Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O.[CH2:32](Br)[CH2:33][CH3:34]>C(#N)C>[CH2:32]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:33][CH3:34]
Reactant: CCCBr
Reactant: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCOc1cccc(-c2cc(=O)oc3cc(OC)ccc23)c1
Temperature: 98.5 °C
Reaction time: 21 h

Procedure:
4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (1.78 kg) and K2CO3 (1.65 kg) were suspended in acetonitrile (7.20 L) and N,N-dimethylformamide (1.80 L) and the mechanically stirred mixture was heated to 65° C. When the reaction had reached 65° C., neat n-propylbromide (1.48 kg) was added and the mixture was stirred another 21 hours. The slurry was heated to 88-109° C. and concentrated by distillation. When 6.8-7.0 L of distillate had been removed, the slurry was cooled to 40° C. and diluted with water (14.4 L) and stirred while cooling slowly to 20° C. The slurry was filtered to collect the title compound as a pink, amorphous solid, which was washed with water (2.0 L). The air-dried product was recrystallized from a mixture of hexanes (11.9 L) and isopropanol (6.2 L) at 50° C. Filtration at 22° C. gave a very pale pink, crystalline solid which was washed with hexanes (250 mL) and air-dried. Weight=1.70 kg (5.58 mol, 83%). A second crop of product was isolated from the partially concentrated mother liquors; the light pink, crystalline solid weighed 307 g (0.989 mol, 15%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[N:40]([CH3:42])[CH3:41])=[CH:34][C:33]=1[C@H:44]1[CH2:48][CH2:47][CH2:46][NH:45]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C@@H:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:1]([NH2:2])=[O:3])[C:12]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:44]2[C:33]2[CH:34]=[C:35]([NH:38][C:39]([N:40]([CH3:42])[CH3:41])=[O:43])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1[C@H]1CCCN1
Agent: Cl
Product: COc1ccc([C@@H](Nc2cccc(C(N)=O)c2)C(=O)N2CCC[C@@H]2c2cc(NC(=O)N(C)C)ccc2S(=O)(=O)C(C)C)cc1OC

Procedure:
Example 56 was prepared according to the general coupling condition using 1A and 31A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.17 (d, J=6.60 Hz, 3 H) 1.42 (d, J=7.15 Hz, 3H) 1.73 (dd, J=12.64, 5.50 Hz, 1H) 1.91-2.21 (m, 2H) 2.47 (dd, J=13.19, 7.70 Hz, 1H) 2.97 (s, 6H) 3.61 (s, 3H) 3.63-3.74 (m, 1H) 3.80-3.85 (m, 3H) 3.87-3.99 (m, 1H) 4.03-4.16 (m, 1H) 5.37 (s, 1H) 5.66 (dd, J=8.25, 4.95 Hz, 1H) 6.79 (s, 1H) 6.83-6.96 (m, 3H) 7.02 (d, J=8.25 Hz, 1H) 7.17-7.28 (m, 3H) 7.39 (dd, J=8.79, 2.20 Hz, 1H) 7.72 (d, J=8.79 Hz, 1H), LC-MS 652 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[NH:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:20])=[O:2])=[C:7]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1NC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Nc1cc(C(C)(C)C)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
3-(4-tert-butyl-2-isopropylaminophenyl)acrylic acid methyl ester (0.14 mmol, 37.7 mg) and NaOH (0.68 mmol, 27.39 mg) were added in methanol and water. The reaction mixture was stirred for 12 hrs at room temperature. The reaction mixture was acidified with 5% HCl solution. The mixture was concentrated in vacuo to yield a yellow solid (36.56 mg, 100%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[CH:16]=[N:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[CH:16]=[N:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33]
Reactant: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
To a solution of 3-(5-isopentyl-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (15 mg, 0.033 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (2.79 mg, 0.066 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 3-(3-hydroxypropyl)-5-isopentyl-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 56.8% yield) as a white solid. 1H NMR (CDCl3) δ: 8.35 (s, 1H), 7.43-7.42 (d, J=4.0 Hz, 2H), 7.28-7.24 (m, 1H), 7.07-7.05 (m, 1H), 4.27 (m, 3H), 3.76 (s, 3H), 3.58 (s, 2H), 3.40-3.31 (m, 2H), 2.68-2.54 (m, 2H), 1.97-1.94 (m, 2H), 1.57 (m, 1H), 1.22-1.19 (m, 3H), 1.08-1.06 (m, 3H), 0.71-0.69 (m, 3H), 0.64-0.62 (d, J=8 Hz, 3H). LCMS: MH+ 424 and TR=3.546 min.
Reaction SMILES: [CH:1]1([C:7]2[C:11](=C)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][Li]>C1COCC1.CCOCC.O>[CH3:13][C:1]1([C:7]2[CH2:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [Li]C
Reactant: C=C1C=CC=C1C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C2=CC=CC2)CCCCC1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of 6.50 g (44.5 mmol) of cyclohexylfulvene in 60 ml of THF, 44.8 ml (51.1 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.72 g (16.76 mmol) of a colorless transparent liquid (yield: 38%) The analyzed values are given below.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CN(C)C=O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]([F:13])([F:23])[F:24])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: Cc1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
Orcinol monohydrate (4.30 g, 30 mmol) in N,N-dimethylformarnide (20 mL) was added to a suspension of sodium hydride (1.5 g, 60 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at ambient temperature for 30 minutes. To the above solution was slowly added 2-trifluoromethylbenzyl chloride (5.0 g,25 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at ambient temperature for 3 hours. After carefully quenching with water (100 mL), the mixture was extracted with ethyl acetate (3×100 mL). The ethyl acetate solution was washed with brine (2×100 mL) and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (3:1 hexane/ethyl acetate) to give the title compound as a white solid (2.9 g, 41%). 1H-NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1 H), 7.68 (d, J=7.9Hz, 1 H), 7.56 (t, J=7.7 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.39 (s, 1 H), 6.28 (s, 2 H), 5.22 (s, 2 H), 4.79 (s, 1 H), 2.27 (s, 3 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[Cl:29].[Br:30]C(Br)(Br)Br>O1CCCC1>[Br:30][CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[Cl:29]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1csc(CO)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1csc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36.1 g (137 mmol) of triphenylphosphine were added at 5° C. to a solution of 21.7 g (125 mmol) of 5-hydroxymethyl-4-chlorothiophene-3-carbonitrile in 250 ml of tetrahydrofuran. Then, a solution of 45.6 g (137 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was stirred overnight at room temperature. The precipitate was filtered off, the filtrate was concentrated on a rotary evaporator under a water pump vacuum, and the residue was purified by column chromatography (eluant petroleum ether:dichloromethane 1:1). This gave 26.0 g (88%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH3:16].C([O-])(=O)C.[NH4+:28].C1(C)C=CC=CC=1>C(OCC)(=O)C>[NH2:9][C:8]1[N:28]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[C:4]([C:3]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=2[Cl:1])[C:5]=1[C:6]#[N:7]
Reactant: CC(=O)c1ccccc1
Reactant: [NH4+]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cc(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
A mixture of 2-(2,4-dichloro-benzylidene)-malononitrile (1.125 g, 5 mmol), acetophenone (601 mg, 5 mmol), ammonium acetate (578 mg, 7.5 mmol), and toluene (5 ml) was stirred for 3 h at reflux. Upon cooling to room temperature, the mixture was taken up in ethyl acetate and extracted with satd. NaHCO3, water, and satd. NaCl, and dried over Na2SO4. The solvent was then evaporated and the title compound (600 mg, 35%), MS: m/e=339.5 (M+H+), was isolated from the residue by column chromatography (silica gel, hexanes, ethyl acetate).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1>CO>[F:17][C:14]1[CH:15]=[CH:16][C:9]([OH:8])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(F)ccc1OCc1ccccc1
Solvent: CO
Product: N#Cc1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
Dry 10% Pd/C (2.48 g) was placed in a 5 L flask under N2. A solution of 2-(benzyloxy)-5-fluorobenzonitrile (148 g, 651 mmol) in methanol (2.34 L) was added slowly under N2. The air of the flask was removed by vacuum and the flask was charged with H2 (balloon) three times. The mixture was stirred at room temperature for 1 hour. The above process was repeated two more times to push the reaction to completion. The mixture was stirred at room temperature for another 2 hours. The mixture was filtered through a Celite pad under N2 and washed with EtOAc (150 mL×2). The palladium waste was rinsed with water (50 mL) and discarded. The filtrates were concentrated to give (94.6 g, 106%) of the desired compound as a yellow solid. MS (APCI-) m/z 137 (M−1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (br, 1H), 7.58 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.43 (m, 1H), 6.91-7.03 (dd, 1H J=4.5 Hz, J=9.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].C1COCC1.[H-].[Na+].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])[C:10]#[N:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
Slurry 2,4-dichlorophenylacetonitrile (I) (5.0 g, 26.9 mmol, 186.04 g/mol) in ethyl trifluoroacetate (6.4 mL, 7.6 g, 142.08 g/mol) and add 20 mL anhydrous THF. Portionwise at ambient temperature add NaH (1.88 g, 47.1 mmol, 60% in mineral oil) over 5 minutes. Heat reaction to reflux (90° C. bath temperature) overnight. Evaporate to thick red-brown oil and partition between Et2O (100 mL) and H2O (60 mL). Separate layers and extract H2O with Et2O (2×75 mL). Acidify the aqueous layer with 1.0 N HCl to pH 1 (becomes cloudy white suspension) and extract aqueous layer with CH2Cl2 (3×100 mL). Dry pooled CH2Cl2 layers over Na2SO4, filter and concentrate to yellow oil (7.5 g, 26.5 mmol). Use without further purification. LCMS=281.9 (MH+); 279.8 (M−)
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][CH:9]([O:12][CH2:13][CH3:14])[CH2:10][OH:11])[CH3:7].CN(C)C(=O)C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1>O>[CH2:6]([O:8][CH:9]([O:12][CH2:13][CH3:14])[CH2:10][O:11][C:22]1[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[CH3:7].[Cl:21][C:22]1[N:27]=[CH:26][C:25]([O:11][CH2:10][CH:9]([O:12][CH2:13][CH3:14])[O:8][CH2:6][CH3:7])=[CH:24][N:23]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: CCOC(CO)OCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Cl)nc1)OCC
Product: CCOC(COc1ncc(F)cn1)OCC
Reaction time: 1 h
Yield: 67 %
Yield: 21 %

Procedure:
With cooling with ice, a tetrahydrofuran solution (2 ml) of 2,2-diethoxyethanol (668 mg, 4.98 mmol) was added to a mixed tetrahydrofuran (4 ml)/N,N-dimethylacetamide (2 ml) solution of 2-chloro-5-fluoropyrimidine (600 mg, 4.53 mmol), and stirred under a nitrogen atmosphere for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. Next, the organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Moritex, acetone:hexane=1:25) to obtain 2-(2,2-diethoxyethoxy)-5-fluoropyrimidine (699 mg, yield: 67%) as a colorless oil, and 2-chloro-5-(2,2-diethoxyethoxy)pyrimidine (233 mg, 21%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC(Cl)=C.Cl>O>[Cl:9][C:10]1[CH:15]=[C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]2=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: O=C1C=C(Cl)C(=O)O1
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Product: O=C1OC(=O)c2cc(Cl)ccc21
Temperature: 105 °C
Yield: 80 %

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing addition funnel, a thermocouple well with thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 13.2 g (0.10 mol) of a 90/10 GC area % mixture of monochloromaleic anhydride and dichloromaleic anhydride and 100 mg of phenothiazine and 0.5 g of activated carbon. The contents of the flask were heated to 80 to 130° C. and 8.8 g (0.1 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 6 hours at 130° C. the contents of the flask were sparged with oxygen for 2 hours between 130° and 150° C., filtered hot, and multiple distilled into two fractions resulting in the isolation of 13.2 g (80% of theoretical) of 4-chlorophthalic anhydride.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[N:12][NH:13][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])[N:13]=[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCn1c(=O)c2[nH]ncc2n(CCCC)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCn1c(=O)c2nn(S(=O)(=O)CCCCl)cc2n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To 222 mg (0.84 mmol) of 4,6-dibutyl-1,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-dione in 10 mL CH2Cl2 was added 0.22 mL (163 mg, 1.26 mmol) of i-Pr2NEt followed by 0.11 mL (164 mg, 0.924 mmol) of 3-chloro-n-propanesulfonyl chloride. The resulting solution was stirred at 23° C. for 16 h after which time TLC shows that all starting material had been consumed. The reaction mixture was poured into brine, extracted with 2×50 mL EtOAc, and the combined organics were washed with 1×50 mL brine, dried over MgSO4, filtered and evaporated to a yellow solid. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (40/1 to 20/1) gave the title compound. Recrystallization from hot hexanes/EtOAc gave 168 mg (0.415 mmol, a 49% yield) of the title compound as a white crystalline solid. mp: 67-68° C.; 1H NMR (300 MHz, CDCl3); δ 0.92-1.02 (m, 6H), 1.34-1.49 (m, 4H), 1.56-1.79 (m, 4H), 2.21-2.34 (m, 2H), 3.65 (t, J=6.1 Hz, 2H), 3.79-3.88 (m, 4H), 4.17 (t, J=7.3 Hz, 2H), 7.87 (s, 1H); IR (KBr, cm-1): 3137w, 2958w, 1718m, 1677s, 1626w, 1380m, 1166m; MS (ES) m/z (relative intensity): 405 (M+ +H, 100); Anal. Calcd. for C16H25ClN4O4S: C, 47.46; H, 6.22, N, 13.84. Found: C, 46.80; H, 6.06; N, 13.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].Cl>CN(C)C=O.O>[CH2:27]([O:26][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A suspension of 6.9 g (30 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10 g (100 mmol) of potassium bicarbonate, and 100 ml of water is stirred at room temperature and 300 ml of dimethylformamide is added followed by 6.0 ml (43 mmol) of benzyl chloroformate. The mixture is stirred at room temperature for 2 hrs and 6.0 ml of benzyl chloroformate and 6.0 g of potassium bicarbonate are added. The reaction is stirred overnight at room temperature and poured into 700 ml of ice water. The pH is adjusted to 3 with hydrochloric acid and the precipitate is filtered, washed with water, and dried to give 9.44 g of 6-[4-(benzyloxycarbonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide-methanol.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:8][CH:9]([CH2:22][CH3:23])[C:10]([NH:12][C:13]([CH3:21])([CH3:20])[C:14]#[C:15][CH2:16][CH2:17][CH2:18]Cl)=[O:11].[I-].[Na+].CCCCCC.[C:36](OCC)(=[O:38])C>CO.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:8][CH:9]([CH2:22][CH3:23])[C:10]([NH:12][C:13]([CH3:21])([CH3:20])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][O:38][CH3:36])=[O:11]
Reactant: CCOC(C)=O
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCCl
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCOC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of sodium methoxide (prepared from sodium, 0.014 g) in methanol (2 ml) at ambient temperature was added 2-(3,5-dichlorophenoxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide (0.20 g) followed by further sodium methoxide (0.3 g) and sodium iodide (0.1 g). The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 4 hours, heated to reflux for a total of 10 hours, cooled to ambient temperature then stored for 18 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (three times) and the extracts were combined, washed with brine then evaporated under reduced pressure to give a yellow oil. The oil was fractionated by chromatography (silica; hexane/ethyl acetate, 3:1 by volume) to give the required product as a colourless oil, 0.055 g, 1H NMR (CDCl3) δ: 0.98-1.04(3H, t); 1.60(6H, s); 1.72-1.78(2H, m); 1.92-2.00(2H, m); 2.24-2.28((2H, t); 3.34(3H, s); 3.42-3.46(2H, t); 4.36-4.38(1H, t); 6.28(1H, s); 6.84(2H, s); 7.02(1H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:39]([NH:42][C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH:49]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:47]=[CH:46]2)(=[O:41])[CH3:40]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:53]([C:48]3[CH:49]=[C:50]4[C:45](=[CH:46][CH:47]=3)[CH:44]=[C:43]([NH:42][C:39](=[O:41])[CH3:40])[CH:52]=[CH:51]4)(=[O:55])=[O:54])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C(O)c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Yield: 61 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.40 mmol) and 6-acetylamino-2-naphthalenesulfonyl chloride (56.7 mg, 0.20 mmol, prepared by the procedure as described in J. Med. Chem., 1995, 38, 8, p. 1344-1354) in acetone (1.5 mL) was stirred at rt for 18 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (20.8 mg, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.38 m, 1 H) 0.66 (d, J=7.35 Hz, 3 H) 0.68 (d, J=6.99 Hz, 3H) 0.80 m, 1 H) 1.30 m, 1 H) 1.53 (s, 3 H) 2.02 m, 1 H) 2.10 (s, 3 H) 2.18 (m, 1 H) 7.52 m, 4 H) 7.69 m, 4 H) 7.99 (d, J=8.82 Hz, 1 H) 8.07 (d, J=8.82 Hz, 1 H) 8.11 (d, J=8.09 Hz, 1H) 8.38 (s, 2 H) 10.32 (s, 1 H) 10.87 (s, 1 H) 13.72 (s, 1 H).