Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH3:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:9][CH:10]=1)[NH2:4].Br[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=O)=[CH:25][C:24]=1[CH2:33]OC.[CH2:36](Cl)[CH2:37]Cl>CC#N.N1C=CC=CC=1>[CH3:30][O:29][CH2:27][C:26]1[CH:25]=[C:24]([C:33]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH3:21])[CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:9][CH:10]=3)[N:4]=2)[CH:23]=[CH:32][C:31]=1[C:8]1[CH:7]=[CH:6][CH:5]=[CH:3][C:36]=1[CH3:37]
Reactant: ClCCCl
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cn1
Solvent: CC#N
Solvent: c1ccncc1
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)nc3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2-(((5-(N′-hydroxycarbamimidoyl)pyridin-2-yl)methyl)(methyl)amino)acetate (0.750 g; 2.55 mmol) and Intermediate A1 (0.654 mg; 2.55 mmol) in MeCN (9 mL) was added EDC (0.538 g; 2.81 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with pyridine (9 mL) and heated at 150° C. in the microwave for 30 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (1:1), affording the title product. 1H NMR (CDCl3, 400 MHz) δ 9.35-9.34 (1 H, m), 8.46-8.43 (2 H, m), 8.19-8.17 (1 H, m), 7.71-7.68 (1 H, m), 7.36-7.28 (4 H, m), 7.14-7.12 (1 H, m), 4.27-4.20 (2 H, m), 3.95 (2 H, s), 3.33 (3 H, s), 3.21 (2 H, s), 2.46 (3 H, s), 2.05 (3 H, s), 1.50 (9 H, s).
Reaction SMILES: [N:1]1([C:6]2[CH:22]=[CH:21][C:9]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B.[Na].CC(C)=O>CO>[OH:11][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCC(=O)c1ccc(-n2ccnc2)cc1
Agent: B
Agent: [Na]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)CCCCCC(O)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
In methanol (90 ml) was dissolved 9.00 g (30 mmole) methyl 6-[4-(1-imidazolyl)benzoyl]hexanoate, and the solution was stirred under ice-cooling. 0.86 Gram (30×0.75 mmole) of of sodium boron hydride was added to it, and stirring was continued for 30 minutes under ice-cooling. After acetone was added, the solvent was distilled off, and chloroform and water were added to the residue to effect extraction. The chloroform layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated to give 9.10 g (100%) of methyl 7-hydroxy-7-[4-(1-imidazolyl)phenyl]heptanoate (part of the compound was recrystallized from ethyl acetate/isopropyl ether. m.p. 77°-78° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH2:9][N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH:13]=2)[N:7]=1
Reactant: CCCCCBr
Reactant: CNc1nc(-c2cccnc2)cs1
Agent: Cl
Solvent: O
Product: CCCCCN1CCC=C(c2csc(NC)n2)C1
Yield: 53 %

Procedure:
The procedure of Example 1 was repeated, using the N-methyl-4-(3-pyridinyl)-2-thiazolamine prepared in Example 14 and an excess of 1-bromopentane as the reactants. The title compound was purified by column chromatography (53% yield) and converted to its HCl salt by the procedure of Example 2. The salt obtained (mp 168°-172° C.) contained 1.5 molecules of HCl and one molecule of water.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[C:9]1([C:2]2([N:1]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCCBr
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccccc2)(N2CCCC2)CC1
Yield: 49 %

Procedure:
A reaction mixture consisting of the free base from 2.69 gm. (0.01 mole) of 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride (prepared in Example 32, above) 2.16 gm. of 1,4-dibromobutane, 2.76 gm. potassium carbonate, and 15.0 ml. ethanol is heated at the reflux temperature, with stirring, for eighteen (18) hours. The volatile components are then substantially removed by evaporation under reduced pressure, and the concentrate thus obtained diluted with water. A precipitate forms which is collected on a filter and dissolved in diethyl ether. The ether solution is treated with an equivalent of 3 N hydrogen chloride in diethyl ether. A precipitate that forms is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 1.57 gm. (49% yield) of 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone, ethylene ketal hydrochloride having a melting range from 238° to 239.5° C.
Reaction SMILES: [Br:1][CH:2]([C:4]1[C:5](=O)[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([F:14])[CH:8]=2)[CH3:3].P(Cl)(Cl)([Cl:18])=O>>[Br:1][CH:2]([C:4]1[C:5]([Cl:18])=[N:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([F:14])[CH:8]=2)[N:13]=1)[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(Br)c1nc2ccc(F)cc2[nH]c1=O
Product: CC(Br)c1nc2ccc(F)cc2nc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A heterogeneous mixture of 3-(1-bromoethyl)-7-fluoroquinoxalin-2(1H)-one (58.86 g, 217.1 mmol) and phosphorous oxychloride (198.8 ml, 2171 mmol) in a 1 L round bottom flask was stirred at 100° C. for 2 h. The mixture was heterogeneous in the beginning of the reaction and then homogeneous black solution over 1 h. After 2 h, the mixture was cooled to rt and concentrated under reduced pressure. To the black residue was carefully added ice (˜400 ml) in portions and then water (200 ml) with stirring. The mixture was neutralized with NH4OH (200 ml) and ice (˜200 ml) with stirring. The resulting precipitate was collected by filtration, rinsed with water (1 L), and dried under high vacuum overnight to give 2-(1-bromoethyl)-3-chloro-6-fluoroquinoxaline (58.31 g, 92.8% yield) including 3-chloro-2-(1-chloroethyl)-6-fluoroquinoxaline as a brown solid. 1H NMR (400 MHz, DMSO-d6), ratio of bromoethyl analog and chloroethyl analog=2.5:1 Mass Spectrum (ESI) m/e=288.9 [M+H(79Br)]+ and 291.0 [M+H (81Br)]+
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([Br:15])[CH:3]=1.C([Li])CCC.CCCCCC.[CH3:27][S:28]SC>C1COCC1.C(OCC)(=O)C>[Br:15][C:4]1[CH:3]=[C:2]([S:28][CH3:27])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)oc1ccccc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cc(Br)cc2oc3ccccc3c12
Temperature: -50 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
A solution of 1,3-dibromodibenzofuran 18 (0.500 g, 1.54 mmol) in THF (53 ml) was cooled to -70° C. and a solution of n-butyllithium in hexane (2.2M, 0.84 ml, 1.8 mmol) was added dropwise. The resulting red solution was allowed to warm to -50° C. over 30 minutes. Methyl disulfide (0.162 ml, 1.84 mmol) was added and the solution was allowed to warm to -10° C. After stirring for 20 minutes, the solution was poured into ethyl acetate and washed successively with 1N NaOH, H2O, and brine. Drying over MgSO4 and evaporation gave a tan solid which was purified by flash chromatography through 40 g of silica gel (10% CH2Cl2 -hexane) to yield 394 mg (87%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13]#[C:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([N:8]1[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=[CH:9]1)[C:13]#[C:14][CH3:15]
Reactant: Clc1nccc2[nH]cnc12
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1cnc2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 μg of 4-chloro-1H-imidazo[4,5-c]pyridine, 1.37 ml of 1-bromo-2-butyne, and 1.98 g of potassium carbonate were suspended in 15 ml of N,N-dimethylformamide, and the suspension was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.79 g of a 1:1 mixture consisting of the title compound and the compound alkylated at the 1-position was obtained from the fraction eluted with hexane-ethyl acetate (1:2).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCCl>[C:20]([C:13]1[C:12]([CH3:16])=[CH:11][C:10]2[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7][C:6]([CH3:19])([CH3:5])[C:15]=2[CH:14]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a suspension of aluminum chloride (0.96 g, 7.17 mmol) in 1 mL of 1,2-dichloroethane under argon at room temperature was added a solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene 29 (1.2 g, 5.93 mmol) and acetyl chloride (0.51 g, 6.52 mmol) in 9 mL of 1,2-dichloroethane. The reaction mixture was stirred for 1 h and then was poured onto ice water and extracted with 40% ethyl acetate/hexane. The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The solution was. dried over anhydrous MgSO4, filtered through a plug of silica gel, and concentrated to afford a white solid 39 (1.45 g, 99%): m.p. 54°-57° C.; Rf 0.62 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1>[C:6]([OH:46])(=[O:7])[CH3:37].[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:46])[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:38][CH:37]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CNC(=O)c6ccccc6)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 124 %

Procedure:
Cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.051 g, 0.0001 mol) was dissolved in anhydrous pyridine (1 mL), benzoyl chloride (0.014 g, 0.0001 mol) was added and the resulting solution was stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]benzamide acetate (0.042 g, 0.000062 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH2:10].[CH3:11][OH:12]>>[NH2:1][C:2]1[C:3]([C:8]([O:12][CH3:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: N#Cc1ncccc1N
Reactant: O
Product: COC(=O)c1ncccc1N
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 3-aminopyridine-2-carbonitrile (9.7 g, 81.8 mmol) in MeOH (100 mL) was placed in a round bottom pressure vessel. The solution was cooled to −78° C. and HCl gas was bubbled through the solution until the volume of the solution had noticeably increased. The flask was sealed and the reaction warmed to room temperature and stirred overnight. At this time, LCMS (sampled after re-cooling the reaction to −78° C.) showed only a small amount of starting cyano compound remaining. Water (14 mL, 818 mmol) was added and the reaction transferred to a flask equipped with a reflux condenser. The reaction was refluxed overnight. The solution was concentrated and the remaining solution was basified with 1N NaOH to pH 9, then extracted with CHCL3 repeatedly until very little UV-active material was removed. The organic layers were dried over Na2SO4, filtered and evaporated to give the product as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:12]=[C:13]([N:32]([CH3:33])[CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:14]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: CNC1CCN(C)CC1
Reactant: Oc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(N(C)c2nc(Nc3ccc(O)c(Cl)c3)nc(NC3CCCCCC3)n2)CC1
Yield: 14.3 %

Procedure:
To E7 (1.00 g, 2.7 mmol) dissolved in THF (25 mL) was added a solution of N-methyl-4-(methylamino)-piperidine (0.45 mL, 3.1 mmol) in THF (5 mL) followed by addition of 2.5 N NaOH (1.1 mL, 2.7 mmol) and 2.5 mL of water. The reaction mixture was stirred and heated at reflux overnight. The reaction mixture was extracted three times using dichloromethane, the combined organic layers were washed with a brine and dried over sodium sulfate. The sample was concentrated and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 100% methanol) yielded an off-white solid (138) (177 mg, 14%); mp 68° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4 (0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 4.7 min, 99.6% purity; MS (TOF ES+) m/z 460 (M+H, 55.3), 251 (100), 224 (51.1).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:27])[O:4][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=[C:20]4[C:24](=[O:25])[NH:23][C:22](=[O:26])[S:21]4)=[CH:15][C:13]=3[CH:14]=2)=[C:6]([CH3:9])[C:7]=1[OH:8].CCO.[H][H]>[Pd].O1CCOCC1>[CH3:1][C:2]1[C:3](=[O:27])[O:4][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]4[C:24](=[O:25])[NH:23][C:22](=[O:26])[S:21]4)=[CH:15][C:13]=3[CH:14]=2)=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: [H][H]
Reactant: Cc1c(-c2cc3cc(C=C4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(-c2cc3cc(CC4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O

Procedure:
To 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene) methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one (350 mg) in a mixed solvent of EtOH (10 ml) and 1,4-dioxane (10 ml) there was added 10% Pd/C (70 mg), and the mixture was stirred for one day in a hydrogen gas atmosphere. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (CH2Cl2/MeOH=5/1) to obtain 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([O:14]C)=[O:13])[CH:4]=[C:3]1[C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1.[OH-].[Na+].O.Cl>C(O)C>[O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([OH:14])=[O:13])[CH:4]=[C:3]1[C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(=O)n2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c(=O)n2ccccc12

Procedure:
0.25 g of methyl 4-oxo-3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizine-1-carboxylate was suspended in 3 ml of ethanol and treated with 3 ml of 1N sodium hydroxide solution. The mixture was heated to reflux until the reaction has finished. 13 ml of water were added and the mixture was acidified with 1N hydrochloric acid. The yellow crystals were removed by filtration and dried. After recrystallization from ethyl acetate, there was obtained 4-oxo-3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizine-1-carboxylic acid as yellow crystals of m.p. 228°-229°.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]Cl)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:13]#[N:14].[Na+].CS(C)=O>O>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:13]#[N:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCC[C@H]1CC[C@H](CCl)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC[C@H]1CC[C@H](CC#N)CC1
Temperature: 25 °C

Procedure:
38 g (0.20 mol) of trans-4-butylcyclohexylchloromethane, 12 g (0.24 mol) of NaCN and 40 cm3 of DMSO were heated up to 140° C. with a mantle heater while stirring. The reactant was cooled to room temperature, 1,000 cm3 of water was added, it was extracted with chloroform, and after washing with water the chloroform was extracted. The remaining oily substance was distilled under reduced pressure (b. p. 90°/3 mmHG) to obtain 34 g (0.19 mol) of trans-4-butylcyclohexylacetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.[OH-].[K+].O.Cl.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:19]3[CH2:20][CH2:21][NH:16][CH2:17][CH:18]=3)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]ccc2n1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2n1
Yield: 67.8 %

Procedure:
A solution of 0.20 gm (1.35 mMol) of 5-methoxypyrrolo-[3,2-b]pyridine, 0.23 mg (4.05 mMol) potassium hydroxide, and 0.31 gm (2.03 mMol) 4-piperidone hydrochloride monohydrate 5 mL methanol was heated at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between water and 3:1 chloroform:isopropanol. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography chromatography (2 mm silica gel plate) eluting with dichloromethane containing 20-40% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.21 gm (68%) of the title compound as a yellow sold. An analytical sample was crystallized from methanol.
Reaction SMILES: ClCl.[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)(=[O:5])[CH3:4].C(Cl)[Cl:26]>C(O)C>[Cl:26][CH2:4][C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)=[O:5]
Reactant: ClCCl
Reactant: CC(=O)c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: ClCl
Solvent: CCO
Product: O=C(CCl)c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
Chlorine gas was led into a stirred mixture of 6-acetyl-4-(3-chloro-4-fluoroanilino)-quinazoline (0.11 g), methylene chloride (40 ml) and ethanol (60 ml) and the mixture was cooled to a temperature in the range 20 to 25° C. After 10 minutes the supply of chlorine was stopped and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-(2-chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline (0.114 g) which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OCCCCc1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCCCc1ccccc1

Procedure:
The title compound, light yellow solid, m.p.=118° C. and MS: m/e=387.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 4-phenyl-butan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:27]
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)CN2CCc3cc(OC)ccc3C2Cc2ccc(OC)c(OC)c2)cc1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-methoxybenzylamine
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH3:7])[NH2:6].[NH2:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>B([O-])([O-])[O-]>[NH2:6][C@H:5]([C:4]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:3])[CH3:7]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [O-]B([O-])[O-]
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
3 μl of the same enzyme fraction as used in Example 5 was added to 100 μl of 100 mM borate buffer (pH 9.0) containing 100 mM L-alanine methyl ester hydrochloride, 200 mM L-glutamine and 10 mM EDTA, and allowed to react at 18° C. As a result, as shown in FIG. 3, 83 mM L-alanyl-L-glutamine (L-Ala-L-Gln) was formed in the case of an enzyme-added lot, and the concentration of by-product L-Ala-L-Ala-L-Gln was 1.3 mM. On the other hand, there was scarcely any production of L-Ala-L-Gln observed in an enzyme-non-added lot, and the enzyme concentration was only about 0.07 mM after reacting for 120 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH:20]=[C:13]34)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH:20]=[C:13]34)[C:8](=[O:12])[N:9]2[C:24]([O:26][CH3:27])=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C21CCCn2cncc21
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1C(=O)C2(CCCn3cncc32)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 mmol of 6′-methoxy-6,7-dihydro-5H-spiro[imidazo[1,5-a]pyridine-8,3′-indol]-2′(1′H)-one in 5 ml of N,N-dimethyl formamide is treated with 1.2 mmol of sodium hydride (60% dispersion in oil). The reaction mixture is stirred for 20 minutes at room temperature, then 1.2 mmol of methyl chloroformate are added. The reaction mixture is stirred for 20 minutes at room temperature, then diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.