Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1C
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (26 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 70 mg (yield 95%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:22]([C:20]1[CH:19]=[CH:18][C:3]([NH:4][C:5]2[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:21]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-{2-Fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (195 mg, 0.50 mmol) was dissolved/suspended in a mixture of MeOH (30 mL) and THF (20 mL) to which was added solid K2CO3 (139 mg, 1.01 mmol). This mixture was stirred for 48 h. at R.T. All solvent was then removed under reduced pressure, the residue taken up into EtOAc containing 10% MeOH (100 mL), and this solution washed with water (2×100 mL) and brine (100 mL). The combined aqueous fractions were back-extracted with EtOAc (2×100 mL). All EtOAc fractions were combined and dried with Na2SO4, the solvent removed under reduced pressure and the residue purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant). This gave 4-(4-ethynyl-2-fluoroanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (152 mg, 96%), m.p. (acetone/MeOH) 265-273° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.44 (br s, 1H), 10.41 (s, 1H), 8.49 (br t, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.45 (dd, J=11.5, 1.8 Hz, 1H), 7.33 (dd, J=8.3, 1.4 Hz, 1H), 5.62 (s, 1H), 4.72 (t, J=5.7 Hz, 1H), 4.24 (s, 1H), 3.50 (q, J=5.8 Hz, 2H), 3.31-3.23 (m, 2H). Anal. Calcd for C16H14FN3O3: C, 61.0; H, 4.5; N, 13.3. Found: C, 61.1; H, 4.3; N, 13.3.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][Si:13]([C:16]1([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17]1)([CH3:15])[CH3:14].Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[CH3:22][Si:21]([C:16]1([Si:13]([CH3:12])([CH3:14])[CH3:15])[C:20]([P:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=[CH:17]1)([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
76.6 ml of a 2.5 molar solution of butyllithium in hexane (0.19 moles) were added over 10 min at 0° C. to a solution of compound 1 (40.2 g, 0.19 moles) in 500 ml of ether. When the addition was complete. the bath was removed and the solution was stirred for 1 h at room temperature. After cooling to 0° C., 42.2 g (0.19 moles) of chlorodiphenylphosphine were added over 10 min, after which the bath was removed and the suspension was heated to room temperature. After stirring for 1 hour at room temperature, the ether was removed under vacuum and the product was dissolved in hexane again. After the salts had been filtered off, the hexane was removed under vacuum to leave 69.1 g (yield: 91%) of compound 16 in the form of an oil. 1H NMR (400 MHz, CDCl3): δ=7.45 (m, 4H); 7.35 (m, 6H); 6.8 (m, 1H); 6.65 (m, 1H); 6.6 (m, 1H); 0 (s, 18H); 31P NMR (161.9 MHz, CDCl3): δ=−19.5 ppm.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][S:18][CH2:19][C:3]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:17][S:18][CH:19]=[C:3]12
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 0 °C

Procedure:
A mixture of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylate (2.0 g., 0.0072 mol) and N-chlorosuccinimide (0.97 g., 0.0072 mol) in pyridine (20 ml) is heated on a steam bath for 18 minutes. The reaction mixture is cooled and poured into a large volume of ice water. The precipitate is filtered, washed with water and dried. Recrystallization from ethanol gives the product (1.1 g.), mp 175°-176° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccn1
Solvent: Cc1ccccc1
Product: N#Cc1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In toluene, 4-hydroxymethylpyridine-2-carbonitrile (111 mg, 0.83 mmol) synthesized in Production Example 87 was dissolved, and thionyl chloride (73 μL) was added thereto. The mixture was refluxed for 30 minutes. Thereafter, the mixture was allowed to cool down to a room temperature and stirred for one hour. After the completion of the reaction was confirmed by HPLC, the solvent was distilled off. The resulting residue was used for the next reaction without purification.
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[NH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>CN(C)C=O>[C:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]([CH3:31])[NH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 80.4 %

Procedure:
With ice-cooling and stirring, a solution of tetradecanoyl chloride (2.83 g) in dimethylformamide (25 ml) was added dropwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.34 g) and N,N-dimethylaniline (1.53 g) in dimethylformamide (23 ml) over a period of 10 minutes. After completion of the addition, the mixture was stirred at room temperature for an additional 1.5 hours. The solvent was then distilled off under reduced pressure and 10% hydrochloric acid was added to the residue. The resulting crystalline powder was collected by filtration, washed with water and dried to give 6-(4-tetradecanoylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3.82 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:24])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-acetylpiperazine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.13 minutes; C22H21Cl2N5O3 (474.35); mass spectrum: (M+H)+=474.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[C:2]1=[N:12][OH:13].[H-].[Na+].S(OC)(O[CH3:20])(=O)=O.O>CN(C)C=O>[CH3:20][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[N:12][OH:13]
Reactant: COS(=O)(=O)OC
Reactant: ON=C1Oc2ccccc2C1=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C1C(=NO)Oc2ccccc21
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A solution of 11 g (0.0617 mol) of benzofuran-2,3-dione dioxime in 50 ml of dimethylformamide is added dropwise to a suspension of 2.4 g (0.06 mol) of 60% strength sodium hydride in 25 ml of dimethylformamide, and stirring is effected at 20° C. for one hour. 7.55 g (0.06 mol) of dimethyl sulphate are then added dropwise and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed over silica gel using hexane/acetone (7:3). Stirring the residue with diethyl ether affords 0.7 g of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime (VIII-1) as a mixture of stereoisomers consisting of 90.6% of isomer A and 9% of isomer B (HPLC).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[C:7]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:3](=[O:4])[CH2:2][NH:1][C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1-c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2-c2ccccc2)c1
Yield: 45.9 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-biphenylyl)acetamido]acetate (5.8 g) and 3-methylphenyl isocyanate (2.3 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-biphenylyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (3.7 g), m.p. 177° C., is obtained.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][C:11]([Cl:24])=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:20][CH2:21][CH2:22][O:23]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(I)c(Cc2ccccc2)nc1N1CCC2(C1)OCCO2
Yield: 59.2 %

Procedure:
A mixture of 500 mg of 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine obtained in Example 118c, 174 mg of N-chlorosuccinimide and 5 ml of N,N-dimethylformamide was stirred under heating for 5 hours in an oil bath kept at 60° C. 1 ml of aqueous solution containing 1 mol of sodium thiosulfate was added to the reaction solution, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 320 mg of 2-benzyl-3-iodo-5-chloro-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine, and then the title compound was obtained in the same procedures as in Example 118d.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:11](=O)[CH:12]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>P(Cl)(Cl)(Cl)=O>[Cl:21][C:11]1[CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=1
Reactant: O=c1cc(-c2ccccn2)[nH]c(-c2ccccn2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
A mixture of 3.99 g (16 mmol) of 1′H-[2,2′;6′,2″]terpyridin-4′-one (L1) and 8.0 g (38 mmol) of phosphorus pentachloride is boiled at reflux in 200 ml of phosphorus oxychloride for sixteen hours. The mixture is allowed to cool and concentrated to dryness. 200 ml of ice-water are then added cautiously to the residue, and the solution is then adjusted to pH 9 with aqueous potassium hydroxide solution. Extraction is carried out three times using chloroform and the organic extracts are dried over sodium sulfate, filtered and concentrated. After recrystallisation from ethanol, 4′-chloro-[2,2′;6′,2″]terpyridine is obtained in the form of white needles.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[C:21](Br)(Br)([Br:23])[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][C:21]([Br:23])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(C=C(Br)Br)cc2OC)cc1
Reaction time: 1 h

Procedure:
A solution of Example 122I (1.35 g, 5.0 mmol) in dichloromethane (30 mL) at room temperature was treated with carbon tetrabromide (1.82 g, 5.5 mmol) and triphenylphosphine (2.88 g, 11 mmol), stirred for 1 hour, treated with hexanes (50 mL), and filtered through silica gel (50 g). The solution was rinsed with 1:1 water/dichloromethane, separated, and the organic phase was concentrated. The concentrate was purified by flash column chromatography on silica gel with 2-10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[CH3:23][N:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]1=[O:39]>>[OH:7][C:6]1[N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[N:4]=[CH:3][C:2]=1[C:28]1[CH:27]=[CH:26][C:25](=[O:39])[N:24]([CH3:23])[CH:29]=1
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(=O)n(C)c3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 212 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70 (quin, J=6.7 Hz, 2H) 3.18 (s, 3H) 3.21-3.29 (m, 2H) 3.32 (t, J=6.3 Hz, 2H) 3.38 (s, 3H) 6.34 (d, J=9.3 Hz, 1H) 7.81 (dd, J=9.5, 2.4 Hz, 1H) 8.03 (s, 1H) 8.20 (d, J=1.8 Hz, 1H) 8.24 (dd, J=8.8, 2.3 Hz, 1H) 8.39 (d, J=8.6 Hz, 1H) 8.56 (t, J=5.4 Hz, 1H) 8.78 (d, J=1.8 Hz, 1H) 12.62 (br. s., 1H). MS m/z 384 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH2:32])[S:31][C:27]=2[CH:26]=1>>[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH:32][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([S:10](=[O:12])(=[O:11])[N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH3:22])=[CH:21][CH:20]=3)[S:31][C:27]=2[CH:26]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc4ccc(OC)cc4s3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (47 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(6-methoxybenzo[d]thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as a yellow solid. Yield: 26 mg (21%). 1H-NMR: 8.28 (d, J=8.5 Hz, 2H), 7.74-7.61 (m, 4H), 7.08 (dd, J=9.0, 2.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.91-6.88 (m, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>O1CCCC1>[CH3:1][Si:2]([C:5]1([Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C1=CC=CC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
14.7 g (0.106 moles) of trimethylsilylcyclopentadiene (obtained from Fluka) and 150 ml of tetrahydrofuran (THF) were placed in a reaction flask and cooled to 0° C. 47.4 ml of a solution of butyllithium in n-hexane (2.3 molar; total amount 0.109 moles) were added dropwise over 20 minutes. When the addition was complete, the yellow solution was stirred for a further one hour and the cooling bath was then removed. At room temperature the solution was stirred for a further one hour and then cooled to −20° C. 14.8 ml (0.117 moles) of trimethylsilyl chloride were then added dropwise over 10 minutes and the reaction mixture was stirred for two hours at −10° C. The cooling bath was then removed and the reaction solution was heated to room temperature and subsequently stirred for a further one hour. The reaction mixture was filtered through Celite; the filter was washed with hexane and the hexane was removed from the combined filtrates under vacuum. On distillation at 26° C. under 0.4 mbar, the crude product gave 19 g of pure compound 1 (85% of the theoretical yield). Boiling point and NMR data are consistent with the literature (J. Organometallic Chem. 29, (1971), 227; ibid. 30, (1971), C 57; J. Am. Chem. Soc. 102, (1980), 4429; J. Gen. Chem. USSR, Eng. Transl. 43, (1973), 1970; J. Chem. Soc., Dalton Trans. 1980, 1156). 1H NMR (400 MHz, C6D6): δ=6.74 (m, 2H); 6.43 (m, 2H); −0.04 (s, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[H][H]>[Pt].C(O)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: Nc1ccc(Br)c2ccncc12
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A mixture of Example 801A (500 mg, 2 mmol), 5% Pt/C and acetic acid (50 mL) was equipped with a balloon of hydrogen gas and stirred at room temperature. When the reaction was complete, the solution was filtered through Celite. The mixture was treated with 50% sodium hydroxide solution until pH reached 10. Filtration provided 267 mg (60%) of the desired product as a yellow solid. MS (ESI) m/e 223 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[O:17][CH3:18])=[O:7].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:17][CH3:18])=[CH:10][C:11]([O:15][CH3:16])=[C:12]([NH:14][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH:13]=1)=[O:7]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(C(=O)CCCCCl)cc1NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 5-chloro-1-(5-amino-2,4-dimethoxyphenyl)-1-pentanone (0.27 g, 1 mmol), prepared as in Example 14, α,α,α-trifluoro-p-tolyl isocyanate (0.16 mL, 1.1 mmol), toluene (3 mL) and ethyl acetate (0.5 mL) was heated 10 minutes with stirring at approximately 50° C. The mixture was concentrated and the residue was recrystallized from hexane/ethyl acetate. The solids were collected and dried at 70° C. to give 1-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-3-(4-trifluoromethylphenyl)urea (0.43 g, 0.94 mmol), m.p. 154°-156° C.
Reaction SMILES: [N+]([CH2:3][C:4](OCC)=O)#[C-].[C-]#N.[Na+].N#[C-].[CH2:14]([O:16][C:17]([C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH3:24])=[O:18])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH2:24][CH2:3][CH3:4])=[O:18])[CH3:15]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCOC(=O)c1ncsc1C
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCCc1scnc1C(=O)OCC
Reaction time: 0.08 h

Procedure:
A solution of 2.25 g. (0.02 m) of ethyl isocyanoacetate and 2.08 g. (0.02 m) 0-ethyl thioacetate in 10 ml. absolute ethanol is added dropwise to a suspension of 0.25 g. sodium cyanide in 10 ml. absolute ethanol. After 5 minutes a mild exotherm occurs and the temperature rises to from 22° to 32° C. remaining there for about 1/2 hour. The reaction mixture is then heated at 50° C. for 8 hours at which time the smell of isonitrile is gone. The reaction mixture is then evaporated to dryness in vacuo leaving a dark oil which is extracted several times with hot hexane. The hexane is evaporated affording 2.8 g. (82%) of a tan solid which is the desired 4-ethoxycarbonyl-5-methylthiazole. This solid is recrystallized from ether/hexane affording a pure product with a m.p. 89°-90° C. Following the foregoing procedures employing 0-ethyl thiobutyrate in place of 0-ethyl thioacetate, there is obtained 4-ethoxycarbonyl-5-(n-propyl) thiazole with a boiling point of 85°-87° C. at 0.15 mm of Hg.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:18][CH2:19][OH:20].[ClH:21]>>[ClH:21].[OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:20][CH2:19][CH3:18]
Reactant: CCO
Reactant: COCCOCCOc1cccc(C#N)c1O
Agent: Cl
Product: CCOC(=N)c1cccc(OCCOCCOC)c1O

Procedure:
A solution of 2-hydroxy-3-(2-(2-methoxyethoxy)ethoxy)benzonitrile (6 g) in EtOH/HCl (g) (150 mL) was heated to 40° C. overnight in a sealed tube. The solvent was evaporated under vacuum and the residue (7 g, crude) was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(S(N)(=O)=O)c3)nc21
Yield: 232.1 %

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (3.15 g; 4.502 mmol) and 3-amino-5-nitro-benzenesulfonamide (3.49 g; 14.502 mmol), 4.4 g (10.45 mmol; 72% yield) of the desired nitro-product were obtained as a powder.