Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[C:15]([F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (486 mg, 87%).
Reaction SMILES: CO[CH2:3][CH2:4]CN=C=O.[CH2:9]([C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:31])[N:19]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)[C:18]=2[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:49]([NH:51][CH2:52][CH2:53][OH:54])[CH3:50]>ClCCCl>[CH2:9]([C:16]1[N:24]([CH2:50][CH2:49][N:51]([CH2:3][CH3:4])[CH2:52][CH2:53][OH:54])[C:23]2[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:31])[N:19]([CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)[C:18]=2[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCCN=C=O
Reactant: COCCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: CCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCO)CCn1c(Cc2ccccc2)nc2c1c(=O)n(CCCOC)c(=O)n2CCc1ccc([N+](=O)[O-])cc1

Procedure:
By methods well known in the art 3-methoxypropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol to yield 8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. By the method of Example 4 this substance is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-(3-methoxypropyl)xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[Cl:28][C:29]1[CH:36]=[CH:35]C(CO)=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccc(Cl)cc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 9.90 g of 4-chlorobenzyl alcohol is heated at 130° for 48 hours, the mixture is diluted with about 20 ml of methylene chloride and chromatographed on about 300 g of silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained p-chlorobenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 183°-184°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2c(Cl)ccnc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(Cl)ccnc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
200 mg of the above-prepared 7-chloro-2-n-propyl-3H-imidazo[4,5-b]pyridine and 380 mg of methyl 2-(4-bromomethylphenyl)benzoate were dissolved in dimethylformamide, and 50 mg of sodium hydride was added to the solution. The mixture was stirred at room temperature for 20 min, and water was added thereto, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (benzene:ethyl acetate=40:1→20:1) to prepare the intended product as a colorless oleaginous substance. The yield was 140 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:3]1=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:3]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(=O)OCCN1CCN(C)C1=O
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone (13.4 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.6 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7 ml) for 30 hours at 80°-85° C. gave 4-{2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolidinylideneamino]phenyl}morpholine.
Reaction SMILES: CN1CCNCC1.C([Li])CCC.[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=1.C([Li])(C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:28][C:16]1[CH:17]=[CH:18][C:19]([CH:21]=[O:22])=[N:20][C:15]=1[O:14][CH3:13]
Reactant: COc1cccc(C=O)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN1CCNCC1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C=O)ccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
A solution of methylpiperazine (2.31 g) in tetrahydrofuran (20 mL) was cooled to −78° C., and n-butyllithium (2.64 M, 7.55 mL) was added dropwise in an argon gas atmosphere. After stirring at the same temperature for 15 minutes, a solution of 6-methoxypicolinaldehyde (2.5 g) in tetrahydrofuran was added and the mixture was stirred for 30 minutes. t-Butyllithium (1.59 M, 17.1 mL) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for one hour and at −40° C. for 15 minutes. The reaction solution was cooled again to −78° C. A solution of hexachloroethane (12.9 g) in tetrahydrofuran (20 mL) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→10:1) to give 5-chloro-6-methoxypyridine-2-carbaldehyde as a colorless powder (1.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH2:12]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH3:15].O>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]([CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCCCNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 4-bromo-2-fluoro-nitro benzene (34 g, 0.15 mol), N-n-butyl glycine (20 g, 0.15 mol) in ethanol (600 ml), and water (150 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with 2N sodium hydroxide, extracted with CH2Cl2 and the pH was adjusted to 5 with 1N HCl. The mixture was extracted with CH2Cl2, the CH2Cl2 solution was dried (MgSO4) and evaporated to obtain the crude product (11 g, 22%) as a brown oil, which was used without further purification. 1H-NMR (DMSO-d6) δ 0.84 (t, J=7.30 Hz, 3H), 1.23 (m, 2H), 1.45 (m, 2H), 3.18 (t, J=7.30 Hz, 2H), 3.91 (s, 2H), 7.16 (dd, J=8.68, 1.91 Hz, 1H), 7.40 (d, J=1.94 Hz, 1H), 7.69 (d, J=8.68 Hz, 1H); MS (EI) m/z 331 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[NH:14]1[CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:14]2[CH2:17][CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccc(F)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and azetidine hydrochloride (68 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, and extraction was carried out twice with dichloromethane (15 mL). Washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (132 mg, yield 78%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:20](N)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(#[N:29])C>>[CH3:20][CH2:21][CH:22]([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN
Reactant: O=C(c1ccccc1)c1ccc(OCCCCl)cc1
Reactant: CC#N
Product: CCCC(CC)NCCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
10 g (36 mmol) 4-(3-chloropropoxy)benzophenone was dissolved in 100 mL acetonitrile. 36.4 g (0.36 mol) n.-hexyl amine was added and the mixture was heated to 70° C. for 20 hours. The solvent was evaporated under reduced pressure. The oily residue was treated with 500 mL water. The mixture was acidified to pH=1 and stirred for 16 hours at room temperature. The precipitated compounds were isolated by filtration and washed with 200 mL 1 N HCl. The precipitate was treated with 200 mL 1 N NaOH. The mixture was extracted with 200 mL methylene chloride. The organic fraction was dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude 4-[(3-hexylamino)propoxy]benzophenone was purified by preparative column chromatography on a Prochrom LC80 column, using Kromasil Si 60A 10 mm as silica and a gradient elution from methylene chloride to methylene chloride/methanol 68/32 at a flow rate of 150 mL per minute. 3.9 g of 4-[(3-hexylamino)propoxy]benzophenone was isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.[I-].[K+]>C(N(CC)CC)C>[OH2:5].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Product: O
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A mixture of 4.7 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 3.015 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 0.1 parts of potassium iodide, 3 parts of N,N-diethylethanamine and 45 parts of N,N-dimethylformiade was stirred and heated for 18 hours at 60° C. The reaction mixture was poured onto water. The precipitated product was filtered off and dissolved in trichloromethane. The solution was washed with water. The organic phase was separated, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.11 parts (42.8%) of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate; mp. 109.8° C. (compound 1).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1-n1cccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc2c1-n1cccc1C1(CCNCC1)O2
Reaction time: 12 h
Yield: 79.3 %

Procedure:
3-Fluoro-2-(1H-pyrrol-1-yl)phenol (2.7 g, 16.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.3 g, 16.6 mmol) were dissolved in dry dichloromethane (53.6 mL). TFA (2.3 mL, 30.3 mmol) was added over 15 min and stirring was continued for 12 hours. Additional TFA (2.3 mL, 30.3 mmol) was added at 25° C. The reaction mixture was concentrated under vacuum and the residue diluted with dichloromethane (350 mL) then washed with 1M NaOH (2×50 ml), dried, filtered and evaporated to dryness. The resulting material was purified by silica gel chromatography eluting with 0.5-40% MeOH in dichloromethane to yield 9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (3.4 g, 86%). ESI-MS m/z calc. 258.1. found 259.1 (M+1)+; Retention time 0.90 minutes (3 min run).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([CH:9](O)[CH3:10])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1.Cl[CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl.[O:27]1CCCC1>>[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][O:27][CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1nc2ccccc2n1C(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)COCCn1c(C)nc2ccccc21
Reaction time: 6 h
Yield: 59 %

Procedure:
Sodium hydride (1.46 g, 80% suspension in oil) was suspended in dry tetrahydrofuran (60 ml) under nitrogen. 2-Methylbenzimidazol-1-ylethanol (4.3 g) was added and the suspension was sonicated at 40° C. for 2 hours. Ethyl 4-chloroacetoacetate (4.02 g) in tetrahydrofuran (20 ml) was added dropwise and sonication continued for a further 6 hours. The reaction was poured into 1N hydrochloric acid (50 ml), the tetrahydrofuran was removed under reduced pressure and the aqueous phase washed with toluene. The aqueous phase was adjusted to pH7 with potassium carbonate and extracted with dichloromethane (2×100 ml). The organic extracts were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was chromatographed on silica eluting with 5% methanol in ethyl acetate. The fractions containing the product were combined and evaporated to yield the title compound (4.4 g, 59%) as a red oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH2:12]([N:14]([CH2:23][CH3:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH3:13].O>C1C=CC=CC=1>[CH2:23]([N:14]([CH2:12][CH3:13])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:20][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:17][CH:16]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CC1(C)N=C1c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)c1ccc(C2OC(C)(C)N=C2c2ccccc2)cc1
Yield: 38.3 %

Procedure:
4 g of 2,2-dimethyl-3-phenyl-2H-azirine and 5 g of 4-diethylaminobenzaldehyde were exposed to light in 350 ml of benzene at 230° C. for 4 hours under an atmosphere of argon with a mercury high-pressure lamp of 150 watt in a water-cooled ring-mantle vessel through a 3 mm thick filter of Pyrex glass. After removing the solvent in a water-jet vacuum, the residue was crystallized from n-hexane/acetone and then a second time from n-pentane/acetone. The crystalline product was then dried at 60° C. in the water-jet vacuum, and there were obtained 3,4 g of 5-[p-(diethylamino)-phenyl]-2,2-dimethyl-4-phenyl-3-oxazoline having a melting point of 104°-105° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](I)[CH3:26]>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[N:17]([CH2:25][CH3:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(CN(C)C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
NaH (60% dispersion in mineral oil, 0.25 g, 7.1 mmole) was added portionwise. allowing for gas evolution, to a solution of 2-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (1.40 g, 4.75 mmole) in DMF (35 mL) at 0° C. When the NaH addition was complete, ethyl iodide (0.42 mL, 5.2 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the tide compound (1.30 g, 87%) as an orange solid: MS (ES) m/e 323 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][N:4]=[C:3]1[CH:20]=[O:21]
Reactant: Cn1cncc1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: Cn1c(-c2ccccc2)cnc1C=O

Procedure:
Using the procedure of Example 1D, 640 mg of 1-methyl-5-phenylimidazole, 1.55 ml of 2.6M n-butyllithium and 0.31 ml of dimethylformamide gave 320 mg of the desired product.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[F:16][C:17]1[CH:18]=[C:19]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([N:33]2[CH2:37][C@@H:36]([CH2:38][NH+:39]([O-:6])[C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pertrifluoroacetic acid is prepared in situ by the addition of 30% H2O2 solution (0.15 mL) to trifluoroacetic anhydride (0.45 mL) in 5 mL of methylene chloride at 0° C. This solution is stirred at 0° C. for ten minutes, at 25° C. for 30 minutes and then cooled back to 0° C. (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide (VIII-G, R1=COCH3, R9=CH3, X1F, X2=H) (0.207 g) is added and the reaction is stirred at 25° C. for 30 minutes and then concentrated. The residue is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as the eluent to afford 0.14 g of the N-oxide as a hydrate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[N:20]1([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=[CH:23][CH:22]=[CH:21]1>C(Cl)Cl.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:21]1[N:20]([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(O)c1ccc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc[nH]1)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a suspension of pyrrole-2-carboxylic acid (5.55 g) in 500 ml of DCM was added oxalyl chloride (8.7). The reaction mixture was heated under reflux for 1 hour, cooled to -10° C., and tin (IV) chloride (5.85 ml) was added. After stirring the mixture at -10° C. for 30 minutes, 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (10.6 g) was added in four portions over a period of 30 minutes, followed by stirring at -10° C. for additional 30 minutes. The reaction mixture was then poured into 500 ml of water and extracted with DCM. The combined extracts were washed with 1N sodium hydroxide solution, 1N sulfuric acid, and finally with water. The dried (magnesium sulfate) organic phase was filtered and evaporated in vacuo. The residue was tritated with DCM, affording the product as a powder (10.55 g), mp 204°-206° C.
Reaction SMILES: Cl.[NH2:2]O.[C:4]1([CH3:14])[CH:9]=[CH:8][C:7](S(Cl)(=O)=O)=[CH:6][CH:5]=1.[CH3:15][CH2:16][OH:17]>CN(C1C=CN=CC=1)C>[CH3:14][C:4]1([CH3:5])[CH2:9][CH2:8][CH2:7][C:6]1=[O:17].[CH3:5][C:4]1([CH3:14])[NH:2][C:16](=[O:17])[CH2:15][CH2:8][CH2:9]1
Reactant: NO
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC1(C)CCCC(=O)N1
Product: CC1(C)CCCC1=O

Procedure:
The oxime of 2,2 dimethylcyclopentanone is prepared by reaction of the ketone with hydroxylamine hydrochloride in EtOH, and treated with p-toluenesulfonyl chloride and DMAP. Heating then effects Beckmann rearrangement to give 6,6-dimethyl-2-piperidinone which is deprotonated with NaH in DMF solution. Reaction with n-butyl iodide then gives the title compound.