Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([C:23](Cl)=[O:24])[CH2:20][C:19]1([F:22])[F:21]>[Cu]Br.C1(C)C=CC=CC=1>[F:21][C:19]1([F:22])[CH2:20][C:18]1([C:23]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:24])[CH3:17]
Reactant: CC1(C(=O)Cl)CC1(F)F
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C(=O)C#Cc2ccc(Cl)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
13.7 g (0.1 mol) of p-chlorophenyl-acetylene are added to a mixture of 10.1 g (0.1 mol) of triethylamine, 1.4 g (0.01 mol) of copper(I) bromide and 55 ml of toluene, and the mixture is stirred for 30 minutes at room temperature under argon. After the reaction mixture has been heated to 55° C., 15.5 g (0.1 mol) of 1-methyl-2,2-difluorocyclopropanecarbonyl chloride are added dropwise. After this, the mixture is stirred for 8 hours at 90° C., and then cooled and filtered. The filtrate is washed with dilute aqueous hydrochloric acid and water in succession and concentrated under reduced pressure. 19.2 g of a dark oil remain which is distilled using a bulb tube. A yellow oil, which solidifies on standing, distils over at 0.1 mbar and a jacket temperature of 120° C. 8.4 g (33% of theory) of 2-(4-chlorophenyl)-ethin-1-yl 2,2-difluoro-1-methyl-cycloprop-1-yl ketone of melting point 67°-68° C. are obtained. ##STR54##
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]=[CH:3][CH3:4].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>[Pt](Cl)(Cl)(Cl)Cl.C=CCCCCCC.[Pt]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH:2]=[CH:3][CH3:4]
Reactant: C=CCOCC=CC
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: [Pt]
Solvent: C=CCCCCCC
Product: CC=CCOCCC[Si](OCC)(OCC)OCC
Temperature: 120 °C

Procedure:
About 84 g of allyl but-2-enyl ether are heated under reflux (about 120° C.) in a three-necked flask fitted with a reflux condenser, stirrer and dropping funnel. To this are added dropwise over a period of two hours a solution containing 82 g of triethoxysilane, in which 2 mg of platinum, calculated as the element, are dissolved in the form of a solution of platinum tetrachloride in 1-octene. After heating for an additional five hours under reflux, more than 99 percent of the Si-bonded hydrogen atoms have been converted. The intermediate obtained in this manner, (but-2-enyloxypropyl)triethoxysilane, is purified by distillation at C and at 7 hPa (abs.) and contains 5 percent by weight, based on the total weight of the intermediate, of (but-1-enyloxypropyl)triethoxysilane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.C(N(CC)CC)C.[O:29]=[C:30]1[CH2:34][CH2:33][C:32](=O)[CH:31]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]>C1C=CC=CC=1.O>[Br:20][C:32]1[CH2:33][CH2:34][C:30](=[O:29])[C:31]=1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: BrBr
Reactant: O=C(O)CCCCCCC1C(=O)CCC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CCCCCCC1=C(Br)CCC1=O
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 67 %

Procedure:
A dried triphenyl phosphine (288 mg) was dissolved in a dried benzene (10 ml), and then 1M bromine in benzene solution (1.1 ml) was added thereto while stirring at 0° C. over 3 minutes. The mixture was stirred for 10 minutes at room temperature, and then dried triethyl amine (0.15 ml) was added thereto at 0° C. Continuously, 7-(2,5-dioxocyclopentyl) heptanoic acid (113 mg) were added thereto. The mixture was stirred for 26 hours, and poured into the same volume of water. The aqueous solution was extracted with three 20 ml portions of ether. The ether layer was washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The reaction mixture was purified by thin layer chromatography to afford 7-(2-bromo-5-oxo-1-cyclopentenyl) heptanoic acid (yield 96.6 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+]([O-])=O.[Cl:15]Cl>>[Cl:15][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: ClCl
Product: Fc1ccc(C(F)(F)F)cc1Cl
Temperature: 320 °C

Procedure:
In a continuous process, about 8 parts per hour of 4-fluoro-3-nitrobenzotrifluoride vapors and about 15 parts per hour of chlorine gas were passed simultaneously through a vapor phase reactor maintained at a temperature of about 320° C. and the reaction product vapors were condensed and collected. The process was continued until about 40 parts of 4-fluoro-3-nitrobenzotrifluoride had been passed through the reactor, yielding about 36.3 parts of 3-chloro-4-fluoro benzotrifluoride product. The structure of the product was confirmed by spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(C(=O)Cc2cccc(Br)c2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CC(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(3-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone (126 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-182) as a yellow powder (36 mg, 19%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([CH3:14])[O:11][N:10]=1.[NH2:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)[C:2]=1[O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cc1nc(-c2cccc(F)c2F)no1
Reactant: Cc1nsc(N)n1
Product: Cc1nsc(Nc2ncnc3ccc(Oc4c(F)cccc4-c4noc(C)n4)cc23)n1

Procedure:
The compound of Example 93 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 3-(2,3-difluorophenyl)-5-methyl-1,2,4-oxdiazole, 5-amino-3-methyl-[1,2,4]thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](I)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[CH3:33][O:34][CH2:35][CH2:36][OH:37]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:37][CH2:36][CH2:35][O:34][CH3:33])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: COCCO
Reactant: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: COCCOc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-[4-(6-amino-8-iodopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea and 2-methoxyethanol by using the same techniques as in Example 136.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:18][NH:19][CH3:20].[CH2:21]=O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]2[CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[C:13]([OH:16])=[C:12]([Cl:17])[C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(C)oc2ccc(O)c(Cl)c12
Reactant: CNC
Reactant: C=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)oc2cc(CN(C)C)c(O)c(Cl)c12
Temperature: 25 °C

Procedure:
A solution of 1.9 g of 2-methyl-3-carbethoxy-4-chloro-5-hydroxybenzofuran, 2.6 ml of a 33 percent aqueous solution of dimethylamine and 0.6 ml of 36 percent Formalin in 12 ml of dimethylformamide is refluxed at a temperature of 100° to 105° for 8 hours and then cooled to ambient temperature. The precipitated crystals are filtered off, washed with water and dried in order to yield 0.75 g of crystalline 2-methyl-3-carbethoxy-4-chloro-hydroxy-6-dimethylaminomethylbenzofuran. An additional 0.4 g of crystals is obtained from the parent solution by dilution with water. The total yield is 1.15 g (50%); m.p., 130°-131°C (from alcohol). Mixed melting of the product crystals with a specimen from Example 1a gave no depression of the melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=3[F:23])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: OB(O)c1ccc(F)cc1F
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1F

Procedure:
The title compound, MS: m/e=330.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,4-difluorobenzene boronic acid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH3:48])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH2:47]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1)[CH3:48]
Reactant: CCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 73.7 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (200 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-ethyl-1H-indol-3-yl)propanoic acid (234 mg) synthesized in Referential Example 1(b) were used, whereby the title compound (283 mg) was yielded.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:18][C:19]([NH2:21])=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42]C)=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>O.CN(C)C=O>[CH2:11]([N:18]([CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)NCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccc(OCc2ccc(CN(Cc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (100 mg), N-benzylthiourea (83 mg) and N,N-dimethylformamide (2 mL) was stirred at 80° C. for 1 hr. The reaction mixture was cooled to 0° C., sodium hydride (60% in oil, 80 mg) was added, and the mixture was stirred at room temperature for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (300 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:0 in volume ratio) to give the title compound (110 mg, yield 41%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@H:12]([CH2:13][OH:14])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]([N:27]=C=O)=[O:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][N:9]1[C@H:12]([CH2:13][O:14][C:25](=[O:26])[NH2:27])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO
Reactant: O=C=NC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1COC(N)=O
Yield: 72.4 %

Procedure:
In 6 ml of chloroform dried with molecular sieve is dissolved 390 mg (1.21 mmole) of (3S,4S)-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-hydroxymethyl-2-azetidinone, and a solution of 0.11 ml (1.33 mmole) of chlorocarbonyl isocyanate in 2 ml of dried chloroform is added dropwise to the solution under ice-cooling with stirring. After the stirring under ice-cooling for 30 minutes, the same amount of chlorocarbonyl isocyanate is furthermore added to the reaction solution in the same manner. After the stirring under ice-cooling for further 30 minutes, 10 ml of saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution. The chloroform is distilled off under reduced pressure, and 10 ml of 3N hydrochloric acid and ethyl acetate are added to the residue, followed by thorough shaking. The ethyl acetate layer is separated, while the aqueous layer is extracted again with ethyl acetate, and the ethyl acetate layers are combined, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ether and n-hexaneare added to the residue, and the resulting crystals are recovered by filtration to give 320 mg of (3S,4S)-1benzyloxy-3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-2azetidinone.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])=[CH2:2].[CH2:10]([O:12][C:13]([C:15]#[C:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14])[CH3:11]>>[CH:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:5]2[C:4]=1[C:17](=[O:18])[CH:16]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[NH:6]2)=[CH2:2].[CH:1]([C:3]1[CH:4]=[C:5]2[C:7]([C:13](=[O:14])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6]2)=[CH:8][CH:9]=1)=[CH2:2]
Reactant: C=Cc1cccc(N)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: C=Cc1ccc2c(=O)cc(C(=O)OCC)[nH]c2c1
Product: C=Cc1cccc2[nH]c(C(=O)OCC)cc(=O)c12

Procedure:
Treatment of 3-ethenylaniline (7 g) with diethylacetylene dicarboxylate (9.4 g), as described in Example 1b, gave ethyl 5-ethenyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.16 g), mp 168°-170° C., δ (360 MHz, DMSO-d6) 1.37 (3H, t, CH3), 4.41 (2H, q, CH2), 5.25 and 5.55 (2H, 2dd, =CH2), 6.56 (1H, s, 3H), 7.38 (1H, d, 6-H), 7.62 (1H, t, 7-H), 7.90 (1H, d, 8-H), 8.15 (1H, 2d, CH=) and 11.87 (1H, bs, NH) and ethyl 7-ethenyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.46 g), mp 177°-179° C., δ (360 MHz, DMSO-d6) 1.37 (3H, t, CH3),4.42 (2H, q, CH2), 5.47 and 5.99 (2H, 2d, =CH2), 6.65 (1H, bs, 3-H), 6.84 (1H, 2d, CH=), 7.54 (1H, d, 6-H) and 7.93 (1H, s, 8-H), 8.04 (1H, d, 5-H), 11.97 (1H, bs, NH).
Reaction SMILES: CC1C(C)=CC=CC=1CCN.[CH3:12][NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18]C=CC=2)[C:16]=1[CH2:25]CC.Cl.[O:29]=[C:30]1[NH:39][C:38]2[N:37]=[CH:36][C:35](/[CH:40]=[CH:41]/[C:42](O)=[O:43])=[CH:34][C:33]=2[CH2:32][CH2:31]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:25][C:16]1[C:17]([CH3:18])=[CH:22][CH:23]=[CH:24][C:15]=1[CH2:14][N:13]([CH3:12])[C:42](=[O:43])/[CH:41]=[CH:40]/[C:35]1[CH:36]=[N:37][C:38]2[NH:39][C:30](=[O:29])[CH2:31][CH2:32][C:33]=2[CH:34]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cc1cccc(CCN)c1C
Agent: Cl
Product: Cc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c1C
Yield: 75 %

Procedure:
According to the procedure of Example 1 (a), except substituting 2,3-dimethylbenzylmethyl amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.368 g, 75%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.68-10.64 (m, 1H), 8.38-8.32 (m, 1H), 8.10-7.99 (m, 1H), 7.57-7.50 (m, 1H), 7.29-7.04 (m, 3H), 6.94-6.77 (m, 1H), 4.82-4.65 (m, 2H), 3.06-2.85 (m, 5H), 2.57-2.48 (m 2H), 2.28-2.14 (m, 6H); MS (APCI) m/e 350 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:35])([CH:33]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([S:8][C:9]([CH3:35])([CH2:33][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1cccc2cc(C(=O)NCC(C)(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.40 g), morpholine (0.13 ml) and 1,2-dichloroethane (4 ml) was added sodium triacetoxyborohydride (0.36 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.25 g, yield 55%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). melting point 150-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].S(Cl)(Cl)=O.[CH2:18]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH2:18]([N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)c2nccn2Cc2ccccc2)c1
Yield: 85.2 %

Procedure:
A solution of 3-(methoxycarbonyl)benzoic acid (2.53 g, 14.0 mmol) in thionyl chloride (7.17 ml, 98.30 mmol) was heated at reflux for 1 h. The mixture was cooled and concentrated in vacuo and to the residue was added toluene. This solution was concentrated in vacuo and to the residue was added anhydrous acetonitrile (24 ml), 1-benzyl-1H-imidazole (2.22 g, 14.0 mmol) and triethylamine (2.35 ml, 16.9 mmol). The reaction mixture was heated at reflux for 18 h and then cooled and concentrated in vacuo. To the residue was added ethyl acetate and the solution was washed with water and saturated aqueous sodium hydrogen carbonate solution. The organic phase was filtered through silica, eluting with ethyl acetate, and the filtrate was concentrated in vacuo to give the title compound (3.82 g).
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])(=[O:3])[NH2:2].[C:11]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[CH:12]=[CH2:13].O>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:5]([OH:10])(=[O:14])/[CH:6]=[CH:7]\[C:8](=[O:9])[NH:4][C:1](=[O:3])[NH2:2].[C:11]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[CH:12]=[CH2:13]
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: C=CC(=O)OCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)O
Reaction time: 5 h
Yield: 167.2 %

Procedure:
A mixture of 140 g of N-carbamylmaleimide (1 mole), 121.8 g of 2-hydroxyethyl acrylate (1.05 moles) and 1.36 g of zinc chloride (0.01 moles) in 200 mL of acetonitrile was heated to reflux. After 5 hours, the mixture was poured into 500 mL of water. The solid was filtered, washed with water and dried to afford 240.7 g (94% yield) of 2-hydroxyethyl acrylate maleurate. M.P.: 88°-90° C. (dec.); 1H NMR (CDCl3): δ10.4 (br s, 1H), 8.2 (br s, 1H), 6.4 (m, 3H), 6.2 (d of d, 1H), 5.9 (m, 2H), 4.4 (A2B2, 4H); 13C NMR (CDCl3): δ165.9, 165.3, 165.2, 155.1, 133.1, 131.6, 129.5, 127.8, 63.2, 61.9; HPLC (10% CH3CN/H2O, C18): Rt=5.7 minutes.
Reaction SMILES: O=C1N2CC3C(C2=C([C:15]([O:17][CH2:18][C:19](=O)[N:20]([CH3:22])C)=O)C=C1C1C=CC=CC=1)=CC=CC=3.CN(C)CCOC(C1C=C(C2C=CC=CC=2)C(=O)N2CC3C(=CC=CC=3)C=12)=O.FC1C=CC=C2C=1C1=C(C(OC)=O)C=C(C3C=CC=CC=3)C(=O)N1C2.[Cl:83][C:84]1[CH:85]=[CH:86][CH:87]=[C:88]2[C:92]=1[C:91]1=[C:93]([C:104](OC)=[O:105])[CH:94]=[C:95]([C:98]3[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=3)[C:96](=[O:97])[N:90]1[CH2:89]2>>[Cl:83][C:84]1[CH:85]=[CH:86][CH:87]=[C:88]2[C:92]=1[C:91]1=[C:93]([C:104]([N:20]3[CH2:19][CH:18]([O:17][CH3:15])[CH2:22]3)=[O:105])[CH:94]=[C:95]([C:98]3[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=3)[C:96](=[O:97])[N:90]1[CH2:89]2
Reactant: CN(C)C(=O)COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1c(Cl)cccc1C2
Agent: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1c(F)cccc1C2
Product: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2c(Cl)cccc2C3)C1

Procedure:
A method according to claim 14 wherein the compound is selected from methyl 4,6-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]isoindole-1-carboxylate; (dimethylcarbamoyl)methyl 4,6-dihydro-4-oxo-3-phenylpyrido-[2,1-a]isoindole-1-carboxylate; 2-(dimethylamino)ethyl-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate; and methyl 10-fluoro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate; and methyl 10-chloro-4, 6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate.