Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 73.6 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (772 mg, 4 mmol), aniline (364 μL, 4 mmol) and DIEA (838 μL, 24.8 mmol) in 10 mL THF was stirred at r.t. for 70 h. After removal of the solvent, the residue was dissolved in DCM, and subjected to silica gel column purification to give 735 mg (yield 74%) of the title compound. LC-MS: Calculated mass=249. Observed mass=250.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[O:12]1[C:11]2([CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Temperature: 25 °C
Yield: 100 %

Procedure:
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.55 g, 3.85 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (15 ml). The reaction was stirred and allowed to slowly warm to ambient temperature during 3 hours. The solution was concentrated in vacuo to give crude 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione which was used directly in the following step (assumed 100% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In an inert atmosphere, 0.268 g of bis(triphenylphosphine) palladium dichloride and 0.072 g of cuprous iodide was added with stirring to a deoxygenated solution of 5 g of 4-bromoisoquinoline, 3.02 g of 3-butyn-1-ol and 10 mL of triethylamine in 20 mL of dichloromethane. The reaction was stirred at room temperature for 1 hour and then at reflux for 18 hours. The cooled mixture was filtered and the filtrate was washed with water. The dried (Na2SO4) organic phase was concentrated in vacuo and the residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=1)[C:14]([NH:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15].Br[CH2:29][C:30]([NH2:32])=[O:31]>CS(C)=O.O>[C:30]([CH2:29][N:7]1[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=2)[C:14]([NH:16][CH2:17][C:18]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])[C:2]1=[O:1])(=[O:31])[NH2:32]
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Reactant: NC(=O)CBr
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-n2ncc(=O)n(CC(N)=O)c2=O)cc1C(=O)NCC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO, (290.3 mg, 0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambient temperature for 14 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo to a tan oil. The crude was triturated from IPE/Et2O/CH2Cl2 to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (26.3 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.47 mL, 0.0276 mol) in tetrahydrofuran (33.61 mL). The reaction was warmed to room temperature and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.0 g, 0.025 mol) in tetrahydrofuran (6.72 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexanes, to give the desired product (5.40 g, 97%). LCMS (M+Na) 244.9.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31]O)[CH:8]=2)[N:3]=1.S(Cl)([Cl:35])=O>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31][Cl:35])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: O=S(Cl)Cl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of thionyl chloride are added to 2 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone, and the mixture is stirred at 25° C. for 1 h. The mixture is subsequently evaporated to dryness in vacuo, the residue is taken up a further twice with 50 ml of dichloromethane each time, and the mixture is again evaporated to dryness in vacuo.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17]
Reactant: COc1c(OC(C)=O)ccc(C=O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A mixture of 4-formyl-2-methoxy-3-nitrophenyl acetate 438 g (1.8 mol) and potassium carbonate (506 g, 3.7 mol) in MeOH (4000 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford a viscous oil. This was dissolved in water, acidified using a solution of HCl (2 N) and extracted with EtOAc. The organic layer was washed with a saturated sodium chloride solution, dried (magnesium sulfate) and filtered. The solvent was concentrated under reduced pressure to ⅓ volume and the resulting solids were filtered and air-dried to give 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (317 g, 88%): 1H NMR (DMSO-d6) δ: 9.69 (1H, s), 7.68 (1H, d), 7.19 (1H, d), 3.82 (3H, s).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[K+]>O.C(O)C>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution 4-benzyloxy-benzoic acid methyl ester (3) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature, quenched with hydrochloric acid (5%). The resulting white solid was filtered, washed with water, and dried under vacuum to give 4-benzyloxy-benzoic acid (4)) as a white solid (80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a suspension of 15.0 g of methyl 4-benzyloxybenzoate in 225 ml of methanol were added 18.6 ml of a 5N solution of sodium hydroxide. The mixture was heated at reflux for 18 hours. The solution was cooled to room temperature and acidified to pH 3 by addition of 6N hydrochloric acid. The resulting white precipitate was filtered to give 13.6 g of the title compound: 300-MHz 1H NMR (DMSO-d6) δ5.18 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.26-7.49 (m, 5H), 7.86 (d, J=9 Hz, 2H), 12.3 (b s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[C:12](Br)[CH:13]=4)[C:4]=2[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:23][C:15]1([CH3:22])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:13]=2
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cc(Br)cc1c32
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32

Procedure:
19.8 g (45 mmol) of 3,6-dibromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine, 11.4 g (94 mmol) of phenylboronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1500 ml of toluene and 150 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh)3 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1>[O-2].[O-2].[Mn+4].O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([C:10]([CH3:11])=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(C)=O)n1Cc1ccccc1Cl
Reaction time: 17 h
Yield: 59.2 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(α-hydroxy)ethyl-1H-imidazole (1.07 g, 3.65 mmol), activated manganese dioxide (6 g) and toluene (75 mL) was heated at 90° to 100° C. under a slight vacuum with a Dean Stark water separator for 17 hours. The inorganics were filtered, the concentrated filtrate was applied to a flash silica gel column and the product was eluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].O>[Fe].C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reaction time: 3 h
Yield: 90 %

Procedure:
(4-Nitro-benzyl)-carbamic acid tert-butyl ester (6.34 g, 25.1 mmol), iron powder (6.5 g, 116 mmol), ammonium formate (13.0 g, 206 mmol), H2O (75 mls), and toluene (75 mls) were combined and heated to reflux. After 3 hrs the reaction mixture was allowed to cool and filtered through Celite with thorough washing with EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The organic phase was further washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give (4-amino-benzyl)-carbamic acid tert-butyl ester (5.02 g, 90% yield). LC/MS Calcd for [M+H]+ 223.1, found 167.1 (minus t-butyl).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2ccnc2)ncn1
Yield: 63.1 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), imidazole (2.72 g, 40.0 mmol), and potassium carbonate (5.53 g, 40.0 mmol) was stirred in DMF (50 mL) at room temperature for 18 h. The reaction was diluted into 500 mL water and extracted five times with 150 mL EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 0 to 10% methanol in ethyl acetate to yield 4-chloro-6-(1H-imidazol-1-yl)pyrimidine (4.56 g, 63% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.85 (1H, d, J=0.76 Hz), 8.45 (1H, s), 7.62 (1H, t, J=1.51 Hz), 7.34 (1H, d, J=0.76 Hz), 7.23 (1H, dd, J=1.38, 0.88 Hz). LCMS: RT=0.47 min, MH+=181.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[C:15]([CH3:17])[S:14][C:13]=2[CH3:18])=[C:4](Cl)[N:3]=1.Cl.[OH-:21].[Na+]>>[CH3:18][C:13]1[S:14][C:15]([CH3:17])=[CH:16][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:21])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: [OH-]
Reactant: Cc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(C)s1
Agent: Cl
Agent: [Na+]
Product: Cc1cc(Cn2cnc3c(=O)[nH]c(N)nc32)c(C)s1

Procedure:
A mixture of 2-amino-9-[(2,5-dimethyl-3-thienyl)methyl]-6-chloropurine (3.8g, 0.0129 mol) and 2N HCl was heated on a steambath for 3.0 hours and then heated under reflux for another hour. At the end of this time 1N NaOH solution was added to the solution till basic and the mixture was heated for another five minutes. The mixture was then acidified with acetic acid,cooled, and filtered to give 3.6 g, of the product. An analytical sample was obtained by chromatography over silica gel using 10% methanol/chloroform as eluting solvent, mp>300° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (312) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in Pyridine (0.13 ml, 1.53 mmol)-CH2Cl2 (3.7 ml) was stirred at room temperature for 12 hr. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 181 (237 mg, 41%, in 3 steps).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[NH4+]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: CC1=NCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Product: CC1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Methyl-3,4-dihydroisoquinoline (4.25 g, 29.3 mmol) was dissolved in ice cold concentrated sulfuric acid (15 ml) and to this was added potassium nitrate (3.25 g, 32.2 mmol) portionwise with cooling. The mixture was stirred overnight, poured over ice, basified with concentrated ammonium hydroxide, and the precipitated solid was collected, washed with water and dried: 4.47 g (80%), MS (M+H)+ 191, 1H NMR (D2O), 8.30 (d, 1H), 8.22 (dd, 1H), 7.39 (d, 1H), 3.80-3.62 (m, 2H), 2.92-2.70 (m, 2H), 2.48 (broad s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Yield: 226.5 %

Procedure:
To 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added triphosgene (3.55 g, 12 mmol). This mixture was heated to reflux under a nitrogen atmosphere for 3 hours. It was cooled to ambient temperature, and diethyl ether (50 mL) was added. The mixture was filtered to yield 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (5.25 g, 91%) as a solid.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[SH:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].Cl.CN(C)CCCN=C=NCC>ClCCl>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:15](=[O:17])[C@H:2]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2)[CH:12]=1)[CH3:1]
Reactant: OCCCCS
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)SCCCCO)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of naproxen (5.03 g, 21.9 mmol), 4-mercapto-1-butanol (2.32 g, 21.9 mmol) and N,N-dimethylaminopyridine (DMAP) (0.534 g, 4.37 mmol) in dichloromethane (200 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC) (5.03 g, 26.2 mmol) as a solid, in portions. The reaction mixture was stirred for 3 hours at room temperature, then partitioned between dichloromethane and water, and the water layer was washed with more dichloromethane. The combined organic layer was washed with water and brine, then dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 50% ethyl acetate/hexane. The appropriate fractions were combined, and the solvent removed by rotary evaporation to give an oil, 2.647 g, which contained 19% 4-mercapto-1-butanol by weight (product weight 2.07 g, 6.5 mmol, 30% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=2.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 4.02 (q, J=7.1 Hz, 1H), 3.92 (s, 3H), 3.61-3.64 (m, 2H), 2.87 (m, 2H), 1.61 (d, J=7.1 Hz, 3H), 1.59 (m, 2H), 1.41 (m, 2H); mass spectrum (API-TIS) m/z 319 (M+H+), 336 (M+18+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=[O:10])=[CH:3][CH:2]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=C=O)=[CH:18][CH:17]=1)([O:13][CH2:14][CH3:15])=[O:12]>>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1C=O
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Product: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 170 °C

Procedure:
A mixture of o-phthalicdicarboxaldehyde (17.54 g, 0.131 mol) and p-carbethoxyphenylisocyanate (25.0 g, 0.131 mol) is heated in an oil bath at 170° C. for 4.0 hours under nitrogen atmosphere. The hot melt is then slowly poured into CHC13 (300 ml). The solution is then evaporated to dryness when a solid residue is obtained. The crude 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester is triturated with isopropyl ether and then recrystallized from CH2Cl2 - isopropyl ether (1:1, 300 ml) to give white solid. Yield 5.07 g (13.8%); mp 182°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([OH:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[H-].[Na+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6.5 g of (S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 175 ml of DMF was cooled to 0° C. Then, 644 mg of sodium hydride (60% in mineral oil) was added portionwise over 20 min. Further 20 min after completion of the addition 2.9 g of 1-Bromo-3,3-dimethyl-butan-2-one was added and the reaction mixture was allowed to warm to RT. After striring for 16 h the reaction mixture was diluted with brine and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 3.3 g.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Under inert atmosphere 10 ml of BH3 ·THF complex (1.0 M THF solution) were added to 30 ml THF solution of 2.15 gr (6.41 mmole) of 16-bromohexadecanoic acid at -20° C. Reaction mixture was stirred at this temperature for 2 hrs and then additional 1 hr at RT. After that time the resulted mixture was poured, with stirring, into a vessel containing 200 ml of ice/saturated sodium bicarbonate aqueous solution. Organic compounds were extracted with 3×200 ml of ether. The ether fractions were combined and dried over sodium sulfate. After removal of ether material was dissolved in minimum amount of dicloromethane and purified by silica gel chromatography (100% dicloromethane as eluent). 1.92 gr (93% yield) of the desired product were obtained.