Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[H-].[Na+].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29]>CN(C)C=O>[N+:25]([C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[CH:16]=[C:17]([C:28]([F:29])([F:30])[F:31])[C:18]=1[N:8]1[C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][C:5](=[O:10])[NH:6][C:7]1=[O:9])([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)n(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c(=O)[nH]1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
1.0 g of 6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added to 10 ml of dimethylformamide, followed by addition of 0.65 g of sodium hydride (purity: 55%) with stirring at 0° C. The mixed solution was stirred at room temperature for 30 minutes, then cooled to 0° C. and added dropwise with a 5 ml dimethylformamide solution of 1.89 g of 2-chloro-3,5-dinitrobenzotrifluoride. After the solution was further stirred at room temperature for 3 hours, the solvent was distilled away under reduced pressure. After addition of cooled dilute hydrochloric acid thereto, the residue was extracted with 100 ml of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then the solvent was distilled away under reduced pressure to form a crude product. This crude product was recrystallized from a mixed solvent of chloroform and petroleum ether to obtain 0.77 g of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCS(=O)(=O)CC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(1,1-dioxo-thiomorph-olin-4-yl)-nicotinamide was prepared starting from intermediate E and thiomorpholine-1,1-dioxide. MS calcd. for C26H23ClN4O4S [(M+H)+] 523.1, obsd. 523.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11](O)=[O:12])[N:10]=2)[CH:7]=1.C[N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([NH2:16])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)nc2ccc(I)cn12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)nc2ccc(I)cn12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g) in DMF (15 ml) were added HATU (1.88 g) and triethylamine (1.38 ml) at 0° C. The mixture was allowed to warm to room temperature for 30 min, and then NH4Cl (725 mg) was added thereto. The resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH4Cl solution, saturated aqueous NaHCO3 solution, water and brine. The DCM layer was then dried over Na2SO4 and concentrated in vacuo to give the title compound (600 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.CCOCC>C(O)(=O)C>[Br-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.50 g of p-(dimethylamino)benzaldehyde are added to a solution of 3.7 g of 1-amino-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide in 25 ml of glacial acetic acid. The mixture is stirred at room temperature for 15 hours. Then, 20 ml of ether are added thereto and, after an additional 3 hours, the product is removed by filtration. After recrystallization from ethanol/ether, there is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide of melting point 241°.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.[N:26]1([C:31](=N)[NH2:32])C=CC=N1>C(#N)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:31]([NH2:32])=[NH:26])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: N=C(N)n1cccn1
Reactant: FCCOc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N=C(N)N1CCN(c2ccc(OCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1-(4-(2-fluoroethoxy)phenyl)piperazine (50 mg, 0.15 mmol) and diisopropylethylamine (59 μL, 0.34 mmol) in ACN (1 mL) was added 1H-pyrazole-1-carboximidamide (25 mg, 0.17 mmol). The reaction stirred at room temperature for 1 h, monitored by LC-MS. The precipitate was then filtered and washed with ACN to obtain the desired product as a white solid (33.8 mg, 58% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.55 (br s, 3H), 6.95-6.86 (m, 4H), 4.78 (m, 1H), 4.62 (m, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 3.57 (dd, 4H, J=5.2, 4.9 Hz), 3.09 (dd, 4H, J=5.1, 5.0 Hz); 19F NMR (DMSO-d6): δ−222.037 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 156.0, 152.2, 144.9, 119.2, 115.1, 82.2 (81.1), 67.4 (67.2), 48.9, 44.9; HRMS calcd. for C12H17FN2O: 267.16157 found 267.16146.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH:11][CH2:12][CH3:13])=[O:9])[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([N:11]([CH2:12][CH3:13])[NH:10][C:8]([C:6]1[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])=[O:33]
Reactant: CCNNC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: CCN(NC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N′-ethyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (10-a) (320 mg) was dissolved in pyridine (4 mL), methyl chloroformate (190 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 95 μL) was added. After 1 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=2:1, Rf=0.10) to afford 308 mg of the title compound (10) of the present invention of the formula
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=2)[CH:32]=[CH:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:42])=[CH:36][CH:37]=2)[CH:32]=[CH:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCSc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1SCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
0.37 g of amorphous compound 51 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.30 g of ethyl 4-(2-aminophenylthio)butyrate and 1.0 g of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:7][CH2:1][CH:2]1[CH2:3][CH2:4][O:5][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6]1
Reactant: OCCC(O)CO
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1CCOC(c2ccccc2)O1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture of 1,2,4-butanetriol (3.0 g, 28.3 mmol) and benzaldehyde (11.48 ml, 113 mmol) in dry toluene (50 mL) with p-toluenesulfonic acid monohydrate (0.269 g, 1.413 mmol) was heated under reflux in a Dean-Stark apparatus. After ˜1 h, the solution was washed with sat. aq NaHCO3, dried and concentrated under high vac to remove most of the benzaldehyde. Chromatography gave syrupy title compound (2.88 g, 14.83 mmol, 52.5% yield). The NMR's were the same as reported (Tetrahedron Asymm. 1996, 7, 3209-3246).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([OH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].[H-].[Na+].[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][C:22]([N:21]([CH3:25])[CH3:20])=[S:23])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 65.0 g of 3-chloro-2-(4-chloro-3-hydroxyphenyl)-5-trifluoromethylpyridine in 200 ml of dimethylformamide, and then 31.3 g of dimethylthiocarbamoyl chloride, were added dropwise to a suspension of 6.7 g of 80% sodium hydride in 300 ml of anhydrous dimethylformamide. The solution was stirred at 80° C. for one hour and then poured into 2.5 1 of 1% by weight sodium hydroxide solution. After extraction three times with 250 ml of tert-butyl methyl ether each time the combined organic phases were washed twice with 150 ml of water each time and then dried over sodium sulfate and concentrated until crystallization started. After removal of the crystals, the mother liquor was concentrated further until more of the product started to crystallized out.
Reaction SMILES: C1(O)C=CC=CC=1.C1(C)C=CC(S([N:17]2[CH2:24][C:23]3[CH2:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][C:19]=3[CH2:18]2)(=O)=O)=CC=1.[BrH:36]>>[BrH:36].[BrH:36].[C:19]12[CH2:20][NH:21][CH2:22][C:23]=1[CH2:24][NH:17][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2CC3=C(C2)CN(S(=O)(=O)c2ccc(C)cc2)C3)cc1
Agent: Br
Solvent: Oc1ccccc1
Product: C1NCC2=C1CNC2
Temperature: 25 °C

Procedure:
60 ml of 48% hydrobromic acid and 7 g of phenol were added to 10.8 g 3,7-bis-p-toluenesulfonyl-3,7-diazabicyclo [3.3.0]oct-1(5)-ene, prepared in Preparation 1. The mixture was refluxed for 4 hours and cooled to room temperature. The aqueous phase was separated by adding 100 ml of chloroform and 50 ml of water. The aqueous phase was washed with chloroform (100 ml×4) and decolorized with active carbon. The aqueous phase was concentrated under vacuum and the remained solid was washed with 1:1 methanol-ethyl ether solvent. 5 g of the title compound was obtained as white solid (yield 71%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:23])([CH3:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:22][C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]=[CH:6]1)([CH3:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCNC(=O)c2ccccc2)c1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.50 g) and benzoyl chloride (1.10 g) were reacted in a similar manner to Example 55 to give N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)-propyl]imidazol-4-yl}ethyl)benzamide, as an oil. The compound contained 8% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl)benzamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([CH3:9])[CH:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:9][N:5]1[C:6](=[O:8])[CH2:7][CH:3]([CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)CC(CO)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2c2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
To 27.8 g. of 3-hydroxymethyl-1-methyl-2-phenyl-pyrrolidin-5-one in 40 ml. of potassium hydroxide dried pyridine was added in portions at 0°-5° 29.4 g. of p-toluenesulfonyl chloride. The orange solution was then stirred at 15° C. for 4 hours and then decanted into 180 ml. of ice cold 10% hydrochloric acid. The resulting solid was collected by filtration and washed with water and air dried. Washing with ether provided 37 g. of crude product.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)[C:20]([NH:22][CH2:23][CH:24]2[CH2:29][CH:28]3[CH2:30][CH:25]2[CH:26]=[CH:27]3)=[O:21])C=CC=CC=1.CN(C)C=O.[H-].[Na+]>CCOCC>[CH:28]12[CH2:30][CH:25]([CH:24]([CH2:23][NH:22][C:20]([NH:12][S:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])=[O:21])[CH2:29]1)[CH:26]=[CH:27]2
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: O=C(NCC1CC2C=CC1C2)N(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(NCC1CC2C=CC1C2)NS(=O)(=O)C=Cc1ccccc1

Procedure:
To a solution of 1.8 g. of 2-phenylethenesulfonamide and 4.8 g. of 1,1-diphenyl-3-(bicyclo[2.2.1]hept-2-en-5-ylmethyl)urea in 20 ml. of N,N-dimethylformamide, is added, with stirring 0.64 g. of a 56.6% dispersion of sodium hydride in mineral oil. The mixture is stirred at ambient temperature overnight, during which time a heavy precipitate forms. To the reaction mixture is then added 200 ml. of ether. After stirring for 15 minutes, the precipitate is filtered off. It is dissolved in 50 ml. of water, and then the crude product is precipitated by acidification usng concentrated hydrochloric acid. It is filtered off and recrystallized from aqueous acetone. The yield is 1.9 g. (56%) of a solid, m.p. 161°-163.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26]OCC1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:12](=[CH2:26])[C:11]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1
Reactant: ClCOCc1ccccc1
Product: C=C1C(=O)N(COCc2ccccc2)CCCN1C(=O)OC(C)(C)C

Procedure:
The title was prepared from tert-butyl 4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate and benzyl chloromethyl ether essentially following the procedure described in Example 3, Step 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)c1
Yield: 66 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 3-methoxyphenyl isocyanate (0.0098 mL, 0.076 mmol) were reacted to give the title compound as a white solid (20.1 mg, 66%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.39-7.47 (m, 3H), 7.13-7.27 (m, 4H), 6.98-7.10 (m, 2H), 6.93 (d, J=7.6 Hz, 1H), 6.55 (dd, J=8.4, 2.2 Hz, 1H), 4.18-4.26 (m, 1H), 3.73 (s, 4H), 3.48-3.62 (m, 2H), 2.90-3.02 (m, 1H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[O:18][CH2:17][O:16]3)=[N:10][C:9]=1[CH2:22][C:23]1[O:27][C:26](/[CH:28]=[CH:29]/[CH2:30][S:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:25][CH:24]=1>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[O:18][CH2:17][O:16]3)=[N:10][C:9]=1[CH2:22][C:23]1[O:27][C:26](/[CH:28]=[CH:29]/[CH2:30][S:31]([CH2:32][C:33]([OH:35])=[O:34])=[O:1])=[CH:25][CH:24]=1
Reactant: Cc1oc(-c2ccc3c(c2)OCO3)nc1Cc1ccc(/C=C/CSCC(=O)O)o1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc3c(c2)OCO3)nc1Cc1ccc(/C=C/CS(=O)CC(=O)O)o1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
A aqueous solution (100 ml) of OXONE (trade mark) (891 mg) was added dropwise to a solution of the compound prepared in Example 3(2) (1.0 g) in tetrahydrofuran (200 ml) over a period of 30 minutes at −2˜−3° C., and the resultant solution was stirred for 10 minutes at 0° C. Ice water was added to the reaction solution, and the resultant solution was extracted with ethyl acetate, and the extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1→10:1) to give the title compound (750 mg) having the following physical data.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:29])[C:18]1[C:23]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:28])[CH3:12].[CH2:30](I)[CH3:31]>C1COCC1>[Cl:28][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=1[C:17]([N:16]([CH2:15][CH2:14][O:13][CH2:11][CH3:12])[CH2:30][CH3:31])=[O:29]
Reactant: CCOCCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A 1M THF solution of sodium bis(trimethylsilyl)amide (7.7 mL, 7.7 mmol) was added dropwise over 5 min to a solution of N-(2-ethoxyethyl)-2-chloro-6-(trimethylsilyl)benzamide (2.1 g, 7 mmol) in THF (30 mL). The resulting mixture was stirred for 1 h at RT, then a solution of ethyl iodide (1.31 g, 8.4 mmol) in THF (15 mL) was added with a mild exotherm. The resulting reaction mixture was stirred overnight, then was partitioned between ethyl acetate and dilute aq citric acid. The ethyl acetate phase was washed with sat aq NaHCO3 followed with brine, then was dried (MgSO4) and concentrated to afford 1.9 g of the title compound as an amber oil, an 83% yield.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)(=[O:8])=[O:7]>C(OCC)(=O)C>[CH3:5][S:6]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)(=[O:8])=[O:7]
Reactant: O=C(Cl)Cl
Reactant: CS(=O)(=O)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylsulfonyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.[ClH:33]>N1C=CC=CC=1.C(O)C>[ClH:33].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:28](=[O:29])[C@H:23]5[C@H:22]([CH2:27][CH2:26][CH2:25][CH2:24]5)[C:31]4=[O:30])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229°-231° C. ANALYSIS: Calculated for C24H30FN3O3.HCl: 62.13%C 6.73%H 9.06%N Found: 61.79%C 6.68%H 8.92%N