Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:45][C@H:46]1[CH2:51][CH2:50][C@H:49]([OH:52])[CH2:48][CH2:47]1>ClCCl>[OH:52][C@H:49]1[CH2:50][CH2:51][C@H:46]([NH:45][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=2)=[O:23])[CH2:47][CH2:48]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@H](O)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
In a 100 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.150 g, 0.295 mmol), EDC (61 mg, 0.32 mmol), DIEA (52 μl, 0.295 mmol) were combined with dichloromethane (3 ml) to give a yellow solution. Stirred for 30 min then trans-4-aminocyclohexanol (48 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 24 h then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 5% MeOH in DCM) and recrystallized from ethyl acetate to afford 60 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-4-hydroxy-cyclohexyl)amide as a white solid. MS: [M+H]+=555.
Reaction SMILES: [Cl:1][C:2]1[C:3](SC)=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8].O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[C:3]([NH:19][NH2:20])=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]
Reactant: NN
Reactant: CSc1nc(=O)n(Cc2cccs2)c(C)c1Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)c(NN)nc(=O)n1Cc1cccs1

Procedure:
A solution of 5-chloro-6-methyl-4-methylthio-1-(2-thienylmethyl)pyrimidin-2-one (987 mg) and hydrazine hydrate (98-100%) (2.5 ml) in ethanol (50 ml) was stirred and heated at reflux for one hour. The solution was evaporated to a gum which crystallised from ethanol to give pale purple crystals of the title pyrimidinone (649 mg) m.p. 184°-187° C.; λmax (EtOH) 232 nm (ε 14,720), 291.5 nm (ε 10,400).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.Cl.[N+:11]([CH:14]([CH:17]=O)[CH:15]=O)([O-:13])=[O:12]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]2[CH:17]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1nc(N)c2cc([N+](=O)[O-])cnc2n1
Reaction time: 0.17 h

Procedure:
About 1 equivalent of 2,4,6-triamino pyrimidine was suspended in about 50 ml of refluxing absolute ethanol with stirring under an atmosphere of nitrogen. Concentrated HCl was added dropwise to effect solution and as soon as solution occurred, about 1.2 equivalents of nitromalonaldehyde was added all at once. Within 10 minutes, a thick reddish voluminous precipitate started forming. TLC analysis indicated the presence of a yellow spot corresponding to that of the desired product along with staring materials. The reaction mixture was stirred at reflux for 3.5 hours, immediately diluted with 30 ml of water, cooled and neutralized with concentrated NH4OH. The precipitate was collected on a funnel and was washed repeatedly with water to remove unreacted triamino pyrimidine to yield pure 2,4-diamino-6-nitropyrido[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].[CH:13]1[CH:18]=[C:17]([CH:19]([CH:22]=O)[CH:20]=O)[N:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:22]=[C:19]([C:17]2[CH:18]=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:20]=[N:12]1
Reactant: NNc1ccc([N+](=O)[O-])cc1F
Reactant: O=CC(C=O)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1
Yield: 85.4 %

Procedure:
2-fluoro-4-nitrophenylhydrazine (700 mg) and 2-(2-pyridyl)malondialdehyde (610 mg) was dissolved in ethanol (30 mL). Then, p-toluenesulfonic acid (70 mg) was added into the mixture to serve as a catalyst. The reaction mixture was heated to reflux for 2 h. After completion of the reaction, the resultant mixture was cooled down to room temperature and filtered to obtain 993 mg brown solid, with a yield of 85.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH2:24][C:25]([OH:27])=O)[C:11](=[O:28])[CH:10]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH2:24][C:25]([NH:42][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:27])[C:11](=[O:28])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)n(CCC(=O)O)nc2-c2ccc(OC)cc2)cc1
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(-c2cc(=O)n(CCC(=O)NCc3ccccc3)nc2-c2ccc(OC)cc2)cc1
Yield: 52.2 %

Procedure:
After 5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-pyridazin-3-one was reacted with oxalyl chloride in a similar manner as in Example 113-(3), a further reaction was conducted with benzylamine, whereby the title compound was obtained in a yield of 52.2%.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[O:6][C:5]1=[O:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:14]1([CH2:2][CH2:3][N:4]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[O:6][C:5]2=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=c1oc2cccnc2n1CCBr
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1oc2cccnc2n1CCN1CCCCC1
Reaction time: 12 h

Procedure:
0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]-pyridin-2-one, dissolved in acetonitrile, 0.15 mol of piperidine and 0.015 mol of diisopropylethylamine are introduced into a round-bottomed flask placed under argon and surmounted by a condenser. The mixture is brought to 80° C. for 12 hours It is cooled, the acetonitrile is evaporated off under vacuum and the residue is taken up with water. The alkalinity of the medium is checked and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated and the residue is recrystallized.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:11][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)[CH2:14][CH2:13]1
Reactant: O=Cc1cn[nH]c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cnn(CC2CC2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Add 1H-pyrazole-4-carbaldehyde (0.200 g, 2.08 mmol) to a suspension of sodium hydride (0.092 g, 2.29 mmol) in DMF (3 mL) at 0° C. Stir for 20 min. at 0° C. Add a solution of 1-(bromomethyl)cyclopropane (0.295 g, 2.18 mmol) in DMF (4 mL) dropwise to the reaction mixture. Stir reaction to ambient temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry combined organics (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 60:40 ethyl acetate:hexanes) to give the title preparation (175 mg, 56%). GC-MS: m/z=150 [M+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.P(Cl)(Cl)([Cl:22])=O.C(Cl)(Cl)Cl>>[Cl:22][C:11]1[N:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc(-c2cccc(F)c2)n[nH]1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1cccc(-c2cnc(Cl)nn2)c1
Yield: 21 %

Procedure:
A mixture of 6-(3-fluoro-phenyl)-2H-[1,2,4]triazin-3-one (15.2 g, 79.5 mmol, crude) and 2 ml of DMF in 250 ml of 1:1 phosphorous oxychloride-chloroform was maintained at reflux overnight. The mixture was then concentrated at reduced pressure, diluted with methylene chloride and poured onto ice with stirring. When the ice melted the mixture was neutralized with sodium bicarbonate solution, and the layers were separated, the aqueous layer was extracted with dichloromethane once, the combined organic layer was washed with water, dried and concentrated to a brown oil which was purified by column chromatography (eluting with pure petroleum) to give title compound as a pale yellow solid (3.5 g, 21.0%): 1H NMR (CDCl3): δ 8.88 (s, 1H), 7.87-7.82 (m, 2H), 7.60-7.52 (m, 1H), 7.32-7.27 (m, 1H).
Reaction SMILES: CS[C:3]1[NH:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][NH2:28]>CC(O)(C)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][NH:28][C:3]1[NH:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COC(=O)c1ccc2c(c1)N=C(SC)NC2
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc2c(c1)N=C(NCc1ccc(OC)cc1OC)NC2
Yield: 67 %

Procedure:
Methyl 2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate (1.30 g, 4.2 mmol) was dissolved in tBuOH (10 mL) and (2,4-dimethoxyphenyl)methanamine (2.8 g, 16.8 mmol) was added. The reaction mixture was heated at reflux overnight. After cooling, the solid was filtrated to afford methyl 2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylate (1.0 g) as brown solid.
Reaction SMILES: N(C(=CC1SC=C(F)C=1)C(OCC)=O)=[N+]=[N-].[N:17]([C:20](=[CH:26][C:27]1[S:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+]=[N-].CCOC(C)=O.CCCCCCC.COC1C=CC(C=O)=CC=1>C1(C)C=CC=C(C)C=1>[F:32][C:29]1[S:28][C:27]2[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:17][C:31]=2[CH:30]=1
Reactant: CCOC(=O)C(=Cc1ccc(F)s1)N=[N+]=[N-]
Agent: CCOC(=O)C(=Cc1cc(F)cs1)N=[N+]=[N-]
Agent: COc1ccc(C=O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)c1
Solvent: CCCCCCC
Product: CCOC(=O)c1cc2sc(F)cc2[nH]1
Temperature: 145 °C
Yield: 15 %

Procedure:
A mixture of ethyl 2-azido-3-(4-fluorothiophen-2-yl)acrylate and ethyl 2-azido-3-(5-fluorothiophen-2-yl)acrylate (0.37 g) was dissolved in m-xylene (˜10 mL) and heated at 145° C. for 20 min in a capped 40-mL vial. The m-xylene was evaporated in vacuo and the resulting residue was chromatographed over silica gel (0 to 40% EtOAc in heptane over 30 min) to give two products: (a) 0.15 g of an impure pale oil with an Rf=0.25 (10:90 EtOAc/heptane), which stained a bright violet color when developed using anisaldehyde and heat, which was further purified via preparative HPLC using a Chromeleon purification system (methanol/0.1% formic acid-1% acetonitrile mixture in water, 50 mm Dynamax C-18, 28 mL/min (initial gradient of 20% methanol and increasing to 100% over 7 min) to give ethyl 2-fluoro-4H-thieno[3,2-b]pyrrole-5-carboxylate (48.9 mg, 3%). tR of product: 4.2-4.4 min. 1H NMR (400 MHz, CD3CN) δ ppm 10.10 (s, 1H), 6.98-7.05 (m, 1H), 6.69 (dd, J=2.05, 0.49 Hz, 1H), 4.29 (q, J=7.09 Hz, 2H), 1.33 (t, J=7.13 Hz, 3H). 19F NMR (376 MHz, CD3CN) δ ppm −122.18 (d, J=2.29 Hz, 1F). (b) 10.5 mg of an impure pale oil with an Rf=0.30 (10:90 EtOAc/heptane), which stained a bright red color when developed using anisaldehyde and heat, was further purified via preparative HPLC as described above (40%-100% methanol over 7 min) to give ethyl 3-fluoro-4H-thieno[3,2-b]pyrrole-5-carboxylate (5.4 mg, 0.3%). tR of product: 3-3.4 min. 1H NMR (400 MHz, CD3CN) δ ppm 10.30 (s, 1H), 7.06 (t, J=2.05 Hz, 1H), 6.90 (d, J=2.54 Hz, 1H), 4.32 (q, J=7.09 Hz, 2H), 1.34 (t, J=7.10 Hz, 3H). 19F NMR (376 MHz, CD3CN) δ ppm −144.16 (t, J=2.29 Hz, 1F).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([O:39]CC)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 52.2 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg), NaOH (80 mg), H2O (5 mL) and THF (2 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 100 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCCCCCCc1ccc(CCN)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCCCc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1

Procedure:
By the reaction of ethyl 7-[4-(2-aminoethyl)-phenyl]-heptane-carboxylate hydrochloride with 4-chlorobenzoyl chloride, there is obtained 7-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-heptane-carboxylic acid; m.p. 145°-148° C., after recrystallization from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=1.Cl>C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)ccc2Cl)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1ccc(Cl)c(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117 %

Procedure:
To a solution of tert-butyl 4-(2-chloro-5-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (15, 0.573 g, 1.84 mmol) in CH2Cl2 (11 mL) was added HCl (2.0 N solution in Et2O, 11.0 mL) and the mixture stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (30 mL), and the resulting precipitate was collected by filtration to provide 4-(2-chloro-5-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (16) as a white solid (0.267 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 9.15 (br s, 2H), 7.54 (dd, J=9.0, 5.4 Hz, 1H), 7.29-7.17 (m, 1H), 7.14 (dd, J=9.3, 3.0 Hz, 1H), 5.84-5.79 (m, 1H), 3.76-3.68 (m, 2H), 3.28 (t, J=5.7 Hz, 2H), 2.62-2.53 (m, 2H); ESI MS m/z 212 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])=O.[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[C:4]([C:13]([O:15][CH3:16])=[O:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(Cl)c1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cl)cc2nc1C(=O)OC
Yield: 134.8 %

Procedure:
A stirred mixture of dimethyl 4,7-dichloroquinoline-2,3-dicarboxylate (5.00 g, 15.9 mM), sodium formate (1.63 g, 23.9 mM) and tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.80 mM) in anhydrous dimethylformamide (75 mL) under a nitrogen atmosphere was heated at 90°-95° C. for 7 hr. No reaction occurred so the reaction mixture was degassed and an additional quantity of tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.80 mM) was added and the reaction mixture again heated at 90°-95° C. for 6 hr. The cooled reaction mixture was poured into water and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave an gummy solid (6.0 g). Trituration of this residue with ethyl acetate and subsequent filtration separated a crystalline solid which was shown to be dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate. The filtrate was concentrated and the residue was flash chromatographed over silica gel (eluant: hexane/ethyl acetate, 3/2) to provide the title diester (1.13 g, 25.4%) as a light yellow crystalline solid; MS(CI): 280 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(OCC)(=O)C>CN(C)C=O.O>[O:7]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CN1CCCCC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 24.5 %

Procedure:
Under a nitrogen atmosphere, to a solution of piperidin-2-one (9.8 g, 99 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (4.4 g, 110 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, benzyl bromoacetate (19 ml, 120 mmol) was added, and the mixture was further stirred for 2 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (6.0 g, yield 24%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[F:1][C:2]1[CH:16]=[CH:15][C:5](/[C:6](/[Cl:19])=[N:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccccc1)c1ccc(F)cc1
Product: Fc1ccc(/C(Cl)=N/c2ccccc2)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 4-fluoro-N-phenylbenzamide (50 g; 233 mmol) and thionyl chloride (200 mL). The mixture was stirred at refluxed for 3 h and then the solvent was evaporated to dryness to afford (Z)-4-fluoro-N-phenylbenzimidoyl chloride as white solid. The solid was dissolved into chlorobenzene and SnCl4 (39.0 mmol) and ethyl cyanoformate (39.0 mmol) were added. The reaction mixture was heated at 140° C. for 1 hour and concentrated to get black oil. The black oil was added into water, made alkaline with 20% NaOH, and extracted with 2×300 mL of dichloromethane. The organic layer was washed with 1×100 mL of brine and dried over sodium sulphate and concentrated to get the crude product, which was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to afford ethyl 2-(4-fluorophenyl)quinazoline-4-carboxylate as white solid (8.1 g, 11.7%, 2 steps). MS (ESI) m/z 297 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7].[OH2:13]>CC#N>[OH:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O
Reactant: Cc1cc(CBr)cc(C(=O)O)c1
Solvent: CC#N
Product: Cc1cc(CO)cc(C(=O)O)c1

Procedure:
To a solution of 3-bromomethyl-5-methyl-benzoic acid (3.90 g, 17 mmol) in water (30 mL) and MeCN (30 mL), Cu(NO3)2 hemipentahydrate (12.77 g, 68 mmol) followed by water (50 mL) was added. The turquoise mixture was refluxed for 2 h before it was concentrated to about half of the original volume. The dark green solution was extracted three times with EA (150 mL). The org. extracts were washed twice with water (2×50 mL), combined, dried over Na2SO4, filtered and concentrated. The white residue was separated by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 95% MeCN in water containing 0.5% of formic acid) to give 3-hydroxymethyl-5-methyl-benzoic acid as a white solid (897 mg; LC-MS*: tR=0.17 min; [M−1]−=164.86), along with the title compound as a white solid (160 mg). To a solution of the above 3-hydroxymethyl-5-methyl-benzoic acid (947 mg, 5.70 mmol) in MeCN (40 mL), MnO2 (1.49 g, 17.1 mmol) was added and the resulting mixture was stirred at 80° C. for 16 h before another portion of MnO2 (1.21 g, 13.9 mmol) and acetonitrile (40 mL) was added and stirring was continued at 80° C. for 4 h. The mixture was filtered over a glass fibre filter, the colourless filtrate was concentrated and purified by prep. HPLC (as above) to give the title compound (504 mg) as a white solid. LC-MS*: tR=0.26 min; [M−1]−=162.88; 1H NMR (D6-DMSO): δ 2.47 (s, 3H), 7.96 (s, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 10.06 (s, 1H), 13.28 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH3:15])[CH:9]=[C:8]2Cl)(=[O:3])[CH3:2].C(NC1C=C2C(=CC=1)NC(C)CC2)(=O)C.N1C2C(=CC=CC=2)CCC1.C([O:44][CH:45]=[C:46]([C:52](OCC)=O)[C:47]([O:49]CC)=[O:48])C.NC1C=C2C3N(C=C(C(O)=O)C2=O)C(C)CCC=3C=1.C(OC(=O)C)(=O)C>>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:12]3[N:11]([CH:52]=[C:46]([C:47]([OH:49])=[O:48])[C:45]2=[O:44])[CH:10]([CH3:15])[CH2:9][CH2:8][C:7]=3[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)Nc1ccc2nc(C)cc(Cl)c2c1
Agent: CC(=O)Nc1ccc2c(c1)CCC(C)N2
Agent: CC1CCc2cc(N)cc3c(=O)c(C(=O)O)cn1c23
Agent: c1ccc2c(c1)CCCN2
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c3c(c1)c(=O)c(C(=O)O)cn3C(C)CC2
Temperature: 140 °C

Procedure:
6-Acetamido-4-chloro-2-methylquinoline is reduced catalytically to the novel compound 6-acetamido-2-methyl-1,2,3,4-tetrahydroquinoline. The tetrahydroquinoline is condensed with diethyl ethoxymethylenemalonate by heating without a solvent for one hour at 140° C. Polyphosphoric acid is added, and the solution is heated at 100° C. for one-half hour. The product, 9-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride as described in Example 49 to provide 9-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >310° C. The product is characterized by spectral analysis and elemental analysis, which are found to be consistent with the indicated structure.
Reaction SMILES: Cl.[C:2]([NH:7][CH:8]([CH2:14][SH:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)[CH2:3][CH2:4][CH3:5]>C(O)C>[CH2:3]([C:2]1[S:15][CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1)[CH2:4][CH3:5]
Reactant: CCCC(=O)NC(CS)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCCc1nc(C(=O)OCC)cs1
Reaction time: 8 h

Procedure:
A solution of HCl (4M in 1,4-dioxane, 20 mL) was added to a solution of ethyl 2-butyramido-3-mercaptopropanoate (example 56, step a) (3 g) in ethanol (20 mL) and the resulting mixture stirred overnight. The solvent was evaporated and the residue azeotroped twice with toluene. The residue was redissolved in acetonitrile (50 mL), manganese dioxide (11.9 g) was added and the mixture heated at reflux overnight. The reaction was filtered through a pad of Celite. The filter pad was washed with MeCN (3×100 mL). The combined filtrate and washings were evaporated and the residue was purified by silica gel chromatography eluting with 9:1 isohexane:ethyl acetate. The product containing fractions were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.24 g.