Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Br:15])#[N:11]>C1(C)C=CC=CC=1>[BrH:15].[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[CH2:14][C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[NH:11]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cccc(C)c1N
Solvent: Cc1ccccc1
Product: Br
Product: Cc1cccc(C)c1N1Cc2ccccc2C1=N
Yield: 9.3 %

Procedure:
2,6-dimethylaniline (6.2 g, 51 mmol) was added to a solution of 2-cyanobenzylbromide (10.0 g, 51 mmol) in toluene (250 ml). The solution was heated to reflux for 18 hours. The formed solid was filtered off and washed with toluene (2×25 ml). After drying 11.5 g of the desired compound was obtained as a white solid. The filtrate was heated to reflux for 20 hours. Another 1.5 g of pure product was obtained leading to a total yield of 13.0 g (80%). The product was characterized by
Reaction SMILES: C(OC([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH:13]([CH3:29])[CH2:12]1)=O)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:29][CH:13]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[NH:11][CH2:12]1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCN(c1ncnc3[nH]ccc13)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Yield: 93.2 %

Procedure:
To a solution of an optically-active compound of 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (2.84 g) in methanol/tetrahydrofuran (14 ml/14 ml) was added 10% palladium carbon (568 mg), and the mixture was hydrogenated under 4 atmospheres. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was slurry-washed with toluene/tetrahydrofuran (95/5, 9 ml) to give the titled compound (1.74 g).
Reaction SMILES: [OH-:1].[Na+].C1C2=CC3C=CC=[CH:13][C:14]=3N2CC1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:25])=[CH:17]1>>[CH2:13]1[C:17]2=[C:18]([CH:25]=[O:1])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[N:16]2[CH2:15][CH2:14]1
Reactant: [OH-]
Reactant: c1ccc2c(c1)cc1n2CCC1
Reactant: Cc1cn(C)c2ccccc12
Agent: [Na+]
Product: O=Cc1c2n(c3ccccc13)CCC2
Yield: 60 %

Procedure:
According to the procedure of Preparation 40 (b), except substituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene (J. Med. Chem. 1965, 8, 700; 0.24 g, 1.53 mmole) for the 1,3-dimethylindole, the title compound (0.17 g, 60%) was prepared as a yellow solid: MS (ES) m/e 186 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:9]=1[C:10]([OH:12])=[O:11].Cl[N:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[NH:20]1.Cl>CN(C)C=O.O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][N:19]2[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[NH:24]2)[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1c(O)cccc1Cl
Reactant: COC1=CC(OC)=NN(Cl)N1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC(OC)=NN(Oc2cccc(Cl)c2C(=O)O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 25° C., 20.2 g of potassium tert-butylate is added in portions to 15.5 g of 2-chloro-6-hydroxybenzoic acid in 50 ml of dimethylformamide. Subsequently, 15.7 g of 2-chloro-4,6-dimethoxytriazine is added. The mixture is stirred for 12 hours at 25° C. and poured into cold water, and the resulting mixture is acidified with hydrochloric acid. Extraction is then carried out with ethyl acetate, and the extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is stirred with a small amount of diethyl ether, followed by filtration. The residue is dried under reduced pressure (m.p. 128°-131° C.).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O>C1COCC1.O.CO>[C:1]1([CH:7]([CH2:12][O:13][Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:21]([CH3:22])[CH3:23])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(CO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[Si](OCC(C(=O)O)c1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-phenyl-3-(triisopropylsilyloxy)propanoate (E399) in THF/H2O/MeOH was added LiOH*H2O and the solution was stir at room temperature overnight. The solution was poured into NH4Cl(sat)/HCl (1 N) (3:1) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (0%-4% MeOH/CH2Cl2) gave pure 2-phenyl-3-(triisopropylsilyloxy)propanoic acid (E400).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 14.5 g of 3-(2-quinolinylmethyloxy)benzyl alcohol in 150 ml of CHCl3 is added dropwise 7.5 ml of thionyl chloride during 10 min. The reaction mixture is stirred for 4 hours at room temperature, and then washed with NaHCO3 solution. The organic solution is separated, dried, and evaporated to 3-(2-quinolinylmethyloxy)benzyl chloride which is used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:21][C:20](=O)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]=O>O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21](=[CH:44][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=5)[CH2:20][CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-n2ncc3cc4c(cc32)CCCC(=O)C4)ccn1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-n2ncc3cc4c(cc32)CCCCC4=Cc2ccccn2)ccn1
Temperature: -77 °C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=2-methylpyridin-4-yl) (2.83 g, 9.71 mmol) and THF (43 mL). The solution was cooled to about −77° C. and then lithium bis(trimethylsilyl)amide (1.0 M in THF, 10.0 mL, 10.0 mmol) was added over about 30 min, keeping the internal temperature below about −75° C. After the addition was the mixture was stirred for about 5 min, the cold bath was removed and the mixture was allowed to warm to about 0° C. over about 1 h. The mixture was again cooled to about −75° C. then 2-pyridinecarboxaldehyde (3.2 mL, 34 mmol) was added. The mixture was allowed to warm to about −10° C. over about 1 h, and then water (40 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×40 mL) and then the combined organics were washed with brine (50 mL), dried over Na2SO4 and then concentrated under reduced pressure. The crude material was purified on silica gel (120 g, eluted with 0% to 2.5% MeOH in DCM). Collection and concentration of the appropriate fractions gave 1-(2-methylpyridin-4-yl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H-one (83, R1=2-methylpyridin-4-yl, R2′=pyridin-2-yl) (3.45 g, 93%) LC/MS, method 3, Rt=1.95 min, MS m/z 381 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=5.7 Hz, 1H), 8.61-8.53 (m, 1H), 8.11-8.08 (m, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.80-7.64 (m, 2H), 7.53 (s, 1H), 7.44-7.35 (m, 1H), 7.14-7.06 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 3.14-3.06 (m, 2H), 2.78 (s, 3H), 2.56-2.48 (m, 2H), 2.23-2.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:36](=[O:37])[N:35]([CH3:38])[C:12]2[N:13]([CH3:34])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27]C2CCCCO2)[N:21]=1)=[CH:16][CH:15]=3.C(O)(=O)C.C1COCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:36](=[O:37])[N:35]([CH3:38])[C:12]2[N:13]([CH3:34])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOC5CCCCO5)n4)ccc3n(C)c21
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Temperature: 45 °C

Procedure:
A solution containing 311 mg (0.56 mmol) of compound A 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazol-3-yl}-1,9-dihydropyrido[2,3-b]indol-2-one, 2.7 ml of acetic acid, 1.3 ml of THF and 0.7 ml of H2O is heated at 45° C. for 16 h. The reaction medium is allowed to cool, adsorbed onto silica and purified by flash chromatography, elution being carried out with EtOAc/20% cyclohexane, then 100% EtOAc, and, finally, EtOAc/5% MeOH. The residue is taken up in MeOH and the product is filtered and then washed with MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:23]4[C:19](=[CH:20][N:21]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:22]=4)[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Reactant: CCOC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2n1
Product: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 30 %
Yield: 55 %

Procedure:
5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazole (D4) (122 mg, 0.344 mmol) in DMF (2 ml) was treated with ethyl 3-bromo-2,2-dimethylpropanoate (D98) (79 mg, 0.378 mmol) and Cs2CO3 (134 mg, 0.413 mmol) and the resulting mixture was stirred at 80° C. overnight. More ethyl 3-bromo-2,2-dimethylpropanoate (D98) (29 mg, 0.4 mmol) and Cs2CO3 (56 mg, 0.5 mmol) were added and the resulting mixture stirred at 80° C. for 6 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water then brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D100) (92 mg, 55%) and ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2H-indazol-2-yl]-2,2-dimethylpropanoate (D101) (49 mg, 30%). MS (ES) C25H27ClN4O4 requires 482, found 483 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[CH2:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:8]2.P(Cl)(Cl)([Cl:26])=O.CN(C)[CH:31]=[O:32]>>[Cl:26][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[O:8][CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]=1[CH:31]=[O:32]
Reactant: COc1cc2c(c(OC)c1OC)C(=O)CC(c1ccccc1)O2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: COc1cc2c(c(OC)c1OC)C(Cl)=C(C=O)C(c1ccccc1)O2

Procedure:
As in example 1, but using 15 g 5,6,7-trimethoxyflavanone, 150 ml dimethylformamide and 26 ml phosphorous oxychloride. Reaction time is forty eight hours at room temperature. After hydrolysis and usual work up, the residual solid is purified by preparative HPLC and the best fractions are crystallised in hexane. 4-chloro-3-formyl-5,6,7-trimethoxyflav-3-ene is obtained as yellow crystals; m.p. 84°-87° C.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:7]([CH2:8][CH2:9][CH2:10][N:16]1[CH2:17][CH2:18][C:13]([OH:12])([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:15]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: ClCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cnc3ccccc3c2)CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 0.112 gm (0.7 mMol) 3-chloropropyl phenyl ether, 0.150 gm (0.7 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, and 0.136 gm (1.5 mMol) potassium carbonate in 5 mL acetonitrile was heated to reflux for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 25:2 dichloromethane:methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.142 gm (60%) of 1-(3-phenoxyprop-1-yl)-4-hydroxy-4-(quinolin-3-yl)piperidine as a light yellow, viscous oil. The oil was converted to the oxalate salt to provide the title compound.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: ClCc1ccccc1Cl
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: Clc1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-chlorobenzyl chloride (0.198 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 105 mg of the product 208. 1H NMR (DMSO-d6) δ 11.38 (s, 2 H), 7.90-7.70 (m, 1 H), 7.70-7.55 (m, 1 H), 7.55-7.35 (m, 2 H), 7.20-7.00 (m, 6 H), 7.00-6.85 (m, 4 H), 5.81 (s, 2 H), 4.88 (s, 2 H); MS: m/z 379 (M++1).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:6]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:6]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:11])[N:8]([CH3:25])[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(C)=O)C1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
1.0 g (3.2 mmol) of the compound from Example I are dissolved in 15 ml of DMF and treated under argon with 180 mg of NaH. The mixture is stirred at 0° C. for 15 minutes. 0.51 ml (6.2 mmol) of MeI is then added dropwise and the mixture is stirred again for 30 min. It is treated successively with H2O and ethyl acetate and the organic phase is washed with saturated aqueous NaCl solution. It is then concentrated and the residue is separated on silica gel (petroleum ether/AcOEt=1+1). The appropriate fractions crystallize from Et2O/petroleum ether. 230 mg of the title compound are obtained. MS:333.8 Rf =0.57 (petroleum ether/AcOEt=1+1)
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH2:20][CH3:21])[C:12](=O)[CH2:13][C:14]([O:16]CC)=[O:15].O.CO>C1(C)C=CC=CC=1>[CH2:20]([C:11]1[S:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[CH2:13][C:14]([OH:16])=[O:15])[CH3:21]
Reactant: CCOC(=O)CC(=O)C(Br)CC
Reactant: NC(=S)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1sc(-c2ccccc2)nc1CC(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A suspension of 8.7 g (63.3 mmol) of thiobenzamide and 10 g (42.2 mmol) of ethyl 4-bromo-3-oxo-hexanoate in 45 mL of toluene was refluxed for 6 hrs with Dean-Stark trap removal of water. Cooled, added methanol, and continued reflux for 1 h. Cooled, partially concentrated (˜½ volume), then 30 mL of 2.0 M NaOH solution was added. Stirred the mixture at 80° C. for 2 hrs before cooling and extraction of the aqueous with EtOAc. The aqueous phase was treated with 70 mL of 1.0 M citric acid with heating (70° C.) for 45 min. The mixture was extracted with EtOAc, and the extracts were dried. over MgSO4, filtered and concentrated to yield a yellow colored solid upon standing at ambient temperature (8.4 g, ˜80% yield); 1H NMR (CDCl3, 300 MHz) δ7.95-7.87 (m, 2H), 7.48-7.45 (m, 3H), 3.86 (s, 2H), 2.85 (q, 2H, J=7.5), 1.36 (t, 3H, J=7.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH2:19][OH:18])[C:6]=2[CH:16]=1
Reactant: CCOC(=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1CCO
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (80 mg, 0.347 mmol) in anhydrous DMF (5 mL) under a nitrogen atmosphere was added ethyl carbonate (122 mg, 1.387 mmol), K2CO3 (96 mg, 0.694 mmol), and 18-crown-6 (18.31 mg, 0.069 mmol). The reaction mixture was heated to 80° C. for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under reduced pressure to afford 8-chloro-6-(2-hydroxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (80 mg, 0.291 mmol, 84% crude yield) The material was carried on without further purification. LC/MS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12ClN2O2, 275.1]; 1H NMR (400 MHz, MeOD) δ 9.55 (s, 1H), 8.87 (d, J=5.6 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.44 (dd, J=8.4, 2.0 Hz, 1H), 4.57 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:14]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)O)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of 4-methoxyphenyl ethanol (15.0 g, 98.2 mmol) in 150 mL of methylene chloride was stirred at 0° C. while Dess-Martin periodinane (50 g, 1.2 eq.) was added in small portions. The ice-bath was removed and the reaction was stirred at rt for 1 h. The reaction mixture was then diluted with methylene chloride (100 mL), washed with 10% sodium thiosulfate, saturated NaHCO3 solution, water, saturated NaCl solution, and dried over Na2SO4. The product was purified using silica gel chromatography (100% hexanes to 20% EtOAC/hexanes) to afford 5.3 g (34%) of 4-methoxyphenyl acetaldehyde.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Thionyl chloride (4.5 g, 0.038 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0.037 mole) and methylene chloride (100 ml . The mixture was warmed to 30°-35° C. for 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of ethyl 3-amino-4-methylbenzoate (6.7 g, 0.037 mole) and triethylamine (4.0 g, 0.040 mole) in methylene chloride (100 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent gave an oil, which solidified. After recrystallization from ethanol (30 ml), the product (7.1 g, 59% yield) melted at 105°-107° C.
Reaction SMILES: CC1C=C(P(C2C=C(C)C=C(C)C=2)C2C=CC3OCOC=3C=2C2C3OCOC=3C=CC=2P(C2C=C(C)C=C(C)C=2)C2C=C(C)C=C(C)C=2)C=C(C)C=1.[C:53]([O-:56])(=[O:55])[CH3:54].[NH4+:57].[C:58]([O:64][CH3:65])(=[O:63])[CH2:59][C:60]([CH3:62])=O.CO>O1CCOCC1>[C:53]([OH:56])(=[O:55])[CH3:54].[NH2:57][C@H:60]([CH3:62])[CH2:59][C:58]([O:64][CH3:65])=[O:63]
Reactant: CC(=O)[O-]
Reactant: COC(=O)CC(C)=O
Reactant: [NH4+]
Agent: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccc3c(c2-c2c(P(c4cc(C)cc(C)c4)c4cc(C)cc(C)c4)ccc4c2OCO4)OCO3)c1
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)O
Product: COC(=O)C[C@@H](C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, a mixture of [RuCl2(p-cymene)]2 (0.527 g, 0.861 mmol), (R)-DM-SEGPHOS (1.276 g, 1.77 mmol), and ammonium acetate (0.664 g, 8.61 mmol) was stirred in 1,4-dioxane (10 mL) at 120° C. for 5 hours and then cooled to room temperature. The resultant mixture was added to a mixture of methyl acetoacetate (100.00 g, 861 mmol), ammonium acetate (66.38 g, 861 mmol) and methanol (500 mL) in a 1 L stainless steel autoclave. The reaction mixture was stirred under a hydrogen pressure of 3 MPa at 85° C. for 8 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R)-3-aminobutanoate acetate as a crude material (161.20 g). The crude product was treated with 7N ammonia/methanol and analyzed by GLC using a capillary column TC-5HT, indicating that the yield of methyl 3-aminobutanoate was 87.2%, that of the by-produced methyl 3-hydroxybutanoate was 0.3%, that of the by-produced methyl 3-aminocrotonate was 0.4% and that of the by-produced methyl 3-(2-methoxycarbonyl-1-methyl-1-ethylamino)-2-butenoate was 6.6%. The enantiomeric excess of methyl(3R)-3-aminobutanoate in the crude product was determined to be 94.4% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)butanoate.