Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](CC)=[CH:4][CH:3]=1.CCCCC.C([Li])(C)(C)C.C([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=O)=[CH:24][C:23]=1O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:2]1([CH:26]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:31][CH:30]=2)[OH:28])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-bromo-4-ethylbenzene (0.41 mL) in tetrahydrofuran (15 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (2.3 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.18 g) in tetrahydrofuran (5 mL) was added to the reaction mixture. After the mixture was stirred under ice-cooling for 45 minutes, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give a diphenylmethanol compound (0.27 g). The obtained diphenylmethanol compound (0.27 g) was dissolved in methanol (5 mL), and concentrated hydrochloric acid (0.08 mL) and 10% palladium-carbon powder (54 mg) were added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (0.20 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O>C(OC)(C)(C)C>[Cl:16][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)Cl
Solvent: COC(C)(C)C
Product: O=C(CCl)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 67 %

Procedure:
3′-Nitroacetophenone (2.00 g) was suspended in methyl t-butyl ether (12.1 ml), and sulfuryl chloride (4.90 g) was dropwise added thereto at 20° C. over 15 minutes. After stirring for 2 hours, precipitated solids were filtered and washed with methyl t-butyl ether. Drying under reduced pressure yielded the desired 2-chloro-3′-nitroacetophenone (1.62 g; 67.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccnn2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1

Procedure:
To a solution of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine. The mixture is heated under reflux for 3 hours, and the mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid, exact mass by mass spectrometry: 305. 1402 (M+H).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([NH2:12])[CH2:10][NH2:11]>>[NH2:11][CH2:10][CH2:9][NH:12][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: NCCN
Reactant: Brc1ccncc1
Agent: Cl
Product: NCCNc1ccncc1
Reaction time: 13 h

Procedure:
The starting material can be prepared as follows: A mixture of 38.9 g of 4-bromo-pyridine-hydrochloride and 480 g of ethylenediamine is refluxed with stirring for 13 hours. The reaction mixture is thereafter concentrated under reduced pressure and the residue is treated with toluene and concentrated once more. The residue is made alkaline with a concentrated aqueous solution of sodium hydroxide and extracted with five 75 ml portions of methylene chloride. The combined extracts are dried over sodium sulphate and concentrated under reduced pressure. Recrystallisation of the residue from methylene chloride yields 4-(2-aminoethylamino)-pyridine as a light yellow crystalline substance with a melting point of 120°-121° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].Cl.O1CCOCC1.S(Cl)([Cl:20])=O>>[ClH:20].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](O)CCN
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cl)CCN
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (498 mg; 391 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 5 ml of 4 N-HCl/dioxane, followed by further addition of 321 μL of thionyl chloride. The mixture was stirred at 50° C. for 4 hours. The solvent was distilled off under reduced pressure to give 530 mg of methyl (R)-4-amino-2-chlorobutyrate hydrochloride (yield quantitative, optical purity 98.5% ee). The analysis of the optical purity was carried out by derivatizing into (R)-3-chloro-2-pyrrolidinone with sodium hydrogen carbonate, followed by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.C(N)(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[CH:33]1[O:45][C@H:44]([CH3:46])[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]1[O:35][C:36](=[O:38])[CH3:37])(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[N:3]([C@@H:33]2[O:45][C@H:44]([CH3:46])[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]2[O:35][C:36](=[O:38])[CH3:37])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(N)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
2-Bromo-5,6-dichloro-1H-benzimidazole (5.11 g, 19.21 mmol), and N,O-bis(trimethylsiyl) acetamide (Aldrich, 4.81 mL, 19.21 mmol) were combined with acetonitrile (Aldrich Sure Seal, 100 mL) and refluxed under nitrogen for 3 h. The solution was cooled to rt and trimethylsilyl triflate (Aldrich, 7.70 mL, 38.42 mmol) was added. After 15 min, 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (5.0 g, 19.21 mmol) in acetonitrile (4 mL) was added. The solution was stirred under nitrogen at rt for 3.5 h, then poured into 10% aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were washed with water (1×100 mL), dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column with 1:30 acetone:CH2Cl2 to give the title compound (6.96 g, 14.93 mmol, 78%); MS (El): m/z (rel. intensity) 489 (0.22, M++Na); 1H NMR (DMSO-d6) δ8.13 (s, 1H, Ar—H), 8.02 (s, 1H, Ar—H), 6.17 (d, 1H, CH, J=6.6 Hz), 5.67 (t, 1H, CH, J=13.9 Hz), 5.29 (t, 1H, CH, J=7.2 Hz), 4.28 (m, 1H, CH), 2.16 (s, 3H, OAc), 2.04 (s, 3H, OAc), 1.53 (d, 3H, CH3, J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[N+:10]([N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1)([O-:12])=[O:11]>>[CH:6]1[C:5]([CH2:8][N:15]2[CH2:16][CH2:17][NH:18]/[C:14]/2=[N:13]\[N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1
Product: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1

Procedure:
Preferably, the reaction of 2-chloro-5-chloromethyl pyridine with 2-nitroiminoimidazolidine is carried out at 50° C., so as to obtain good yields of imidacloprid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].Cl>O.CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Yield: 88.8 %

Procedure:
A solution of 4-acetylamino-N-tert-butylbenzenesulfonamide (8.0 g, 29.6 mmol), KOH (8.30 g, 148 mmol), H2O (6 mL) and MeOH (24 mL) is heated at 100° C. for 2 h. H2O (24 mL) is added and the mixture is heated for two more hours. It is allowed to cool, H2O is added and it is brought to pH 8 with 1N HCl. It is then extracted with EtOAc, dried over Na2SO4 and the solvent is removed, to give 6.0 g of the product as a white solid (yield: 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][NH:7][C:8]2=[O:13])([O-])=O.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][NH:7][C:8]2=[O:13]
Reactant: O=C1NCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cccc2c1CNC2=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82492.3 %

Procedure:
To a solution of 4-nitro-2,3-dihydro-1H-isoindol-1-one (compound 3, 3.2 gm, 0.018 mmol.) in DMF (10 ml), was added ammonium formate (5.750 gm), and Pd—C (100 mg), and the reaction mixture was stirred at 100° C. for 30 min. The mixture was then filtered through a pad of celite, and the celite was washed with DMF (10 ml) and water (10 ml). The filtrate was concentrated under vacuum to give compound 4 (2.2 gm, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B2OCCCO2)=[C:23]([F:33])[C:22]=1[O:34][CH3:35].[F-].[Cs+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:34][CH3:35])[C:23]=2[F:33])[N:5]=[C:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(Cl)c2Cl)c1F
Temperature: 25 °C

Procedure:
A 250 mL three-neck flask equipped with a reflux condenser and nitrogen inlet was charged with benzyl 4,5,6-trichloropicolinate (17.77 g, 56.10 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (19.20 g, 79.0 mmol) and CsF (17.04 g, 112.0 mmol). Acetonitrile (100 mL) and water (30 mL) were added. The reaction mixture was evacuated/backfilled with nitrogen (5×). Solid Pd(PPh3)2Cl2 (1.724 g, 2.456 mmol) was added. The solution was evacuated/backfilled with nitrogen (5×) and then stirred at reflux for 90 min. A white solid precipitated upon cooling to room temperature. The solid was filtered, washed with water and dried in air (18.66 g, 75%): 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H, pyridine H), 7.52-7.32 (m, 5H, phenyl), 7.27 (dd, JH-H=8.4 Hz, JF-H=1.7 Hz, 1H, aromatic), 7.10 (dd, JH-H=8.4 Hz, JF-H=6.8 Hz, 1H, aromatic), 5.44 (s, 2H, CH2Ph), 3.98 (d, J JF-H=1.3 Hz, 3H, OMe); 13C{1H} NMR (101 MHz, CDCl3) δ 163.0, 153.7, 153.5 (d, JF-C=253 Hz, C2′), 146.0, 144.5 (d, JF-C=13 Hz), 144.1, 135.0, 134.2, 129.9 (d, JF-C=3 Hz), 128.5, 126.1, 125.8 (d, JF-C=14 Hz), 125.3 (d, JF-C=3 Hz), 124.9 (d, JF-C=2 Hz), 67.9 (CH2), 61.5 (d, JF-C=4 Hz, OMe). Anal. Calcd for C20H13Cl3FNO3: C, 54.51; H, 2.97; N, 3.18. Found: C, 54.60; H, 3.08; N, 3.16.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[B:10]([OH:12])[OH:11])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[B:10]([OH:12])[OH:11]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1B(O)O
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 2-nitrophenylboronic acid (500 mg, 2.99 mmol) and MeOH (10 mL) was added 10% Pd/C (250 mg). The mixture was stirred under hydrogen at atmospheric pressure for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-50% CMA in CH2Cl2) to afford the sub-title compound (182 mg, 44%).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=CC(C(OC)=O)=CN=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][N:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)nc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)nc1
Yield: 72 %

Procedure:
Methyl 6-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)nicotinate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (83 mg, 0.125 mmol) and methyl 6-chloronicotinate following General Procedure A. Flash chromatography (5-10% EtOAc/hexanes) yielded the title compound as a clear oil (46 mg, 72%): 1H NMR (CDCl3, 500 MHz) δ 9.28 (d, 1H, J=2.0 Hz), 8.43 (dd, 1H, J=10.0, 6.0 Hz), 7.84 (s, 1H), 7.78 (d, 1H, J=8.5 Hz), 7.35-7.32 (m, 2H), 7.25-7.22 (m, 3H), 4.95 (t, 1H, J=7.0 Hz), 4.04 (s, 3H), 2.67 (t, 2H, J=7.5 Hz), 2.05-1.98 (m, 2H), 1.74-1.67 (m, 2H), 1.48-1.40 (m, 6H), 0.98 (s, 9H), 0.18 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 167.1, 165.8, 151.6, 151.0, 150.5, 143.2, 138.5, 128.8, 128.6, 127.9, 126.0, 125.0, 118.7, 69.2, 52.9, 36.9, 36.3, 31.8, 29.6, 26.1, 26.1, 25.5, 18.6, −4.5, −4.7.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].CO>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CO)CC1
Reaction time: 4 h

Procedure:
To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.0 g, 53.7 mmol) in tetrahydrofuran (540 ml) was added borane-dimethylsulfide complex (6.80 g, 80.6 mmol) at 0-5° C. The cooling bath was removed after 15 minutes and the mixture was stirred for 4 h. The reaction mixture was quenched with methanol (17.2 g, 537 mmol), stirred for 20 minutes and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (300 ml) and filtrated over a pad of Decalite. The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (300 ml) and 1 M aqueous sodium hydroxide solution (100 ml). The layers were separated. The organic layer was washed with one 100 ml-portion of water. The combined aqueous layers were extracted with one 150-ml portion of ethyl acetate. The combined organic layers were washed with one 50 ml-portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.75 g, 94.6%) as colorless oil, which can be used without further purification. MS m/e: 172 (M+)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C:14]=12)=[O:4].C1COCC1.CO.[Li+].[OH-]>O>[CH:28]([O:27][C:12]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=12)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl ester 212 (54 mg, 0.10 mmol) in 1.0 mL of a 1:1:1 mixture of THF:MeOH: H2O was stirred with LiOH (9.7 mg, 0.41 mmol) overnight when the starting materials were completely consumed as judged by TLC (DPM=benzhydryl, Ph2CH—). The reaction mixture was dried under reduced pressure and the residue was dissolved in EtOAc. The organic layer was stirred with saturated aqueous NH4Cl for 30 minutes. The aqueous layer was checked by TLC to assure complete transfer of the products to the organic layer. The organic layer was dried in vacuo to yield 45.5 mg (87%) of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 as a white solid. The product was carried on without purification. MS (m/z) 519.2 [M+H]+, 541.2 [M+Na]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.[Na].C(OCC)(=[O:31])C.[Cl-].[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:31]
Reactant: CCOC(C)=O
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of 21.9 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 544 in methanol (3 ml) was added a solution of sodium metaperiodide (118.7 mg) in water (0.5 ml), and the mixture was stirred for 18 hours. To the reaction mixture were added ethyl acetate and saturated aqueous sodium chloride, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 9.6 mg (yield 42%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[CH3:17][O:18][C:19](Cl)=[O:20].Cl>O1CCCC1.O>[CH3:17][O:18][C:19]([NH:11][C@H:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:8]([OH:10])=[O:9])=[O:20]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
D-(−)-α-Phenylglycine (0.165 mmol) was dissolved in tetrahydrofuran (500 mL), followed by the addition of NaHCO3 (0.496 mmol) in water (500 mL), and then the addition of methylchloroformate (0.182 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was acidified to pH=3 with HCl (1N) and the volatile was concentrated in vacuo. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give compound 31 as a pale yellow solid in 80% yield. MS (ESI, EI+) m/z=209 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH3:17])(=[O:4])=[O:3]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.64 mL) was added dropwise to an ice-cooled mixture of (R)-(+)-2-(tert-butoxycarbonylamino)-propanol (1.31 g) and triethylamine (1.6 mL) in methylene chloride (20 mL) with stirring, and the mixture was stirred at that temperature for 1 hr. The reaction mixture was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (1.93 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:16][O:17][NH:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:18]([O:17][CH3:16])[CH3:19])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (5.34 g, 20 mmol) in DCM (120 mL) was added O,N-dimethylhydroxylamine hydrochloride (2.9 g, 30 mmol), HATU (9.2 g, 30 mmol) and Et3N (8.0 g, 80 mmol). The mixture was stirred at rt overnight, concentrated and purified by CC (hexane) to afford compound P30a (5.1 g, 83%) as a solid.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:23])[CH:7]=[CH:6][N:5]=1.C(O)(=O)C.O>CC1C=CC=CC=1C.COCCOCCOC>[CH3:23][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]=12
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOCCOC
Solvent: Cc1ccccc1C
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 132.5 °C
Reaction time: 1 h

Procedure:
Sodium hydride (9.15 g, 65% w/w) was suspended in o-xylene (187.5 ml) at 25-30° C. under nitrogen atmosphere and slowly heated to 130-135° C. N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide (25 g) was dissolved in diglyme (50 ml) at 70-80° C. and added to the above suspension over a period of 10-20 min at 135-138° C. and stirred for 1 h at 135-140° C. Thereafter the reaction mixture was cooled to 5° C. and acetic acid (8.75 ml) was added slowly below 15° C. Then cold DM water (100 ml) was added to the reaction mixture slowly below 15° C. and pH of the reaction mixture was adjusted to 6.5 using acetic acid (4.25 ml) at 5-10° C. The temperature of the reaction mixture was raised to 20-25° C. and stirred for 1 h at 20-25° C. and product crystallizes out. The product obtained was filtered and washed with DM water (75 ml) and then with cyclohexane (50 ml) and suck dried the product under suction for 10 min. The wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml) and heated to reflux at 70° C., a clear solution formed. Carbon (2.5 g) was added and stirred for 30 min at reflux. Filtered the carbon in hot condition and washed with hot methanol (50 ml, 60-65° C.). Filtrate was concentrated under reduced pressure at 50-55° C. up to residual weight attained is approximately 225 g. Thereafter cooled the concentrated mass to 5-10° C. and stirred for 30 min at 5-10° C. The product obtained was filtered and washed with cold DM water (25 ml, 5-10° C.), suck dried and dried at 65-70° C. under reduced pressure.