Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)[S:7][CH:8]=1)[CH3:3].[C:18]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[CH2:19]1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])[CH:14]=[CH:15][CH:16]=2)[S:7][CH:8]=1)[CH3:1]
Reactant: CC(C)c1csc(/C=C/c2cccc(N)c2)n1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Product: CC(C)c1csc(/C=C/c2cccc(NC(=O)Cc3ccccc3C(=O)O)c2)n1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of 1.2 g of (E)-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]benzeneamine, 0.8 g of homophthalic anhydride and 25 ml of toluene was heated to reflux for 0.5 hr. Upon cooling to room temperature, the solid reaction product was filtered and washed with ethyl ether to yield 1.7 g of (E)-2-[2-[3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from ethyl alcohol yielded off-white solid material; m.p. 203°-204° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][C@@H:6]([CH2:8][OH:9])[C@H:5]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][N:12]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1.CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[F:30][C:2]1([F:1])[CH2:7][C@@H:6]([C:8]([OH:33])=[O:9])[C@H:5]([C:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:13][N:12]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1
Reactant: CC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2CO)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {(1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexyl}methanol (1.64 g, 3.63 mmol) in acetone (40 mL) was treated at 0° C. with Jones reagent (3.8 mL) followed by stirring at rt for 30 min. Water was added and the mixture was extracted with two portions of ethyl acetate. The combined organics were washed twice with water then with a saturated aqueous solution of NaCl before drying over Na2SO4. Concentration in vacuo gave (1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxylic acid as a faint-yellow foam.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH2:14])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.O1CCCC1>C(OCC)(=O)C>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][Br:22])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(c1ccccc1)c1ccc2nc(N)n(C(C)C)c2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(N)nc2ccc(C(=CBr)c3ccccc3)cc21

Procedure:
Three hundred milligrams (1.08 mmoles) of 1-isopropyl-2-amino-6-(1-phenylethenyl)benzimidazole and 192 mg. (1.08 mmoles) of N-bromosuccinimide were refluxed overnight in 20 ml. of dry tetrahydrofuran. After cooling, ethyl acetate was added and the solution was washed with a saturated solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed over silica gel, first eluting with ethyl acetate to remove impurities, and then with 10% methanol/90% ethyl acetate. The title product was crystallized from ether giving 200 mg. of the cis/trans mixture, M+ =357.
Reaction SMILES: C1(S(O[CH2:11][CH:12]2[N:24]3[C:15](=[N:16][C:17]4[CH:18]=[C:19]([Br:26])[CH:20]=[CH:21][C:22]=4[C:23]3=[O:25])[CH2:14][CH2:13]2)(=O)=O)C=CC=CC=1.[CH3:27][NH2:28]>C(#N)C>[Br:26][C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:25])[N:24]3[CH:12]([CH2:11][NH:28][CH3:27])[CH2:13][CH2:14][C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: CN
Reactant: O=c1c2ccc(Br)cc2nc2n1C(COS(=O)(=O)c1ccccc1)CC2
Solvent: CC#N
Product: CNCC1CCc2nc3cc(Br)ccc3c(=O)n21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To the solution of (6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-yl)methyl benzenesulfonate (100 mg, 0.23 mmol) in acetonitrile (4 mL) was added aq. methylamine (2 mL). The reaction mixture was stirred at 60° C. for 4 h. After concentration, the crude product was purified by column chromatography to give the desired product. MS (ESI): 308, 310 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([CH3:34])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 3-(5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-2-oxopyridin-1(2H)-yl)propanoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI−): m/z=515.3 [M−H]−.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([S:23][CH2:24][C@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([S:23][CH2:24][C@@H:25]([CH3:29])[C:26]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: O=C(O)CNC1Cc2ccccc2C1
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
By reacting N-(2-indanyl)glycine with 3-benzoylthio-2(S)-methylpropionyl chloride in a similar manner to that of Example 37, there is obtained N-(3-benzoylthio-2(S)-methylpropionyl)-N-(2-indanyl)glycine. Colorless needles.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>CN(C)C=O>[CH2:10]([NH:14][C:15]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CN(C)C=O
Product: CCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.4 %

Procedure:
13.0g (0.10 mole) of 5-fluorouracil was dissolved in 70 ml of dimethyl formamide, then 11.9g (0.12 mole) of n-butyl isocyanate was added thereto at room temperature and stirred at the same temperature for 24 hours. The reaction mixture was concentrated to 40ml by removing dimethyl formamide and excess n-butyl isocyanate under reduced pressure. The residue was poured into 300ml of water and resultant precipitate was filtered off. The precipitate was washed and dried and 16.6g (72.3% yield) of 1-(n-butylcarbamoyl)-5-fluorouracil was obtained
Reaction SMILES: [F:1][C:2]([F:18])([S:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].ClC1C=CC=C(C(OO)=O)C=1.[OH2:30].[OH2:31].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>C(Cl)Cl>[F:18][C:2]([F:1])([S:13]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:31])=[O:30])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O
Reactant: OCCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 93.1 %

Procedure:
3-(Perfluorobutylthio)propanol (8.60 g, 27.6 mmol) prepared in Synthetic Example 1 was dissolved in methylene chloride (80 ml), and m-chloroperbenzoic acid (m-CPBA) (52 g, 232 mmol) was added at room temperature in two portions with stirring, the reaction vessel being equipped with a calcium chloride tube. The mixture was stirred at room temperature for 7 days. The reaction mixture was injected into a mixture of sodium thiosulfate pentahydrate (130 g) and water (200 ml), and stirred for 1 hour. Methylene chloride (100 mL) was added and an organic layer was removed and an aqueous layer was extracted with methylene chloride (50 ml). Organic layers were joined, washed with a 5% aqueous sodium hydrogen carbonate and with a saturated saline solution, and then dried over sodium sulfate. A filtrate after filtration was concentrated at reduced pressure. A residue was subjected to a silica gel column chromatography (eluting solvent: hexane/ethyl acetate (2/1)), and fractions having Rf value of 0.32 [Rf value (Thin Layer Chromatography (TLC))=(Migration distance of sample)/(Migration distance of eluting solvent)] were gathered, concentrated at reduced pressure and dried at vacuum to give crystalline 3-(perfluorobutylsulfonyl)propanol (8.79 g). Yield: 91.8%.
Reaction SMILES: Cl.O1CCOCC1.[N:8]([C@H:11]1[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)[CH2:13][C@H:12]1[NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N+:9]=[N-:10].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[N:14]1[CH2:15][C@H:16]([CH3:17])[C@H:11]([N:8]=[N+:9]=[N-:10])[C@H:12]([NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:13]1
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl (4-((3R,4S,5S)-4-azido-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-1-yl)pyridin-3-yl)(tert-butoxycarbonyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.11 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl ((3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-azido-5-methylpiperidin-3-yl)carbamate in 33% yield. LC/MS (m/z)=348.2 (MH+), Rt=0.70 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.18 (m, 3 H), 1.36-1.54 (m, 10 H), 2.19 (qd, J=6.91, 3.91 Hz, 1 H), 2.57 (q, J=10.96 Hz, 2 H), 2.96 (d, J=9.00 Hz, 1 H), 3.20 (dd, J=11.15, 3.72 Hz, 1 H), 3.55-3.73 (m, 2 H), 3.90 (br. s., 1 H), 4.01 (br. s., 1 H), 4.81 (d, J=8.61 Hz, 1 H), 6.72-6.83 (m, 1 H), 7.96 (d, J=5.09 Hz, 1 H), 8.02 (s, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([P:8]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])([O:10][CH2:11][CH2:12][S:13]([CH2:16][C@@H:17]([C:26]([OH:28])=[O:27])[NH:18]C(OC(C)(C)C)=O)(=[O:15])=[O:14])=[O:9])[CH2:5][CH2:6][Cl:7].Cl.C(OCC)C>C(OCC)(=O)C>[Cl:32][CH2:31][CH2:30][N:29]([P:8]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][Cl:7])([O:10][CH2:11][CH2:12][S:13]([CH2:16][C@@H:17]([C:26]([OH:28])=[O:27])[NH2:18])(=[O:14])=[O:15])=[O:9])[CH2:33][CH2:34][Cl:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N[C@@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-N-tert-butoxycarbonyl-L-alanine, 1.82 g (2.91 mmol), was dissolved in 18 mL ethyl acetate, and to this solution was added hydrogen chloride, 1.75 mL of 2 M solution in diethyl ether (3.5 mmol); and the resulting mixture stirred under nitrogen overnight at room temperature. HPLC analysis of the reaction mixture showed that the reaction was incomplete (20.8% product), so an additional 0.9 equivalents of hydrogen chloride solution was added and the reaction mixture stirred for an additional 4 days, resulting in the formation of a slurry. HPLC analysis of the reaction mixture showed 99.7% product and 0.3% starting material. The slurry was filtered under nitrogen, washed with ethyl acetate, and dried under nitrogen for 3 hours to give 3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanine, compound 70A, as the hydrochloride salt, off-white solid, 0.90 g (55% yield). HPLC analysis of the product showed a purity of 99.7%. 1H NMR: δ 8.50-9.10 (bs, 3H), 4.43 (m, 1H), 4.32 (m, 2H), 3.93-3.97 (m, 1H), 3.70-3.80 (m, 11H), 3.34 (m, 8H). 13C NMR: δ 168.2, 58.0, 57.9, 53.8, 53.7, 53.0, 48.3, 48.3, 47.1, 42.3. 31P NMR: δ 17.5 (s, 1P). Mass spectrum: m/z 526 [C13H26Cl4N3O6PS+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16](O)=[S:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.F[P-](F)(F)(F)(F)F.[N:27]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH2:27])=[S:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: OC(=S)c1[nH]c2ccccc2c1-c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=S)c1[nH]c2ccccc2c1-c1ccccc1

Procedure:
The title compound was prepared from 3-phenylthioindole-2-carboxylic acid (prepared according to the procedure described by Atkinson, J. G. et al., Synthesis, p. 480-481 (1988), (4.01 g, 0.015 mol), ammonia (large excess), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (7.2 g, 0.016 mol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide. The title compound was obtained as a pale yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:15](=S)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44]>COCCOC.O>[Cl:17][C:10]1[C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:23][CH:24]=3)[N:7]=[C:6]3[C:4](=[O:5])[N:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH3:36])[N:44]=[C:15]3[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=S
Reactant: Cc1ccccc1NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-n1nc2c3cccc(Cl)c3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Temperature: 92 °C

Procedure:
Ethyl-8-chloro-1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (48 mg, 0.113 mmol), potassium carbonate (78 mg, 0.56 mmol, 5 equiv), and 2-methylphenyl hydrazine (23 mg, 0.19 mmol, 1.7 equiv) were combined in 1,2-dimethoxyethane (2 mL) and heated to 92° C. for 2 hours. The mixture was cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.24 (1H, d, J=7.2 Hz), 7.88 (1H, s), 7.71-7.61 (4H, m), 7.47-7.42 (3H, m), 7.37-7.30 (3H, m), 7.29 (1H, s), 6.4 (1H, m), 6.34 (2H, s), 2.36 (3H, s), ppm; high resolution mass spectrometry (ES+) m/z 467.1388 [(M+H)+; calculated for C26H20ClN6O: 467.1382].
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15](B1OC(C)(C)C(C)(C)O1)=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]3[CH2:41][C:40]([CH3:42])([CH3:43])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]3)=[CH:31][CH:30]=1)=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3cnc(OCc4ccccc4)cc3c2)OC1(C)C
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: CN(c1ccc(-c2ccc3cnc(OCc4ccccc4)cc3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 48.4 %

Procedure:
The title compound (38 mg, 0.077 mmol, 49% yield) was prepared following GENERAL METHOD 1-4 for Suzuki coupling from 3-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (115 mg, 0.318 mmol) and Intermediate 1-1 (45 mg, 0.159 mmol). LCMS Rt=0.61 min [Method Q]; MS (M+1)=482.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.95 (s, 1H), 8.21 (s, 1H), 8.01-8.09 (m, 2H), 7.96 (d, J=9.79 Hz, 1H), 7.49-7.54 (m, 2H), 7.36-7.42 (m, 2H), 7.30-7.35 (m, 1H), 7.23 (s, 1H), 7.16 (d, J=9.79 Hz, 1H), 5.40 (s, 2H), 5.28 (t, J=11.67 Hz, 1H), 3.00 (s, 3H), 1.67-1.73 (m, 2H), 1.56-1.65 (m, 2H), 1.41 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:2]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]=[C:13]=[O:12])[CH:6]=1)[CH3:3]
Reactant: CCSc1cccc(N)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCSc1cccc(N=C=O)c1

Procedure:
To a slurry of the above 3-ethylsulfanylphenylamine hydrochloride (31.6 mmol, 6 g) in toluene (100 mL) was added diphosgene (trichloromethyl chloroformate, 158 mmol, 31.3 g) and the mixture was refluxed for 2 hours affording a clear solution. The solvent was removed in vacuo and the residue was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[C:7]([O:11][CH3:12])[N:6]=[CH:5][N:4]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:9]([C:8]2[C:7]([O:11][CH3:12])=[N:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ncnc(OC)c1C=O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1c(OC)ncnc1OC
Yield: 56 %

Procedure:
Upon heating a solution of 8.4 g 4,6-dimethoxypyrimidine-5-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(4,6-dimethoxypyrimid-5-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 219° C. (ethanol) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:28]=1[CH2:29]Cl.CC(C)=O>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH2:29][C:28]4[C:31]([CH3:36])=[CH:32][C:33]([CH3:35])=[CH:34][C:27]=4[CH3:26])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(Cl)ccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc(Cl)c2C3=O)c(C)c1
Temperature: 10 °C
Yield: 77.7 %

Procedure:
A mechanically stirred mixture of 550.6 g (1.88 mol) of 1,4-dichloro-5-hydroxy-9,10-anthracenedione (1), 413.4 g (2.14 mol) of anhydrous cesium carbonate, 444 g, (2.4 mol) of 2,4,6-trimethylbenzyl chloride, 7.06 l of acetone, and 2.31 l of N,N-dimethylformamide was heated at reflux for 23 hr. During this period, additional portions of 2,4,6-trimethylbenzyl chloride (2.5 hr, 31.7 g; 6.5 hr, 63.4 g; 20 hr, 31.7 g) and one portion of cesium carbonate (20 hr, 4.8 g) were added. The mixture was cooled to 10° C. The precipitate was collected by filtration, washed successively with hot water and methanol, then dried at 7-9 mm/50° C./20 hr to leave 621 g (78%) of 11, mp 216°-218° C., 97.9% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH:18]([N:11]1[CH:12]=[CH:13][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)=[N:10]1)([CH3:20])[CH3:19]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.52 g) was added to a stirred suspension of sodium hydride (60% in oil, 0.096 g) in N,N-dimethylformamide (18 mL) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0° C., treated with 2-iodopropane (0.4 mL) and stirred at room temperature for 16 hours. The mixture was diluted with water (10 mL) and concentrated to low bulk under reduced pressure. The residue was extracted with ethyl acetate, and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound (0.152 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:13][C:12](=O)[C:11]=2[C:10]([CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].Cl.Cl.O>C(O)C>[ClH:23].[CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:13][C:12](=[N:30][NH:29][C:26]([NH2:28])=[NH:27])[C:11]=2[C:10]([CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: Cc1nn(Cc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 195.2 %

Procedure:
A mixture of 1-benzyl-6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.3 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.21 ml), water (0.21 ml) and ethanol (20 ml) was refluxed for 18 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 1-benzyl-6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 149) (0.37 g) as colorless crystals.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12](OC)[CH2:13][Cl:14]>>[CH3:10][O:11][CH:12]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][Cl:14]
Reactant: NC(=O)c1ccccc1
Reactant: COC(CCl)OC
Product: COC(CCl)NC(=O)c1ccccc1
Temperature: 70 °C
Yield: 91 %

Procedure:
85 g of a strongly acidic ion exchanging resin having an exchange capacity of 4 meq/g was placed in a glass column having an inner diameter of 35 mm, and this was heated to a temperature of 70° C. in a hot bath. To this was supplied a solution of 1 part per weight of benzamide dissolved in 10 parts per weight of chloroacetaldehyde dimethyl acetal at a rate of 230 g per hour via a volumetric pump. 230 g of the reaction fluid discharged from the column was concentrated by distillation chloroacetaldehyde dimethyl acetal under reduced pressure so as to reach an amount of 130 g. Next, 100 ml of n-hexane was added thereto, the precipitated crystals were filtered out, and thus 33.7 g of N-(1-methoxy-2-chloroethyl)-benzamide [Compound (1)] was obtained. With respect to the expended benzamide, the yield was 91%.