Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])[CH:5]=[CH:4][N:3]=1.OO.NC(N)=[O:35].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])[CH:5]=[CH:4][N+:3]=1[O-:35]
Reactant: O=c1c2cc(Cc3ccnc(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cc(Cc3cc[n+]([O-])c(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 15, 54.5 mg, 0.129 mmol) in 2 mL of dichloromethane was added urea hydrogen peroxide (60.8 mg, 0.646 mmol), triethylamine (0.090 mL, 0.65 mmol), and trifluoroacetic anhydride (0.036 mL, 0.26 mmol). After 30 min, additional urea hydrogen peroxide (36.5 mg, 0.388 mmol), and triethylamine (0.18 mL, 1.3 mmol), and trifluoroacetic anhydride (0.146 mL, 1.03 mmol) were added. After 3 h, the reaction was cooled to −78° C., treated with 10% aqueous sodium carbonate, and extracted 3× with dichloromethane. The combined organic solutions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was suspended in methanol, and the slurry was filtered and washed with additional methanol to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 438.1214 for [M+H]+ [Calc'd for C23H21ClN3O4, [M+H]+=438.1215]: 1H NMR (400 MHz, d6-DMSO) δ 9.01 (d, J=1.1 Hz, 1H), 8.73 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 8.14 (d, J=7.7 Hz, 1H), 8.06 (s, 1H), 7.82-7.74 (m, 3H), 7.22-7.20 (m, 1H), 5.31 (d, J=5.5 Hz, 1H), 4.67 (br s, 1H), 4.56 (s, 2H), 4.18 (br s, 1H), 4.00-3.93 (m, 2H), 3.46 (t, J=11.0 Hz, 1H), 3.15 (t, J=10.5 Hz, 1H), 2.24 (br s, 1H), 1.92-1.90 (m, 1H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[C:5]([F:20])=[CH:4][CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH:21]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[C:5]([F:20])=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)ccc(F)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)ccc(F)c2C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
A mixture of tert-butyl 9-bromo-6-fluoro-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.16 mmol), cyclopropylboronic acid (298 mg, 3.47 mmol), saturated aqueous sodium carbonate solution (6 ml), and tetrakis(triphenylphosphine)palladium(0) (36.1 mg, 0.0313 mmol) in dimethoxyethane (10 ml) was stirred under a nitrogen atmosphere at 90° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (270 mg, 75.7%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[O:16])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[O:16])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc(C(=O)NC(C)(C)C(=O)O)cs1
Temperature: 25 °C
Yield: 100 %

Procedure:
Methyl 2-(2-((tert-butoxycarbonylamino)methyl) thiazole-4-carboxamido)-2-methylpropanoate (2.4 g, 6.7 mmole) was dissolved in 10 mL methanol and 3 mL water. To the mixture, lithium hydroxide monohydrate (0.56 g, 13.4 mmole) was then added. The reaction was stirred at room temperature until TLC indicated complete consumption of starting material. To the mixture, water and EtOAc were added, and the aqueous layer was acidified with 2 N HCl to about PH 7. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product as a white solid (2.3 g, quantitative yield).
Reaction SMILES: [C:1]([CH2:5][CH2:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:3][CH3:4])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>O>[C:1]([CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:20]([C:19]([C:11]2[CH:10]=[CH:9][C:8]([N:7]([CH3:14])[CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:23])=[O:21])=[CH:10][CH:9]=1)[CH3:14])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCN(C)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)CCN(C)c1ccc(C(=O)C(=O)c2ccc(N(C)CCC(=O)OC)cc2)cc1

Procedure:
4,4'-bis(N-2-carbomethoxyethyl-N-methylamino)benzil was prepared according to the procedure of Tuzun, et al. (Org. Syn., 41, 1 (1961)). Charges were 86.4 g of N-2-carbomethoxyethyl-N-methylaniline (prepared according to the procedure in Example 1), 41.7 g of anhydrous aluminum chloride and 6.7 ml of oxalyl chloride. After the addition of 157 ml of water the reaction mixture was extracted three times with 100 ml portions of chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed on a steam bath and the dark brown residue was chromatographed on Activity I basic alumina (the most active and dried form, in terms of adsorbing power, of chromatographic grade alumina) using a 1:1 mixture of ethyl acetate and heptane. Fractions containing a new product which appeared to be free of starting material by TLC (thin layer chromatography) were combined and concentrated to a brown gum. The combined chromatography fractions were dissolved in 50 ml of 10 percent methanolic sodium hydroxide and refluxed overnight. A tan solid separated which was isolated by filtration, washed with methanol and dried. This material in water had λmax=382 nm and εmax=14,650. This is only one third the extinction coefficient reported for 4,4'-bis(dimethylamino)benzil. No further purification was attempted.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:14]([OH:20])([C:16](F)(F)F)=[O:15].Cl[CH2:22]Cl>>[CH3:22][O:11][C:10](=[O:12])[CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:16][C:14]([OH:20])=[O:15]
Reactant: ClCCl
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C(CCc1ccccc1)CC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of the compound of example 48 in dichloromethane (20 mL) and containing about 1 mL of water was prepared. The solution was cooled in an ice bath and treated with TFA (10 mL). The reaction mixture was stirred for 1 hour while in the ice bath, followed by 1 hour at room temperature. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The aqueous phase was extracted twice with dichloromethane. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude oil was flashed using 10% ethyl acetate in hexanes followed by 2% methanol in chloroform to give the product as a colorless oil. 1H-NMR(CDCl3, 300 MHz: 1.92(m, 2H); 3.70 (s, 3H); 2.62(m, 4H); 2.87(m, 1H); 3.72(s, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([CH:18]([F:20])[F:19])[N:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[C:14]=1[CH2:25][S:26][C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1.[OH2:34]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([CH:18]([F:19])[F:20])[N:16]=[C:15]([C:21]([F:24])([F:22])[F:23])[C:14]=1[CH2:25][S:26]([C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1)(=[O:9])=[O:34]
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(C(F)F)c2Cl)=NO1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(S(=O)(=O)Cc2c(C(F)(F)F)nn(C(F)F)c2Cl)=NO1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
1.4 g of m-chloroperbenzoic acid (purity: 70%, 8.1 mmoles) was added, with ice-cooling, to a solution of 0.69 g (1.9 mmoles) of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.4 g (yield: 53.3%) of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 126.0 to 127.0° C.).
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1([C:16]2[CH:21]=C[C:19]([N+:22]([O-])=[O:23])=[CH:18][CH:17]=2)[O:15][CH2:14][CH2:13][O:12]1.[OH-].[Na+]>CO>[CH3:10][C:11]1([C:16]2[CH:17]=[CH:18][C:19]3[C:8]([CH:21]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:23][N:22]=3)[O:12][CH2:13][CH2:14][O:15]1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2ccc3noc(-c4ccccc4)c3c2)OCCO1
Reaction time: 16 h

Procedure:
Phenylacetonitrile (0.84 g, 7.2 mmol) and 2-methyl-2-(4-nitrophenyl)-1,3-dioxolane (mp. 69°-71° C. (1.50 g 7.2 mmol) were added to a room temperature solution of sodium hydroxide (1.44 g, 36 mmol) in methanol (8 ml). A slight exotherm was noted and stirring was continued for 16 hrs. The mixture was filtered and the collected solid washed several times with water and once with cold methanol to yield a yellow powder (1.60 g) with mp. 137° C. (lit. mp. 137°-138° C., see J. Heterocyclic Chem. 11, 107 (1974)).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[CH:13]=[CH:12][CH:11]=[N:10][C:8]=3[NH:9][C:4]2=[CH:3][CH:2]=1.[CH3:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=3)[N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]=2[CH2:16]1>CC(C)CCO>[CH2:7]1[CH2:13][CH2:12][CH:11]([N:10]=[C:8]=[N:9][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:17][CH2:16]1.[CH3:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=3)[N:18]([CH2:29][C:30]([O:32][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[O:31])[C:17]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CN(C)CC1
Reactant: c1ccc2c(c1)[nH]c1ncccc12
Solvent: CC(C)CCO
Product: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)OCCC(C)C)CN(C)CC1

Procedure:
Method for the preparation of compound 19 [isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate]:p-tolylhydrazine is alkylated with ethyl 2-bromoacetate to give the substituted phenylhydrazine, ethyl 2-(1-p-tolylhydrazinyl)acetate (III). The reaction of III with 4,4-dimethoxy-N-methylbutan-1-amine gives the indole derivative ethyl 2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V). Effecting the indole to standard Pictet Spingler conditions with formaldehyde gives the 3-carboline intermediate (VI) ethyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. Following treatment of VI with base the acid (VII) 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acid is obtained. The treatment of this acid with DCC or other standard coupling reagents with 3-methylbutan-1-ol gives compound 19 isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[Cl:17][C:18]1[CH:19]=C([CH:27]=[CH:28][CH:29]=1)C(N(OC)C)=O>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:11]([C:10]2[O:9][C:3](=[O:8])[CH:4]=[C:5]([OH:6])[CH:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CON(C)C(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(O)cc(-c2cccc(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.4 %

Procedure:
A slurry of 60% NaH (0.790 g, 19.7 mmol) in THF (50 mL) under a N2 atmosphere was cooled to 0° C. and treated with ethyl acetoacetate (2.51 mL, 19.7 mmol). The resulting solution was subsequently treated with n-BuLi (12.3 mL, 19.7 mmol) and stirred for 20 min. at 0° C. to provide an orange solution which was treated via cannula with a solution of 3-chloro-N-methoxy-N-methylbenzamide (2.50 g, 15.15 mmol) in THF (5.0 mL). The mixture was allowed warm to ambient temperature where it was stirred for 14 h before being quenched with 2.0 N HCl. The product was extracted with ethylacetate (3×50 mL), the layers combined, dried with Na2SO4, and the solvent removed in vacuo. The residue was then treated with conc. H2SO4 (20 mL) and the resulting mixture stirred for 18 h at room temperature before being diluted with H2O (200 mL). The product was then extracted with ethylacetate (3×100 mL) being sure to collect all solids. The layers were then combined and diluted with acetone to provide a homogenous solution which was dried with Na2SO4. The solvent was then removed in vacuo and the resulting solid recrystallized from acetone-hexane to provide the title compound (1.33 g, m.p. 254-256° C.). 1H NMR (400 MHz, DMSO-d6) δ11.957 (bs, 1 H), 7.889 (t, 1 H, J =1.5 Hz), 7.839-7.813 (m, 1 H), 7.598-7.524 (m, 2 H), 7.876 (d, 1 H, J=2 Hz), 5.450 (d, 1 H, J=2 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[BH4-].[Na+].[OH2:28]>C(O)C>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([N+:15]([O-:16])=[O:28])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CNCCCN2CCN(CCCNCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 4-nitrobenzaldehyde (792 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h under reflux. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]=[N+:5]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.BrCC(C1C=CC=CC=1)=O.[CH3:32][C:33]1[CH:34]=[N:35]C2C(C=1)=CC=CC=2>C(#N)C>[C:14]([C:13]1[N:5]2[C:6]3[C:11]([CH:12]=[C:3]([CH3:2])[C:4]2=[C:33]([C:34]#[N:35])[CH:32]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cnc2ccccc2c1
Reactant: Cc1cc2ccccc2[n+](CC(=O)c2ccccc2)c1
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1cc2ccccc2n2c(C(=O)c3ccccc3)cc(C#N)c12

Procedure:
3-Methyl-1-phenacyl-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (481 mg, 2.405 mmol), 3-methyl-quinoline (296 mg, 2.08 mmol) and acetonitrile (5 mL), similar to Example 1a, and yielded 640 mg (89%) as an off white solid: 1H NMR (CDCl3) 0.38 (d, J=1.8 Hz, 1H), 8.74 (s, 1H), 8.31 (m, 1H), 8.28 (m, 1H), 8.17 (dd, J=1.5, 8.4 Hz, 1H), 8.01 (m, 1H), 7.94–7.87 (m, 2H), 7.71 (m, 1H), 7.57 (t, J=7.8 Hz, 2H), 7.49 (s, 2H), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](=[N:36]O)[NH2:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]1[N:35]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:36]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(Cc1ccccc1Cl)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccccc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) of 2-(2-chlorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 10 mg (10% of theory)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([S:10][CH:11]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=3[F:30])[C:12]3[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH2:20])=[O:19])=[N:16][CH:17]=3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH2:31].C[OH:33]>C(OCC)(=O)C.OO>[O:1]1[C:5]2[CH:6]=[C:7]([S:10]([CH:11]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=3[F:30])[C:12]3[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH2:20])=[O:19])=[N:16][CH:17]=3)(=[O:33])=[O:31])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CO
Reactant: Cc1cc(C(N)=O)ncc1C(Sc1ccc2ccoc2c1)c1c(F)ccc(F)c1F
Reactant: O
Agent: OO
Solvent: CCOC(C)=O
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc2ccoc2c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 36 %

Procedure:
To a solution of 5-[(1-benzofuran-6-ylthio)(2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (93.0 mg, 0.217 mmol) in ethyl acetate (5 ml) and methanol (5 ml), 30% aqueous hydrogen peroxide (2.5 ml) and hexaammonium heptamolybdate tetrahydrate (10 mg, 0.00809 mmol) were added, and the mixture was stirred for 9 hours at room temperature. Hexaammonium heptamolybdate tetrahydrate (10 mg, 0.00809 mmol) was added to the reaction mixture, and the mixture was stirred for 16 hours at room temperature. Furthermore, 30 aqueous hydrogen peroxide (1.0 ml) was added to the reaction mixture, and the resulting mixture was stirred for 3 hours. Water was added to the reaction mixture, and the organic solvent was distilled off under reduced pressure. The resulting residue was extracted with ethyl acetate, and was washed sequentially with water, sodium thiosulfate, water and saturated brine. The residue was dried over magnesium sulfate, and then was concentrated. The resulting residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated. The resulting solid was recrystallized from ethyl acetate to obtain the title compound (35.8 mg, 0.0778 mmol, 36%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24]C(=O)OC(C)C)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].CO.C(N(CC)CC)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
1-Methylethyl {(2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 95) (327 mg, 0.767 mmol) was added to a cold (ice bath) suspension of aluminium chloride (388 mg, 2.91 mmol) in dichloromethane (DCM) (4 mL). The reaction was stirred at approximately 0° C. for 30 min then an extra amount of aluminium chloride (102 mg, 0.767 mmol) was added and the resulting mixture was stirred at approximately 0° C. for 30 min. Aluminium chloride (102 mg, 0.767 mmol) was further added and the resulting mixture was stirred at approximately 0° C. for 30 min. Further Aluminium chloride (102 mg, 0.767 mmol) was added and the resulting mixture was stirred at approximately 0° C. for 30 min. The reaction mixture was then treated with a solution of methanol (0.884 mL) and triethylamine (2.312 mL, 16.59 mmol) and the resulting mixture was stirred further at approximately 0° C. for 20 min then was partitioned between EtOAc (35 mL) and a saturated NaHCO3 aqueous solution (35 mL). The reaction mixture was then filtered through celite and the insoluble were washed with EtOAc (25 mL) and NaHCO3 (25 mL). The filtered aluminum residues were suspended in MeOH and sonicated. The resulting suspension was filtered and the filtrate was concentrated in vacuovacuo. The white solid residue was loaded onto a 10 g SCX cartridge and eluted with MeOH and then with 2M NH3 in MeOH. The methanol fractions were combined and concentrated in vacuo to give (2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (103 mg, 39%) and the combined ammonia fractions were combined to give (2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (71 mg, 27%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:14])[N:8]([CH:15]([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[CH2:19]([N:21]([CH2:29][CH3:30])[C:22](=[O:28])[O:23][CH2:24][N:25]=[N+:26]=[N-:27])[CH3:20]>S([O-])([O-])(=O)=O.[Cu+2].CC(O)(C)C.O>[CH2:29]([N:21]([CH2:19][CH3:20])[C:22](=[O:28])[O:23][CH2:24][N:25]1[CH:13]=[C:12]([C:10]2[C:9](=[O:14])[N:8]([CH:15]([CH3:16])[CH3:17])[C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:18])[C:5]=3[CH:11]=2)[N:27]=[N:26]1)[CH3:30]
Reactant: CCN(CC)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cc2c(C)nc(N)nc2n(C(C)C)c1=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCN(CC)C(=O)OCn1cc(-c2cc3c(C)nc(N)nc3n(C(C)C)c2=O)nn1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
2-amino-6-ethynyl-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (75 mg, 0.31 mmol) and azidomethyl diethylcarbamate (80 mg, 0.46 mmol) was suspended in 1:1 t-BuOH/H2O (4 mL). To this was added saturated copper sulfate solution (0.05 mL) and stirring was continued for 24 h. The mixture was concentrated and diluted with 5 mL water. The mixture was separated and the organic phase was washed with water and evaporated. Flash chromatography of the residue over silica gel, using 0-5% MeOH/CHCl3, gave the title compound (88 mg, 69%).