Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH:76]1([NH2:79])[CH2:78][CH2:77]1.C(O)(C(F)(F)F)=O>O1CCOCC1.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[CH:76]1([NH:79][C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=3[N:7]=2)[CH2:78][CH2:77]1
Reactant: NC1CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NC3CC3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (100 mg, 0.258 mmol) was dissolved in 1,4-dioxane (2.6 mL) followed by addition of cesium carbonate (336 mg, 1.031 mmol). After degassing with nitrogen for 5 min, Xantphos (44.8 mg, 0.077 mmol) was added. The mixture was degassed for 2 min, Pd2(dba)3 (35.4 mg, 0.039 mmol) was added, and then degassed for 1 min. Cyclopropanamine (0.090 mL, 1.289 mmol) was added and the contents sealed. The suspension was stirred for 3 h at 100° C. (heat block). The reaction mixture was poured onto water and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to a solid residue. The aq. layer was extracted with 10% MeOH/DCM (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a solid. The combined solid residues were dissolved in DMSO and acetonitrile spiked with TFA, and purified by reverse phase HPLC (Gradient B: 10-70%. A: Water+0.1% TFA. B: CH3CN+0.1% TFA) The title compound was collected as 11 mg (10%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.39-0.47 (m, 2 H), 0.68-0.76 (m, 2 H), 1.39 (d, J=6.57 Hz, 6 H), 2.11 (s, 3 H), 2.24 (s, 3 H), 2.20 (s, 3 H), 2.64-2.72 (m, 1 H), 4.30 (d, J=4.80 Hz, 2 H), 4.89 (quin, J=6.69 Hz, 1 H), 5.86 (s, 1 H), 6.34 (s, 1 H), 7.25 (d, J=3.03 Hz, 1 H), 8.41 (t, J=4.93 Hz, 1 H), 11.49 (s, 1 H). LCMS(ES) [M+H]+ 409.1
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[N:11](CC3C=CC(OC)=CC=3)[C:10](=[O:21])[O:9][C:8]([CH2:26][NH:27][C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)([C:22]([F:25])([F:24])[F:23])[C:7]=2[CH:37]=1)#N.Br.[C:39]([OH:42])(=[O:41])C>O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:27][CH2:26][C:8]2([C:22]([F:25])([F:24])[F:23])[C:7]3[CH:37]=[C:3]([C:39]([OH:42])=[O:41])[CH:4]=[CH:5][C:6]=3[NH:11][C:10](=[O:21])[O:9]2)=[O:36])=[CH:34][CH:33]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(C#N)ccc32)cc1
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: O=C1Nc2ccc(C(=O)O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{[6-cyano-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide was dissolved in 25% hydrogen bromide-acetic acid (5 mL) and water (1 mL), and the solution was stirred overnight at 100° C. The temperature of the solution was brought to room temperature, and water was added thereto under stirring. After the solution was stirred at room temperature for 30 minutes, the resulting brown solid was dried under reduced pressure, whereby the objective compound (317 mg, 55%) was obtained as a brown solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[C:20](=[O:39])[C:19]=3[C:18]=2[O:40][CH3:41])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1.C(=O)([O-])O.[Na+]>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[N:29]([CH3:30])[C:17]([C:15]([NH:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:13][CH2:12]3)=[O:16])=[C:18]([O:40][CH3:41])[C:19]=2[C:20]1=[O:39]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1ccccc1Cl)c1ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1ccccc1Cl)c1ccccc21
Yield: 10.8 %

Procedure:
A solution of 2-[4-({[5-(2-chlorobenzyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl]carbonyl}amino)piperidin-1-yl]-2-oxoethyl acetate (80 mg) and potassium carbonate (100 mg, 0.71 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (8 mg, 2%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: C[C@H](CCl)CBr
Reactant: Oc1ccc(Br)cc1
Product: C[C@H](CCl)COc1ccc(Br)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1>>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-methoxy-benzene following the procedure of Example 478: MS (ESI) m/z 514.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 3trifluoromethylaniline using the same procedure described in example 5.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])(C)(C)C.[ClH:28]>C(Cl)Cl.C(OCC)(=O)C>[ClH:28].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred solution of [6-(2-Nitrobenzenesulfonylamino)-hexyl]-carbamic acid t-butyl ester (2.0 g, 4.9 mmol) in 25 mL of methylene chloride at room temperature was added 3 mL of saturated HCl solution in ethyl acetate and stirred for 4 h. The precipitated solid was filtered to yield the titled compound as white solid (1.58 g, 95%); mp 161-162° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[C:20]([Cl:27])=[CH:19][N:18]=1>C(O)(C)C>[Cl:27][C:20]1[C:21]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)=[C:22]([N+:23]([O-:25])=[O:24])[C:17]([NH2:16])=[N:18][CH:19]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: c1ccc(OCCN2CCNCC2)cc1
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(CCOc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
A mixture of 1-(2-phenoxy-ethyl)-piperazine (0.047 g, 0.23 mmol), isopropanol (4.0 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.034 g, 0.16 mmol) was heated at 45° C. for 18 h. The reaction mixture was allowed to cool to room temperature, absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% ethyl acetate in dichloromethane, 20% ethyl acetate in dichloromethane and finally 1% methanol in ethyl acetate/dichloromethane (v/v; 1:4). The title compound was obtained as a yellow solid (0.053 g, 88%); 1H-NMR (500 Mz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 2.76 (t, J=5.62 Hz, 2H, NCH2CH2O), 3.06 (br s, 4H, piperazine N(CH2)2), 4.09 (t, J=5.37 Hz, 2H, NCH2CH2O), 6.95 (m, 5H, 2-NH2 and o-ArH and p-ArH), 7.27 (t, J=11.20 Hz, 2H, m-ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 3.79 min—378, 380 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[O:23]1[CH2:26][C:25](=[O:27])[CH2:24]1>C1COCC1>[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:25]1([OH:27])[CH2:26][O:23][CH2:24]1
Reactant: O=C1COC1
Reactant: Brc1cccnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccncc2Br)COC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a magnetically stirred solution of 2,2,6,6-tetramethylpiperidine (2.50 g, 17.70 mmol) in dry THF (80 mL) under argon at −78° C. was slowly added over 2 min n-butyllithium (2.50 M in hexanes; 5.6 ml, 14.0 mmol). The reaction mixture was stirred at −78° C. for 5 min and then allowed to warm to about 0° C. over 10 min. The reaction mixture was cooled to −78° C. and slowly over 10 min was added dropwise neat 3-bromopyridine (1.335 ml, 13.61 mmol). The reaction mixture was stirred at −78° C. for 15 min, and then slowly treated with neat oxetan-3-one (870 mg, 12.07 mmol) over 2-3 min. The reaction mixture was then allowed to warm to room temperature slowly over 18 h. The reaction mixture was concentrated in vacuo, then partitioned with ethyl acetate/aqueous saturated NH4Cl and solid sodium bicarbonate until pH ˜8-9 was achieved. The aqueous layers were saturated with sodium chloride and back extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to give a red oil. The crude material was purified by Biotage Silica gel chromatography on a 80 g Thompson Single Step™ silica cartridge using a linear gradient from 100% CH2Cl2 to 100% ethyl acetate over 12 column volumes to give to give 860 mg (31%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.75 (1 H, s), 8.58 (1 H, d, J=5.0 Hz), 7.24 (1 H, d, J=5.0 Hz), 5.16 (2 H, m), 4.91 (2 H, m), 3.12 (1 H, br.s). LC/MS (Condition B): ret. T=1.1 min, (M+H)+ 229.89, 231.89.
Reaction SMILES: COC[O:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1.[Li]CCCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>C1COCC1.CCCCCC.O.CO.C(Cl)Cl.CCCCCC>[Cl:19][C:6]1[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COCOc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: Oc1ccc2c(c1Cl)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a cooled (−78° C.) solution of 5-methoxymethoxy-benzo[1,3]dioxole (5.0 g, 27.35 mmol) in THF (25 mL) was slowly added 2.5 M solution of n-BuLi in hexane and stirred at nitrogen atmosphere. After 30 minutes, a solution of hexachloroethane (12.95 g, 54.7 mmol) in THF (25 mL) was added and then resulting mixture was allowed to warm to room temperature and stirred for 7 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4) and concentrated under vacuum to get crude product. The obtained product was dissolved in methanol (50 mL) and 0.5 mL conc. HCl and then heated at 50° C. for 2 h. The reaction was concentrated, dissolved in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate. The solvent was evaporated under vacuum to give crude product. Silica gel column chromatography (30% CH2Cl2/Hexane) gave 4-chloro-benzo[1,3]dioxol-5-ol (3c) (2.5 g, 53%). 1H NMR (CDCl3) δ 5.12 (s, 1H), 6.0 (s, 2H), 6.47 (d, 1H, J=9.0 Hz), 6.62 (d, 1H, J=9.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCl
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nnnc1-c1ccccc1
Yield: 18.1 %

Procedure:
Two grams of 5-phenyltetrazole (13.68 mM) were slowly added to 5 ml of a methanol solution containing 770 mg (13.68 mM) of potassium hydroxide at room temperature. Two milli liters of a methanol solution containing 1.48 g (13.68 mM) of methyl chloroacetate were dropwise added to the resultant solution at room temperature. After the completion of the addition, the reaction solution was refluxed for 20 hours and cooled. The reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elute is chloroform), to give 0.54 g of methyl 5-phenyl-1-tetrazoleacetate (yield: 18.1%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]=[CH:15][C:16]#[N:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]=[CH:15][C:16]#[N:17])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C=CC#N)cc1
Agent: O=S(=O)(O)O
Product: N#CC=CS(=O)(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
3-(4-acetamidobenzenesulfonyl)acrylonitrile, prepared as described in the aforesaid U.S. Pat. No. 3,541,119, is nitrated at about room temperature in a mixture of nitric acid and concentrated sulfuric acid for about two hours, and thereafter drowned in ice water. The 2-cyanovinyl 4-acetamido-3-nitrophenyl sulfone recovered is hydrolyzed in a mixture of dilute hydrochloric acid and ethanol to give 2-cyanovinyl 4-amino-3-nitrophenyl sulfone. 25.3 g (0.1 mol) of this material is carefully dried and is dispersed in 500 ml chloroform and 11.2 g 1,4-diaza-[2.2.2]octane is added thereto. A chloroform solution of difluoromethanesulfonyl chloride in about 10% excess is added to the stirred mixture of the substituted aminoarene and the acid acceptor at 50° C. The mixture is stirred at this temperature for 2 hours and is then maintained at room temperature for 2 days. After treatment with dilute HCl to remove the tertiary amine and unreacted starting material, and evaporation of the solvent, a crude material is obtained which is purified by recrystallization, giving 2-cyanovinyl 4-difluoroacetamido-3-nitrophenyl sulfone: ##SPC7##
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([C:11](O)=[O:12])[C:8](=[O:10])[O:9][C:4]=2[C:3]=1[OH:16].S(Cl)([Cl:19])=O>>[OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([C:11]([Cl:19])=[O:12])[C:8](=[O:10])[O:9][C:4]=2[C:3]=1[OH:16]
Reactant: O=C(O)c1cc2ccc(O)c(O)c2oc1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2ccc(O)c(O)c2oc1=O

Procedure:
7,8-Dihydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (50 mg) was heated under reflux for 5.5 hours in thionyl chloride (20 mL), and then thionyl chloride was distilled off. Benzene (10 mL) was added to the residues, and the benzene was distilled off, followed by vacuum drying, to yield 7,8-dihydroxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride.
Reaction SMILES: NC1C([N+]([O-])=O)=CC=C2C=1C=CC=N2.NC1C(N)=CC=C2C=1C=CC=N2.[Sn](Cl)Cl.[NH2:30][C:31]1[C:40]([NH:41][C:42]([CH3:44])=[O:43])=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2.C(OC(=O)C)(=O)C.[CH2:52]([S:58][CH:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[C:60](O)=[O:61])[CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>N1C=CC=CC=1>[NH:41]([C:40]1[C:31]([NH:30][C:60](=[O:61])[CH:59]([S:58][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[CH:33]2)[C:42]([CH3:44])=[O:43]
Reactant: CCCCCCCCC(SCCCCCC)C(=O)O
Reactant: CC(=O)Nc1ccc2ncccc2c1N
Agent: Cl[Sn]Cl
Agent: Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: Nc1ccc2ncccc2c1N
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(NC(C)=O)ccc2ncccc12

Procedure:
Commercially available 5-amino-6-nitroquinoline was reduced to 5,6-diaminoquinoline using a procedure analogous to that described in Example 34, except tin (II) chloride was used in place of iron. 5,6-Diaminoquinoline was converted to 5-amino-6-acetaminoquinoline by reaction with acetic anhydride and pyridine. Using the procedure outlined in Example 25, 5-amino-6-acetaminoquinoline and 2-(hexylthio)decanoic acid were coupled to give the title compound. Mass spectrum m/e: 471.3 (M+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Br[CH2:19][CH2:20][OH:21]>CN(C=O)C.CCOC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:17][CH2:19][CH2:20][OH:21]
Reactant: COc1ccc(O)cc1OC
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCCO)cc1OC
Temperature: 120 °C
Yield: 60 %

Procedure:
K2CO3 (1.07 g, 7.78 mmol) was added to a solution of 3,4,dimethoxyphenol (1.0 g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.81 g, 6.48 mmol) was added, and the mixture was heated overnight at 120° C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4×20 ml), dried over MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 60% yield. B. Synthesis of 4-(2-bromo-ethoxy)-1,2-dimethoxy benzene
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]2([CH3:2])[O:13][CH2:12][CH2:11][O:3]2)=[CH:9][N:8]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Br)nc2)OCCO1
Temperature: 140 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A mixture of 5-acetyl-2-bromopyridine (0.6 g, 3.00 mmol), ethylene glycol (0.535 ml, 9.60 mmol), p-toluenesulfonic acid monohydrate (0.171 g, 0.900 mmol), and toluene (12.00 ml) was stirred at 140° C. for 5 hours. The reaction mixture was washed with saturated sodium bicarbonate and brine. The aqueous layer was back extracted with ethyl acetate and the combined organics dried with magnesium sulfate and concentrated to give crude 2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (0.575 g, 2.356 mmol, 79% yield) as an orange oil. It was used without further purification.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:22][CH2:23][CH2:24][CH3:25])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].O.C(=O)(O)[O-].[Na+:31].C>O1CCOCC1.[Pd]>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:22][CH2:23][CH2:24][CH3:25])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:31]
Reactant: CCCNC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCNC1=C(C(=O)[O-])N2C(=O)C(C(C)O)C2C1
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg) is dissolved in dioxane (2 ml) and water (1 ml) containing sodium bicarbonate (7.5 mg). 10% palladium on powdered charcoal (30 mg) is added and the resulting mixture is hydrogenated at 40 psi for 1 hr. The catalyst is filtered off and washed with water (3 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), conc. in vacuo, and lyophilized to afford sodium 6-(1-hydroxyethyl)-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]2([CH2:24]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]2=[O:23])=[C:4]([OH:26])[CH:3]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]2[O:26][CH2:24][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]3=[O:23])[C:5]=2[CH:6]=1
Reactant: CCCCCN1C(=O)C(CO)(c2cc(Cl)c(Cl)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc(Cl)c(Cl)cc32)c2ccccc21
Yield: 43 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(4,5-dichloro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 43% yield. 1H NMR (300 MHz, CDCl3) δ 7.35 (td, 1H), 7.17-7.03 (m, 3H), 6.94 (d, 1H), 6.76 (s, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.88-3.65 (m, 2H), 1.82-1.67 (m, 2H), 1.47-1.29 (m, 4H), 0.92 (t, 3H). 13C NMR (75 MHz, CDCl3) δ 176.2, 159.9, 142.5, 133.3, 131.5, 129.4, 124.6, 124.5, 123.9, 123.4, 112.4, 108.9, 80.8, 57.5, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 376 (M+1), 378 (M+1).
Reaction SMILES: [OH-].[Na+].CO.C1COCC1.[CH2:10]([N:17]1[C:22]([CH2:23][CH3:24])=[C:21]([CH3:25])[CH:20]=[C:19]([C:26]([O:28]CC)=[O:27])[C:18]1=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O>[CH2:10]([N:17]1[C:22]([CH2:23][CH3:24])=[C:21]([CH3:25])[CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]1=[O:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(C)c(CC)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C)cc(C(=O)O)c(=O)n1Cc1ccccc1
Reaction time: 2 h
Yield: 83.7 %

Procedure:
2M sodium hydroxide solution (7.9 mL, 15.8 mmol) was added to a methanol/THF (7.9 mL/7.9 mL) solution of ethyl 1-benzyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (AA06, 1.92 g, 6.3 mmol), which had been obtained in Example 6, at room temperature and stirred at the same temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and washed with ether (20 mL). 2M hydrochloric acid (8 mL, 16 mmol) was added to the water layer and the obtained mixture was extracted with ethyl acetate (20 mL) two times. The organic layer was washed with water (20 mL) two times and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and yellow oily 1-benzyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (AA07, 1.43 g) was obtained. The product was let alone for a night and was crystallized. The crystal was recrystallized from ethyl acetate and a white columnar crystal (AA07, 1.00 g, 58.5%) was obtained.