Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][NH:9][CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)C.[OH-].[K+].Cl>CCOCC>[ClH:1].[ClH:1].[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:10]([NH:9][CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1CC(NCC1CCCCC1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Nc1ccccc1CC(NCC1CCCCC1)c1ccccc1
Reaction time: 2 h

Procedure:
7.0 g of N-Cyclohexylmethyl-2-nitro-α-phenylphenethylamine hydrochloride is treated with 200 ml of warm 95% ethanol containing 2.07 of potassium hydroxide for 15 minutes, after which the mixture is filtered and placed in a Paar flask containing 0.35 g of 10% palladium on charcoal. The mixture is hydrogenated at 50 psia for 2 hours. After removal of the catalyst, the ethanol is evaporated and the resulting biphasic mixture is poured onto 200 ml of water. The aqueous mixture is extracted with methylene chloride (2×200 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated giving a colorless oil. The oil is dissolved in 100 ml of ether. Ethereal hydrogen chloride (200 ml) is a added and the salt precipitates from solution. The hydrochloride salt is collected as a gummy powder, which is recrystallized from i-propanol to provide crystals, mp 205° C. dec, 2-amino-N-cyclohexylmethyl-α-phenylphenethylamine dihydrochloride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (456 mg) was coupled to p-methoxyphenylboronic acid to provide 3-(3-chloropropyl)-1-(4-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (132 mg):
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([O:11][C:12](=O)[CH:13]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[Cl:28])[C:14](OCC)=[O:15])C>C(O)C>[Cl:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[C:20]([NH:19][C:13]1[C:12]([OH:11])=[N:7][C:5]([CH3:6])=[N:8][C:14]=1[OH:15])=[O:29]
Reactant: CC(=N)N
Reactant: CCOC(=O)C(NC(=O)c1cc(F)ccc1Cl)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(O)c(NC(=O)c2cc(F)ccc2Cl)c(O)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
1.5 equivalents of sodium methoxide (30% in methanol) were added to a suspension of 13.4 g of acetamidine hydrochloride in 150 ml of ethanol. The precipitate was filtered off and washed with 100 ml of ethanol. Additional 1.5 equivalents of sodium methoxide (30% in methanol) were added to the filtrate. Then a solution of 39.3 g of 2-(2-chloro-5-fluoro-benzoylamino)malonic acid diethyl ester in 100 ml of ethanol was added dropwise. The reaction mixture was stirred at 60° C. for 2 h. After cooling to 0° C. for 30 min, the precipitate was filtered off with suction, washed with 100 ml of a solution of hydrogen chloride in isopropanol and dried to give 35.7 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1.[NH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1.CN(C)C=O>[N:33]1([NH:32][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([N:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]([C:11]([N:8]4[CH2:9][CH2:10][CH:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH2:7]4)=[O:12])[CH2:14][CH2:15]3)=[CH:24][CH:25]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Reactant: NN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(NN1CCCCC1)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
0.4 g of 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoic acid, 0.19 g of 1-aminopiperidine, 0.26 g of hydroxybenzotriazole, 0.37 g of EDC.HCl and 7 ml of a dioxane/dimethylformamide 5/2 mixture are introduced into a 100 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture is stirred at ambient temperature for 20 h and concentrated under vacuum. The residue is chromatographed on silica gel eluted with a dichloromethane/acetone/methanol/NH4OH 88/10/2/0.2 and then 82/15/3/0.3 mixture. After triturating in ethyl ether, 0.28 g of N-(piperidin-1-yl)-4-{4-[3-(1H-pyrazol-4-yl)pyrrolidine-1-carbonyl]-3,4-dihydro-2H-quinoxalin-1-yl}benzamide is obtained.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH2:9][C:10]([CH3:12])=[CH2:11])=[CH:6][CH:5]=[CH:4][C:3]=1[O:13][CH3:14].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1>[CH3:11][C:10]1([CH3:12])[C:2]2[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[CH:6][C:7]=2[O:8][CH2:9]1
Reactant: C=C(C)COc1cccc(OC)c1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1C(C)(C)CO2
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of 2-iodo-1-(methyloxy)-3-[(2-methyl-2-propen-1-yl)oxy]benzene (Intermediate 4, 6.08 g) in toluene (50 ml, SCRC) were added AIBN (3.61 g, 21.99 mmol, SCRC) and tributylstannane (11.60 g, 40.0 mmol, Aldrich). The reaction mixture was heated at reflux for 3 hours and then cooled to room temperature. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 times 200 ml, SCRC). The combined organic layers were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc/PE (1/50) to afford the title compound as a yellow liquid (2.7 g).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>CCOC(C)=O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[O:18])=[CH:6][CH:5]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1CCCCC1=Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
An aqueous KOH (0.25 g in 4.4 mL water) solution was added to p-fluorobenzaldehyde Compound 10a (1.04 mL, 10 mMol) and the mixture was heated to 65° C. Cyclohexanone Compound 2a (1.03 mL, 10 mMol) was added dropwise over 10 min and the reaction mixture was refluxed for 5 hrs, then cooled to r.t. and stirred at r.t. overnight. The reaction mixture was acidified with 1N HCl (26 mL) and diluted with EtOAc. The organic layer was separated and washed with brine, then dried with anhydrous sodium sulfate and filtered. The solvent was evaporated to provide a crude product which was then purified by silica gel column (eluted with 6% EtOAc in hexane) to give 2-(4-fluoro-benzylidene)-cyclohexanone Compound 10b (1.1 g, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:23])[CH3:22])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH3:32][C:33]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:22])[CH3:23])[CH:13]([O:20][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCOC(=O)CC(O[Si](C)(C)C(C)(C)C)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Under an argon atmosphere, to a solution (228 mL) of ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate (14.74 g) in dehydrated THF was added 2,6-lutidine (7.33 g) with stirring under ice-cooling, and tert-butyl dimethylsilyl trifluoromethanesulfonate (14.46 g) was added dropwise. The mixture was gradually warmed to room temperature and stirred for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1→4/1) to give ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-{[tert-butyl(dimethyl)silyl]oxy}-5-methylhexanoate as colorless oil (yield: 17.7 g).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Na+].[CH3:17]I>C(O)C>[CH3:13][C:4]1[S:3][C:2]([S:1][CH3:17])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Cc1sc(S)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(-c2ccccc2)c(C)s1
Reaction time: 2 h

Procedure:
To 14.9 g. of 2-mercapto-5-methyl-4-phenyl-thiazole is added 60 ml. of water and 19.5 ml. of a 15% aqueous solution of sodium hydroxide and the mixture is stirred until most of the material dissolves. The stirred mixture is then treated with methyl iodide (5 ml.) in ethanol (20 ml.). After two hours, the reaction is complete (tlc) and the reaction mixture is extracted with ether. The combined ether extracts are washed successively with a 10% solution of sodium carbonate and brine, dried and concentrated in vacuo to an oil, b.p. 138°-140° C. at 0.04 mm Hg.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:13]([F:24])([F:23])[F:12])=[N:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of N,O-dimethylhydroxylamine hydrochloride (9.47 g, 97.1 mmol) and pyridine (18.6 mL, 230 mmol) in CH2Cl2 (100 mL) was added a solution of 6-(trifluoromethyl)nicotinoyl chloride (18.50 g, 88.28 mmol) in CH2Cl2 (250 mL) over 3-5 min. The reaction mixture was stirred at rt overnight, and then carefully quenched with 150 mL of saturated aq. NaHCO3 solution and stirred for about 1 hr. The mixture was diluted with CH2Cl2 (50 mL) and the organic phase was separated and washed with aq. NaHCO3 solution (100 mL) and brine (50 mL), dried (Na2SO4), filtered, and evaporated. The residue was redissolved in toluene (about 50 mL) and evaporated again to azeotrope the pyridine off. This was repeated with toluene (about 50 mL). The product was isolated as a colorless oil (with a small amount of crystalline material) (19.1 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[CH2:28][C:27](=O)[CH2:26][CH2:25]2>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][CH:27]2[CH2:26][CH2:25][C:24]3[C:29](=[C:30]([F:32])[CH:31]=[C:22]([F:21])[CH:23]=3)[CH2:28]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CD3OH) 13.0, 18.1, 24.5, 25.4, 25.8, 27.5, 32.8, 53.1, 53.2, 57.9, 64.7, 100.8, 101.1, 109.9, 110.4, 110.8, 115.8, 128.4, 131.6, 132.3, 139.1, 139.3, 159.5, 160.2, 166.8, 171.2; MS 449.3 m/z (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH3:22])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH3:22])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(c1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(c1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A solution of tert-butyl (Z)-4-{1-[2-(1H-indazol-3-yl)methylene-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl]ethyl}piperazine-1-carboxylate (0.075 g, 0.15 mmol) in methylene chloride (3.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-[1-(piperazin-1-yl)ethyl]benzofuran-3(2H)-one (0.030 g, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:49]([O:51][C:52](=[O:55])[CH2:53]Br)[CH3:50]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][N:20]([CH2:53][C:52]([O:51][CH2:49][CH3:50])=[O:55])[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
68.2 g (118.6 mmol) of 1,4,7-tris-(benzyloxycarbonyl)-1,4,7,10-tetrazacyclododecane (Delaney et al., J Chem. Soc. Perkin Trans. 1991, 3329) is dissolved in 700 ml of acetonitrile and mixed with 75.4 g (545.5 mmol) of sodium carbonate. Then, 39.6 g (355.5 mmol) of bromoacetic acid ethyl ester is added while being stirred vigorously, and it is heated for 20 hours to 40° C. Insoluble components are filtered out, evaporated to the dry state and chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 20:1). The fractions that contain the product are combined and concentrated by evaporation.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](SC)[N:13]=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[CH3:26][OH:27]>C(OCC)C>[CH3:26][O:27][C:12]1[N:13]=[N:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Reactant: CO
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(-c2nnc(OC)nc2-c2ccc(OC)cc2)cc1

Procedure:
Sodium, 3.0 g. (0.13 mole), was added piecewise under a nitrogen atmosphere to 100 ml. of dry methanol, followed by the addition of a slurry of 31.6 g. (0.1 mole) of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine in methanol. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled and filtered. The filter cake and filtrate were extracted with diethyl ether. The diethyl ether was concentrated, giving a solid, m.p. >220° C. The solid was taken up in diethyl ether and the insoluble material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give a solid residue which was recrystallized from petroleum ether to give 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p. about 105°-108° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=O.[CH:31]([NH2:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:31]([NH:34][CH2:4][CH2:3][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH3:1])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CCNC(C)C)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (88 mg, 0.2 mmol), isopropylamine (0.09 ml) in dichloroethane (1 ml) and methylene chloride (1 ml) was stirred at r.t. for 10 min, sodium triacetoxyborohydride (76 mg) was added and the resulting mixture was stirred at r.t. overnight. The mixture was quenched with water, diluted with sodium hydroxide, and extracted with methylene chloride. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography using 3-5% methanol in methylene chloride, then 5% methanol/0.5% ammonium hydroxide in methylene chloride as eluent to give the title compound as a free base form. The free base was treated with 4 N HCl in doxane (0.1 ml) in methylene chloride (1 ml) and concentrated to dryness. The residue was triturated with hexane, pumped to dryness to give a white solid, LC-MS RT=1.8 min, M+1=481.9.
Reaction SMILES: O.O.[O:3]=[C:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:14]([O-:17])(=O)=[O:15])[CH:10]=2)[NH:5]1.[Na+].O=P(Cl)(Cl)[Cl:21].S1(CCCC1)(=O)=O>O>[O:3]=[C:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:14]([Cl:21])(=[O:17])=[O:15])[CH:10]=2)[NH:5]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccc(S(=O)(=O)[O-])cc2C1=O
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 81.7 %

Procedure:
A suspension of sodium 2,3-dioxoindoline-5-sulfonate dihydrate (5.0 g, 17.53 mmol) and POCl3 (8.17 ml, 88 mmol) in sulfolane (25 ml, 264 mmol) was heated at 60° C. for 3 hours. The solution was cooled to 0° C. and water (60 ml) was added drop wise; the green precipitate was filtered and washed with a small amount of water. The solid was dissolved in ethyl acetate and washed three times with water; the organic phase was then dried over sodium sulfate and evaporated to give a crude solid that was purified by crystallization from hexane/ethyl acetate 1:1 to give 2,3-dioxoindoline-5-sulfonyl chloride (3.52 g, 14.33 mmol, 82% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (33 mg, 28%). MS (ISN) 461.0 [(M−H)−]; mp 214-215° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C[N:19](C)[C:20]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)=[CH2:21].[OH-].[NH4+]>C(O)C>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:19]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:21]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: C=C(c1ccco1)N(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccco2)nc1C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of 147 g of diethyl ethoxymethyleneoxalacetate in 600 mL of absolute ethanol is stirred at 5° C. while a solution of 68.8 g of 1-dimethylamino-1-(2-furyl)ethylene in 400 mL of absolute ethanol is added dropwise over 1 hour. After stirring for an additional 2 hours, the reaction mixture is treated with 250 mL of concentrated aqueous ammonium hydroxide. The resulting mixture is stirred at ambient temperature overnight and then concentrated in vacuo. Chromatography of the residue on silica gel using chloroform as eluant affords the desired product.
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH2:14])=[S:13].CN.[CH3:17][N:18]([CH3:21])[CH:19]=O>C(OCC)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:19][N:18]([CH3:21])[CH2:17][NH:14][C:12]1=[S:13]
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC(N)=S)c(C)c1
Agent: C=O
Agent: CN
Solvent: CCOCC
Product: Cc1ccc(N2CN(C)CNC2=S)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Formaldehyde (4.86 g, 37% solution, 30 mmole) was added to a solution of 2,4-dimethyl-phenyl thiourea (4.5 g, 24 mmole) in dimethylformamide (40 ml) and the solution was stirred for 15 minutes at room temperature. Methylamine (3.72 g, 30 mmole) was added dropwise with stirring and the mixture was heated under reflux at 100° C. for 4 hours. The solution was cooled and the solvent removed under vacuum to yield an oil. This was diluted with diethyl-ether and refrigerated to yield 1-(2,4-dimethylphenyl)-5-methyl-tetrahydro-s-triazin-2[1H]-thione as a white crystalline solid which was collected, washed with a little cold diethyl ether and dried (4.5 g, 77%), m.p. 140°-143° C.