Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[O-]CC.[Na+].O[NH:18][C:19](=[NH:22])[CH2:20][CH3:21]>C(O)C>[CH2:20]([C:19]1[N:22]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=2)[O:8][N:18]=1)[CH3:21]
Reactant: CCC(=N)NO
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1noc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a mixture of 29.9 parts of ethyl 4-hydroxybenzoate and 316 parts of ethanol were added portionwise 35.6 parts of sodium ethoxide. After stirring for 1/2 hour at room temperature, there was added dropwise a solution of 31.7 parts of N-hydroxypropanimidamide in 79 parts of ethanol. Stirring was continued for 1/2 hour at room temperature and overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. After neutralizing with acetic acid, the precipitate was filtered off and dried. It was purified by column chromatography (HPLC; silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was stirred in petroleumether. The precipitate was filtered off and dried, yielding 7.56 parts (22.1%) of 4-(3-ethyl-1,2,4-oxadiazol-5-yl)phenol; mp. 137.7° C. (interm. 27).
Reaction SMILES: [N+:1]1([O-])[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N+:14]([O-])=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:8]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.C[N:22]([CH3:26])C(Cl)=O.C[Si]([C:31]#[N:32])(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:31]([C:6]1[N:1]=[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:26]#[N:22])[N:14]=3)[N:8]=2)[CH:3]=[CH:4][CH:5]=1)#[N:32]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccccc1-c1cccc(-c2cccc[n+]2[O-])n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cccc(-c2cccc(-c3cccc(C#N)n3)n2)n1
Temperature: 25 °C

Procedure:
2,2';6',2"-Terpyridine-N,N"-dioxide (7a) (0.96 g, 3.6 mmol) was suspended in dichloromethane (10 ml). N,N-dimethylcarbamyl chloride (0.95 g, 8.8 mmol) and trimethylsilyl cyanide (1.26 g, 12.7 mmol) were added. After stirring for two weeks at room temperature, 10% potassium carbonate was added until the solution was neutral. The phases were separated and the water phase was extracted with chloroform. The chloroform was evaporated and the residue was crystallized from a mixture of acetonitrile and tetrahydrofurane.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:24][CH:25]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCCOC(=O)c1ccc(N)cc1
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 100 %

Procedure:
The procedure is carried out as in Example 1, starting with 472.5 mg of 2,6-dichloropurine, 5 ml of butanol and 602.9 mg of butyl 4-aminobenzoate. 864.5 mg of the expected product are thus obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:43]([CH:44]=1)[C:24]1[N:25]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)[C:26](=[O:33])[C:27]3[C:32]([C:23]=1[N:22]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3>CN(C=O)C>[N:5]1([CH2:4][CH2:3][O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:43]([CH:44]=2)[C:24]2[N:25]([C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=4)[C:26](=[O:33])[C:27]4[C:32]([C:23]=2[N:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c2nc3ccc(OCCN4CCOCC4)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Yield: 39.9 %

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (1.2 equiv., 0.806 mmol, 0.121 g) and potassium carbonate (3 equiv., 2.01 mmol, 0.278 g) were added to a solution compound 10 (1.0 equiv., 6.71 mmol, 0.250 g) in DMF (3 ml). The mixture was heated at reflux for 2 h. The reaction product was precipitated by the addition of water, filtered off and washed with isopropanol and isopropyl ether successively to give 9-[2-(4-morpholinyl)-ethoxy]-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (79) (0.156 g, yield=46%, purity (LC)=95%) as a brown powder.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)#[N:2].C(O)(=[O:28])C.B(F)(F)F.[OH-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)(=[O:28])[NH2:2]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C#N)cc23)c(OC)c1
Reactant: CC(=O)O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cccc3ccc(C(N)=O)cc23)c(OC)c1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of methyl 4-(7-cyanonaphth-1-ylmethyl)-3-methoxybenzoate (394 mg), acetic acid (0.68 ml) and BF3 -etherate (0.22 ml) was heated to 120° C. for 15 min. After cooling, to the reaction mixture was added methylene chloride (50 ml) and 6N sodium hydroxide (3.5 ml) and it was stirred for 10 min. The aqueous layer was extracted with methylene chloride. The combined organic extract was washed (brine) and dried (MgSO4). Evaporation and trituration with hot ethyl acetate afforded methyl 4-(7-carbamoylnaphth-1-ylmethyl)-3-methoxybenzoate (262 mg, 63%) as a white solid; mp 215.0°-216.5° C.; MS(CI), m/e=350(M+H).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:23])[CH2:15][C@@H:16]([CH2:20][CH2:21][CH3:22])[C:17](O)=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29](=[O:37])[CH2:30][CH:31]([NH2:36])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:24]([O:28][C:29](=[O:37])[CH2:30][CH:31]([NH:36][C:17](=[O:18])[CH:16]([CH2:15][C:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:23])[CH2:20][CH2:21][CH3:22])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Yield: 53 %

Procedure:
A stirred mixture of (2R)-2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoic acid (2.94 g, 9.50 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.07 g, 9.99 mmol), HOBT (1.41 g, 10.43 mmol), DMAP (1.34 g, 10.97 mmol) and anhydrous THF (40 mL) was cooled to 0° C. then EDC (2.00 g, 10.43 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue purified by flash chromatography (33% EtOAc in 40/60 hexanes).to give the sub-title compound (2.51 g, 53%) as a foam: 1H NMR (400 MHz, CDCl3) δ 0.90-1.03 (3H, m), 1.20-1.90 (13H, m), 2.50-3.00 (3H, m), 3.12-3.26 (1H, m), 3.59-3.80 (2H, m), 4.00-4.68 (3H, m), 6.53-6.89 (1H, m), 7.30-7.52 (4H, m), 7.95-8.05 (2H, m), 8.15-8.26 (2H, m) 19F NMR (376 MHz, CDCl3) δ −229.10, −229.34, −230.95, 231.09.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH3:7][C:8]([CH3:10])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH3:7][C:8]1([CH3:10])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1
Reactant: CC(C)=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CC1CCSC(C)(C)O1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 3.2 grams (0.055 moles) of acetone is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 7.2 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18]3=[N:19][C:20]4[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=4[CH:26]=[C:17]3[C:16](=[O:28])[O:15][C:14]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].NC1C=C(OC)C(OC)=CC=1.N1C=CC=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH:12]=[C:13]([C:14]([OH:15])=[O:29])[C:18]3[N:19]=[C:20]4[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]4=[CH:26][C:17]=3[C:16]2=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC=C2C(=O)OC(=O)c3cc4cccc(C)c4nc32)cc1OC
Agent: COc1ccc(N)cc1OC
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(-n2cc(C(=O)O)c3nc4c(C)cccc4cc3c2=O)cc1OC
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of 19 (0.23 g), 4-aminoveratrole (0.46 g), pyridine (15 mL) and triethylamine (1 mL) was heated under reflux for 8 h (dissolution occurred during the heating). The reaction mixture was allowed to stand at −10° C. overnight and the resulting precipitate was collected by filtration and washed with a little cold acetone to give the product as a yellow solid (0.18 g, 78%), mp 297-298° C. (after forming needles->285° C.). 1H NMR (d6-DMSO): δ 2.73 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 7.12 (s, 2H), 7.23 (s, 1H), 7.67 (t, 1H, J=7.4 Hz, H-8), 7.95 (d, 1H, J=6.7 Hz), 8.23 (d, 1H, J=8.2 Hz), 8.45 (s, 1H), 9.50 (s, 1H, H-10), 15.98 (br s, 1H, COOH).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[N:6][C:7]#[N:8].[K].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13]>C(#N)C>[O:13]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[N:6][C:7]#[N:8]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: N#CN=C1CCCN1
Agent: [K]
Solvent: CC#N
Product: Cc1ccc(C(=O)CN2CCCC2=NC#N)cc1
Yield: 83.7 %

Procedure:
A suspension of N-(pyrrolidin-2-ylidene)cyanamide (1.09 g; 10 mmol) in acetonitrile (20 mL) was heated gently until dissolution and then potassium hydrogenocarbonate (1.66 g; 12 mmol) and 2-bromo-1-p-tolylethanone (2.98 g; 14 mmol) were added. The well stirred mixture was heated at reflux for 21 h and an extra amount of 2-bromo-1-p-tolylethanone (0.426 g; 2 mmol) was added. The reaction mixture was heated for 6 additional hours. After cooling, the precipitate was filtered, washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (1-20%) in dichloromethane to furnish 2.02 g (84%) of N-(1-(2-oxo-2-p-tolylethyl)pyrrolidin-2-ylidene)cyanamide as an orange solid. ESI/APCI(+): 242 (M+H). 1H NMR (CDI3) δ 7.83 (d, J=8.22 Hz, 2H, Harom.); 7.29 (d, J=8.04 Hz, 2H, Harom.); 4.81 (s, 2H, COCH2); 3.69 (m, 2H, CH2); 3.03 (m, 2H, CH2); 2.43 (s, 3H, CH3); 2.24 (m, 2H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>O1CCOCC1>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:4][C:3]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:2]=1[F:1])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OCc2cc([N+](=O)[O-])ccc2F)cc1
Reactant: CCNCC
Solvent: C1COCCO1
Product: CCN(CC)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-fluoro-5-nitro-benzyl ester (0.696 g, 2.13 mmoles) in 1,4-dioxane (4 mL) was added TEA (0.45 mL, 3.20 mmoles) and diethylamine (0.33 mL, 3.21 mmoles). The reaction mixture was stirred for 8 h at 55° C., concentrated and purified by TLC (petroleum ether/AcOEt/NH4OH//8/2/0.2). The expected compound was obtained as a yellow oil (0.365 g, 76% yield). MALDI-TOF: m/z 227.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ8.44; (dd, J=6.3 Hz and 2.9 Hz, 1H), 8.12; (ddd, 4-CH, J=8.9 Hz, 2.9 Hz and 4.4 Hz, 1H), 7.15; (dd, J=8.9 Hz and 8.9 Hz, 1H), 3.67; (s, 2H), 2.58; (q, J=7.1 Hz, 4H), 1.08; (t, J=7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ126.7; (CH, d, J=6.9 Hz), 124.1; (CH, d, J=10.2 Hz), 115.9; (CH, d, J=24.6 Hz), 49.6; (CH2), 47.1; (CH2), 11.8; (CH3).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18].C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:22]([OH:23])=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH3:7])[N:6]=2)[C:17]=1[OH:18]
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nc2nc(O)c(-c3ccc(F)cc3F)c(O)n2n1

Procedure:
4 g (40.95 mmol) 3-Amino-5-methyl-1,2,4-triazole, 10 g diethyl (2,4-difluorophenyl)malonate and 9 g tributylamine are stirred at 180° C. over night. The solution is diluted with 2N NaOH solution and water and the resulting mixture is extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified at 0° C. with concentrated HCl. The precipitate is collected by filtration, washed with water and dried. This product (4.47 g=33.4%) is used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:9])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: NS(=O)(=O)c1cccs1
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4-nitrobenzenesulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-nitrobenzenesulfonyl chloride, which afforded the title compound 1.953 g (96.6%) as a pale yellow solid, m.p.: 178-180° C. 1H-NMR, 400 MHz, d6-DMSO, δ (ppm): 8.40 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.6 Hz, 2H), 7.72 (br, 2H). HRMS (ESI-ve) m/z calculated for C6H6N2O4S (M−H)− 200.9976. Found 200.9986.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](SC)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.Cl[C:35]1C=CC=C(C(OO)=O)C=1.[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([S:45]([CH3:35])(=[O:49])=[O:47])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CSc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of the compound obtained in Example 32 (940 mg) in methylene chloride (40 mL) was added 3-chloroperbenzoic acid (1.09 g) under ice-cooling and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added an aqueous sodium thiosulfate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on NH-silica gel (Chromatorex NH silica gel/Fuji Silicia Chem., solvent; hexane/ethyl acetate=50/50 to 0/100) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)-2-methylsulfonyl-pyrazolo[1,5-a]pyrimidine (1.0 g; yield: 100%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH2:17]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2)[CH3:18]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: CCOc1ccccc1N
Product: CCOc1ccccc1Nc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 86.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-ethoxyaniline (119 mg, 0.87 mmol) to provide 198 (123 mg, 86% yield) as a white solid. LC-MS (M+H=332, obsd.=332).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[N:10]([CH3:11])[C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Cl:19][C:9]1[N:10]([CH3:11])[C:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[N:8]=1
Reactant: COC(=O)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc(Cl)n(C)c12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Methyl 7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (150 mg, 0.63 mmol) was dissolved in 3 mL of phosphorous oxychloride and heated at 110° C. overnight. The reaction mixture was allowed to cool to room temperature, poured into a crushed ice, and stirred for 1 h. The resultant was diluted in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained (147 mg, 90%) was used in the next reaction without further purification.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].S(O)(O)(=O)=O.CS[C:17](=[NH:19])[NH2:18]>[OH-].[Na+].O>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:17]([NH2:19])=[NH:18]
Reactant: O=P(O)(O)CCCNO
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)N(O)CCCP(=O)(O)O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g.) in 1 N aqueous sodium hydroxide solution (10 ml.) and S-methylisothiourea sulfate (1.40 g.) in water (5 ml.) was heated to reflux for 1.5 hours and allowed to stand overnight at ambient temperature to give crystalline precipitates, which was collected by filtration and washed with water and then with ethanol to give 3-(1-hydroxyguanidino)propylphosphonic acid (690 mg.), mp: 244°-247° C. (dec.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][CH:9]([C:14](=O)[CH3:15])[C:10](OC)=[O:11])=[CH:6][CH:5]=1)#[N:2].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25].C(O)(=O)C>CO.O>[NH2:26][C:24]1[N:25]=[C:10]([OH:11])[C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=2)=[C:14]([CH3:15])[N:23]=1
Reactant: N=C(N)N
Reactant: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O
Agent: O=C(O)O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of the crude product from step (i) and guanidine carbonate (128.1 g) in methanol (915 mL) was heated under reflux for 5 hours. The mixture was cooled to room temperature, diluted with water (923 mL) and nuetralised with acetic acid. The mixture was then cooled to 10° C. and the resulting precipitate collected by filtration, washed with methanol (501 mL) and dried under reduced pressure to give the subtitle compound as a solid, 82.4 g; 1H NMR DMSO-d6: δ 10.91 (brs, 1H), 7.20-7.17 (m, 4H), 6.38 (s, 2H), 3.95 (s, 2H), 3.63 (s, 2H), 2.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=[CH:15][C:3]=12.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[C:4]3[NH:5][CH:6]=[C:7]4[C:8](=[O:10])[N:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:32]=[C:2]4[C:3]=3[CH:15]=[N:14]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Reactant: NNc1ccccc1
Product: COc1ccc(Cn2ncc3c4nn(-c5ccccc5)c(=O)c-4c[nH]c32)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A suspension of compound 3 and 10 equivalents of phenyl hydrazine was stirred at 90° C. for 16 hours. Reaction was quenched with iced water. The aqueous layer was removed, residue was suspended in ethanol and stirred with 1N NaOH solution at room temperature for 1 hour. pH was adjusted to 5 using acetic acid and solvent was removed in vacuo. Compound 4 was collected by filtration.
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[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50]>>[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[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:37][CH2:38][CH2:39][N:40]3[C:44](=[O:45])[C:43]4=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]4[C:41]3=[O:50])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CCCN5C(=O)c6ccccc6C5=O)c4=O)CC3)c2cc1OC
Yield: 42 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 478.0 mg (1.00 mol) of Compound 24 was used and N-(3-bromopropyl)phthalimide was used in place of methyl iodide. As a result, 280 mg (yield: 42%) of Compound 34 was obtained as a pale yellow amorphous solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:13]N)[CH:6]=[C:7]([CH3:12])[C:8]=1[O:9][CH2:10][CH3:11].[CH3:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=O.[OH-].[Na+]>C(O)(=O)C.O>[CH2:10]([O:9][C:8]1[C:3]([CH3:2])=[CH:4][C:5]2[N:13]=[C:17]3[C:18]4[C:23]([CH2:24][C:16]3([CH3:15])[C:6]=2[C:7]=1[CH3:12])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:11]
Reactant: CCOc1c(C)cc(NN)cc1C
Reactant: CC1Cc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c(C)cc2c(c1C)C1(C)Cc3ccccc3C1=N2
Yield: 96.1 %

Procedure:
A solution of 2.16 g (0.01 mol) of 3,5-dimethyl-4-ethoxyphenylhydrazine hydrochloride and 1.46 g (0.01 mol) of 2-methyl-1-indanone in 20 ml of acetic acid was stirred overnight at room temperature and then refluxed for 3 hours. The mixture was diluted with water, alkalinized with 10N sodium hydroxide solution and extracted three times with methylene chloride. The combined organic phase was washed with water, dried (Na2SO4) and evaporated giving 2.8 g of crude product which was recrystallized from light petroleum/ethyl acetate (5/1). Yield 2.1 g (72%). M.p. 164° C.