. The mixture was stirred at 0° C. for 10 minutes, then at room temperature for 30 minutes and quenched by pouring into 150 mL of 10% HCl solution and extracting with 500 mL of ether/hexanes (1/1). The aqueous layer was separated and extracted with 100 mL of ether. The combined organic fractions were washed with 50 mL of H2O and extracted with 5×50 mL of saturated NaHCO3 solution. The combined bicarbonate extracts were washed with 50 mL of ether/hexanes (1/1), acidified to pH below 2 with 10% HCl solution and extracted with 3×200 mL of ether. The combined ether extracts were washed with 100 mL of brine, dried (MgSO4) and concentrated to give 6.7 g, (93% yield) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)-furanone as a white solid, which was not further purified: mp 101-104° C., 1H NMR (CDCl3) δ 7.40-7.27 (m, 5H), 5.06, (dd, J=11.4 Hz, 2H), 4.69 (dd, J=3.4, 8.0 Hz, 1H), 3.06 (t, J=7.3 Hz, 2H), 2.41-2.29 (m, 1H), 2.02-1.90 (m, 1H); 13C NMR (CDCl3) δ 170.33, 160.61, 136.32, 128.77, 128.69, 128.58, 120.11, 75.76, 73.39, 35.77, −2.03; Anal Calcd for C13H13O4I: C, 43.35; H, 3.64. Found: C, 43.94; H, 3.69.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH:21](OCC)=O.[OH-].[Na+]>O1CCCC1.O>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH3:7])[CH2:16][CH2:17]1
Reactant: CCOC=O
Reactant: COc1ccccc1N1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N1CCN(C)CC1
Temperature: 0 °C
Yield: 53.1 %

Procedure:
To an ice-cooled, stirred suspension of lithium aluminium hydride (7.9 g, 0.21 mol) in dry tetrahydrofuran (1 50 ml) was added a solution of 1-(2-methoxyphenyl) piperazine (10 g, 52 mmol) in dry tetrahydrofuran (150 ml) over 0.5 h under argon. A solution of ethyl formate (12.6 ml, 0.156 mol) in dry tetrahydrofuran (25 ml) was added to the cold mixture over 0.25 h and the resulting suspension was stirred for a further 2 h at room temperature. Dilute sodium hydroxide solution (15%, 8 ml) was slowly added to the cooled mixture, followed by water (24 ml) and the whole left to stir for 0.25 h. The mixture was filtered and the filtrate concentrated to an oil which was partitioned between dichloromethane and water. The organic phase was dried and concentrated to an oil which was purified by column chromatography on silica gel eluting with a methanol/dichloromethane gradient to afford the title compound as a colourless oil (5.7 g, 53%)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=[C:37]([CH:45]([CH3:47])[CH3:46])[C:36]=2[CH2:48][OH:49])=[CH:31][CH:30]=1.CCOC(C)=O>C(Cl)Cl.CCOCC.[OH-].[Na+].CCCCCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=[C:37]([CH:45]([CH3:47])[CH3:46])[C:36]=2[CH:48]=[O:49])=[CH:31][CH:30]=1
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CCCCCC
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Dess-Martin periodinane (1.018 gm, 2.40 mmol) was dissolved in dry CH2Cl2 (12 ml), treated with t-butanol (178 mg, 2.40 mmol) and the resulting mixture was stirred at room temperature for 15 minutes. A solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinemethanol (539 mg, 1.82 mmol) in CH2Cl2 (8 ml) was then added. After 25 minutes, the solution was then diluted with Et2O (40 ml) and 1N NaOH (25 ml), then stirred an additional 5 minutes. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with saturated NaHCO3 and brine, then dried (Na2SO4), filtered and stripped to give a yellow solid. Flash chromatography (Merck SiO2, 40% EtOAc in hexane) gave 4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (491 mg, 92%) as a white solid. Analytically pure material was obtained by recrystallization from hot hexane.
Reaction SMILES: [OH:1][C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH:10]2[CH:6]([CH2:7][N:8]([C:11](=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH2:9]2)[C:5](=[O:22])[CH2:4][CH2:3]1.C[Li].[Cl-].[NH4+].[C:35](OCC)(=O)C>C(OCC)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]1([OH:1])[CH2:3][CH2:4][C:5]([CH3:35])([OH:22])[CH:6]2[CH:10]1[CH2:9][N:8]([C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:7]2
Reactant: CCOC(C)=O
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(O)(c3ccccc3OC)C2C1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)CCC2(C)O
Reaction time: 3 h

Procedure:
To a suspension, cooled to -70° C. and under an argon atmosphere, of 0.5 g of (3aRS,7RS,7aSR)-7-hydroxy-7-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl ]-4-perhydroisoindolone are slowly added 4 cm3 of 1.6 M methyllithium solution in ethyl ether. After returning to room temperature and stirring for 3 hours, the reaction mixture is cooled to +5° C., followed by addition of 25 cm3 of saturated aqueous ammonium chloride solution and 20 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.06-0.20 mm) in ethyl acetate and then in a mixture of ethyl acetate and methanol (90/10 by volume). After drying under reduced pressure and recrystallization in acetonitrile, 0.1 g of (3aRS,4RS,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-7-methyl-4,7-perhydroisoindolediol is obtained, in the form of white crystals melting at 180° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[CH:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8]3)[CH:4]=[C:3]1[C:21]([OH:23])=[O:22].[OH-].[Na+:25]>O>[O:1]=[C:2]1[C:11]2=[CH:12][CH:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]3=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8]3)[CH:4]=[C:3]1[C:21]([O-:23])=[O:22].[Na+:25]
Reactant: O=C(O)c1cn2c3c(c(-c4ccccc4)ccc3c1=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cn2c3c(c(-c4ccccc4)ccc3c1=O)CCC2

Procedure:
A sample of 6,7-dihydro-1-oxo-8-phenyl-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 100 ml of water and 0.176 g of sodium hydroxide was heated to obtain solution, filtered, then lyophilized to provide fluffy white solid sodium 6,7-dihydro-1-oxo-8-phenyl-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 230°-231° C. Analysis: Calculated for C20H16NNaO3.1.5H2O: %C, 65.2; %H, 5.2; %N, 3.8; Found: %C, 65.1; %H, 4.8; %N, 3.6. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][N:13](C(OC)OC)C.CO>CN(C=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][N:11]2[N:13]=[CH:12][N:1]=[C:2]2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccn2ncnc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130° C. for 12 hours. The mixture was then concentrated to give a residue. To the residue was added methanol (381 mL), followed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate in 18% yield, 6 g. To a solution of methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6): δ13.5-14.0 (s, 1H), 9.04-9.06 (m, 1H), 8.66 (m, 1H), 8.32 (m, 1H), 67.56-7.58 (m, 1H).