Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][CH3:21])[CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:3])[CH3:2])=[C:15]([CH2:20][CH3:21])[CH:14]=1
Reactant: CC(=O)Cl
Reactant: CCc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(Br)ccc1OC(C)=O
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Acetyl chloride (1.06 mL, 14.9 mmol) followed by triethylamine (2.08 mL, 14.9 mmol) were added to a cooled 0° C. solution of 4-Bromo-2-ethyl-phenol (2.5 g, 12.4 mmol, from Step 1) dissolved in CH2Cl2. The reaction was stirred for 2 hrs and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (2.44 g, 81%). 1H NMR (CDCl3): δ 1.19 (t, 3H, J=7.7 Hz), 2.32 (s, 3H), 2.52 (q, 2H, J=7.7 Hz), 6.89 (d, 1H, J=8.5 Hz), 7.32 (dd, 1H, J=8.5, 2.2 Hz), 7.38 (d, 1H, J=2.2 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[C:4]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Reactant: Cc1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate (1.20 g, 2.68 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (0.730 g, 5.37 mmol, 2.00 equiv), Pd(PPh3)4 (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (12 mL), and water (2 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to provide 1.00 g (81% yield) of tert-butyl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 459 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:19])=[N:13]3)[CH2:4][CH2:3]1.C(O)(=O)C>[C].[Pd].C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][CH:12]([CH3:19])[NH:13]3)[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(N3CCC(O)CC3)c(F)ccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1CCc2c(ccc(F)c2N2CCC(O)CC2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
5-(4-Hydroxy-1-piperidyl)-6-fluoroquinaldine (3.7 g) was dissolved in a mixed solvent consisting of 100 ml of acetic acid and 10 ml of ethyl acetate, and 1 g of 5% palladium-carbon was added to the mixture which then was placed in a vitrified autoclave. The reaction mixture was stirred at room temperature under a hydrogen gas pressure of 5 kg/cm2 for 3 hours. After removing hydrogen gas the reaction mixture was taken out. After removing the catalyst, the content was concentrated to dryness, dissolved in 100 ml of chloroform and neutralized with 50 ml of an aqueous 5% sodium hydroxide solution. After separation and washed with 100 ml of water twice, the chloroform layer was dried and concentrated to dryness. To the residue were added 20 ml of hexane and 0.5 g activated carbon and the mixture was heated to dissolve. After removing activated carbon by filtration the hexane layer was cooled to precipitate crystals which then were collected to give 3.4 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-1,2,3,4-tetrahydroquinaldine.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([NH:3][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:9]([OH:11])=[O:10])=[O:20]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
An aqueous NaOH (1M, 2.6 mL) solution is added, while stirring, to L-Leucine (4 g, 30.5 mmol) in a round bottom flask (250 mL). To this solution was added sodium carbonate (1.62 g, 15.2 mmol). The flask is cooled to 0° C. in an ice-water bath. Methyl chloroformate (2.6 mL, 33.5 mmol) is added drop wise and the reaction mixture is allowed to stir for 15 hours and reach room temperature. The reaction mixture is separated with ether (3×50 mL), and the aqueous layer is contained in a round bottom flask and cooled over an ice-water bath. Concentrated HCl (aq) is added drop wise until pH 2. The reaction mixture is brought to room temperature and extracted with 2-Me-THF (3×50 mL). The organic layers are pooled, dried (MgSO4), the solids removed by filtration, and the solvents of the filtrate removed under reduced pressure. The compound was purified by silicagel chromatography with gradient elution from CH2Cl2 to CH2Cl2/MeOH/acetic acid 17/2/1. Fractions containing product were combined and the solvent were removed in vacuum, resulting in N-methoxycarbonyl-L-leucine (1.9 g, 32%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.Cl.C([O-])(O)=O.[Na+].[Br:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>CCOC(C)=O.C(Cl)Cl>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:26])[CH3:27])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:12][CH:13]=2)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:49])([F:48])[F:50])[CH:37]=1
Reactant: CN(C)c1nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1nc(Nc2ccc(NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a suspension of [4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (380 mg, 1.00 mmol) in EtOAc (4 mL) and CH2Cl2 (4 mL) was added 4 M hydrogen chloride in EtOAc (4 mL). The mixture was stirred at ambient temperature for 4 hr and concentrated to give a white solid. The solid was alkalized with saturated aqueous NaHCO3 filtered, washed with H2O and hexane, and dried at 50° C. under reduced pressure. To a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (680 mg, 2.00 mmol) in CH2Cl2 (30 mL) was added PVP (8 mL). To the resulting suspension was added a solution of the above solid in CH2Cl2 (5 mL). The mixture was stirred at ambient temperature for 10.5 hr and filtered. The filtrate was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, EtOAc) to give a solid. The solid was washed with Et2O and dried at 50° C. under reduced pressure to give 4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide (202 mg, 35%) as a pale yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=O)C1C=CC=CC=1>CCO.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 1-benzyloxycarbonyl-4-(tert-butoxycarbonyl)-2-piperazinecarboxylate (2.49 g) (Tet. Lett. 30(39), 5193-5196) in EtOH, was added Pd/C (0.25 g). The solution was degassed with nitrogen and hydrogen gas was bubbled into the mixture. The reaction mixture was stirred for 3 hours under hydrogen atmosphere. The mixture was filtered through Celite and concentrated to give 1.15 g of ethyl 4-(tert-butoxycarbonyl)-2-piperazinecarboxylate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[Na+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(F)cc1

Procedure:
10 g (46 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 3.74 g (46 mmol) of sodium thiocyanate were stirred in 80 ml ethanol at 50° C. for 2 h. After addition of water the separated solid was isolated by filtration, washed and dried. Yield: 8.96 g.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[S:11]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:16]=1[CH3:29])(=[O:13])=[O:12].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[S:11]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:16]=1[CH3:29])(=[O:13])=[O:12]
Reactant: COc1c(C)cc(C)cc1S(=O)(=O)Nc1c(C)cc(C)c(N2CCCCC2)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C)c(O)c(S(=O)(=O)Nc2c(C)cc(C)c(N3CCCCC3)c2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Under a nitrogen atomersphere, 32 (88 mg, 0.21 mmol) was dissolved in dichloromethane (6 mL) followed by the addition of BBr3 (0.2 mL, 2.1 mmol). The reaction was stirred overnight at room temperature and then quenched with ice. The mixture was partitioned between EtOAc and water and the organic layer was separated, washed with brine, and dried over Na2SO4. The solids were filtered off and the filtrate was concentrated in a rotavap to give 70 mg of the title compound as a brownish solid ESI [M+H+]=402.24.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27]C3C=CC(OC)=CC=3)=[O:25])=[CH:19][CH:18]=2)[C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]1=2)=[O:4].[CH2:40]([OH:42])[CH3:41].[CH2:43]([O:45][CH2:46][CH3:47])C>>[CH3:43][O:45][C:46]1[CH:47]=[CH:36][C:7]([CH2:27][NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:8]3[C:9](=[O:15])[C@H:10]4[CH2:11][CH2:12][CH2:13][C@H:14]4[N:5]([C:3](=[O:4])[CH2:2][N:8]4[C:40](=[O:42])[C:41]5=[CH:14][CH:13]=[CH:12][CH:11]=[C:10]5[C:9]4=[O:15])[C:6]4[CH:39]=[CH:38][CH:37]=[CH:36][C:7]3=4)=[CH:22][CH:21]=2)=[CH:6][CH:39]=1
Reactant: CCOCC
Reactant: COc1ccc(CNC(=O)Nc2ccc(CN3C(=O)[C@H]4CCC[C@H]4N(C(=O)CCl)c4ccccc43)cc2)cc1
Reactant: CCO
Product: COc1ccc(CNC(=O)Nc2ccc(CN3C(=O)[C@H]4CCC[C@H]4N(C(=O)CN4C(=O)c5ccccc5C4=O)c4ccccc43)cc2)cc1
Yield: 38 %

Procedure:
Using (3aR*,10aS*)-4-(chloroacetyl)-9-[4-[3-(4-methoxybenzyl)ureido]benzyl]-2,3,3a,4,9,10a-hexahydro-benzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the title compound was synthesized in otherwise the same manner as Example 30. Yield 38%, m.p. 155.5°-158.5° C. (ethanol-diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[Cl:47][CH2:48][CH2:49][CH2:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[Cl:47][CH2:48][CH2:49][CH2:50][S:51]([NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)(=[O:53])=[O:52]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)CCCCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 12 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2Cl2 (2 mL) was added 3-chloropropane-1-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred at 12° C. for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]([O:29][Si](C)(C)C)[C:27]#N)[CH:23]=[CH:24][CH:25]=1.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1CI)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@@H:42]1[CH2:27][C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)=[O:29])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Reactant: C[Si](C)(C)OC(C#N)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(=O)c1cccc(Cl)c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
Diisopropylamine (764 uL, 5.4 mmol) was dissolved in THF (15 mL) under nitrogen and cooled to −70° C. Then a 1.6 M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) was added and stirring at −70° C. was continued for 15 min. Then a solution of (3-chloro-phenyl)-trimethylsilanyloxy-acetonitrile (1.18 g, 4.9 mmol) in THF (5 mL) was added and stirring at −70° C. was continued for 30 min, producing a yellow color. Then a solution of (S)-2-iodomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.53 g, 4.9 mmol) in THF (5 mL) was added and stirring at −70° C. was continued for 5 h and then allowed to warm up to 20° C. and stirred overnight. The mixture was extracted with AcOEt, 1 M citric acid, and 50% NaCl. The crude product was purified by flash chromatography on silica gel with a heptane/AcOEt gradient 0-15%. One obtained 500 mg (31%) of a yellow oil. MS: m/z=224 [M+].
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:20]2[C:19](=O)[CH2:18][C@@:17]2([CH3:25])[C@H:11]3[CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[CH2:6][C@@H:5]1[OH:26])[CH3:2].C(O)C.[Cl-].[OH:31][NH3+:32]>[OH-].[Na+]>[CH2:1]([O:3][C@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:20]2[C:19](=[N:32][OH:31])[CH2:18][C@@:17]2([CH3:25])[C@H:11]3[CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[CH2:6][C@@H:5]1[OH:26])[CH3:2]
Reactant: [NH3+]O
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Yield: 29.7 %

Procedure:
A solution of (Z)-2β-ethoxy-3α-hydroxy-5α-pregn-17(20)-en-11-one (710 mg) in refluxing ethanol (21 ml) was treated with a slurry of hydroxylammonium chloride (1.43 g) in 50% aqueous sodium hydroxide. After 24 hour refluxing, the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and evaporated to a froth (710 mg). This material was retreated with hydroxylamine as above to give a froth (800 mg) which was purified by preparative TLC (4% methanol in chloroform 22) and crystallisation from ethyl acetate/petrol to yield the title compound (220 mg), m.p. 176°-193°, [α]D +35.9°.
Reaction SMILES: N1CCCC1.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[CH:13]([N:26]1[CH2:29][CH:28]([O:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH:13]([N:26]1[CH2:29][CH:28]([O:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH:13]([N:26]1[CH2:27][CH:6]([N:8]2[CH2:11][CH2:12][CH2:10][CH2:9]2)[CH2:7]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CC(N3CCCC3)C2)cc1
Temperature: 70 °C
Yield: 125.8 %

Procedure:
Pyrrolidine (142 mg, 2 mmol) and triethylamine (100 mg, 1 mmol) were added to a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (317.4 mg, 1 mmol) in DMF (6 mL). (The methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester was prepared as described in J. Org. Chem. 1991, 56, 6729-6730). The reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was treated with water. The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was then removed under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4) afforded the title compound as an oil (184 mg, 65%). MS: 293 (MH+); HPLC Rf: 5.95 min; HPLC purity: 92%.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[NH:8][C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=O>O>[F:18][C:19]([F:26])([F:25])[C:20]1[NH:8][C:9]2[C:10]([CH:15]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1ccccc1N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: O
Product: FC(F)(F)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A 2.5 M solution of n-butyl lithium in hexanes (8.8 mL, 22 mmole) at room temperature, under N2, is treated with N,N,N'N'-tetramethylethylenediamine (TMEDA) (3.3 mL, 22 mole), stirred at room temperature for 0.5 hour, treated with N-trimethylsilyl-o-toluidine (1.79 g, 10 mmole), heated at reflux temperature for 6 hours, cooled to -78° C., treated with ethyl trifluoroacetate (1.4 mL, 12 mmole) stirred at -78° C. for 0.25 hour, warmed to room temperature, diluted with water and extracted with diethyl ether. The combined extracts are washed sequentially with 1 N HCl and saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 4:1 hexanes:ethyl acetate as eluent to afford the title product as a light yellow solid, mp 104°-106° C. (literature mp 102° C.1), 0.81 g (47% yield), further identified by IR, 1HNMR and 19FNMR analyses.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:16][C:17]([NH:32][OH:33])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Yield: 93.1 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (1.50 g, 3.67 mmol), N,N′-carbonyldiimidazole (653 mg, 4.03 mmol) and hydroxylamine hydrochloride (308 mg, 4.43 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (1.45 g, 93% yield): mp, 169.0-171.0° C.; 1H NMR (DMSO-d6) δ1.54-1.85 (m, 8H, C5H8), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.69 (s, 3H, CH3), 4.70-4.72 (m, 1H, CH), 5.67 (t, J=7.9 Hz, 1H, NCH), 6.87 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.79-7.87 (m, 4H, Ar), 8.78 (br s, 1H, OH), 10.58 (1H, NH); 13C NMR (DMSO-d6) δ23.51, 32.17, 34.23, 50.19, 55.53, 79.57, 112.08, 114.16, 119.69, 123.11, 131.16, 131.20, 134.59, 146.73, 149.17, 166.01, 167.63; Anal Calcd for C23H24N2O6: C, 65.08; H, 5.70; N, 6.60. Found: C, 64.73; H, 5.60; N, 6.53.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22]C=O)C>>[CH:20]([N:13]1[CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Reactant: CCOC=O
Product: O=CN1CCN=C1CC(c1ccccc1)c1ccccc1

Procedure:
a mixture of 2.5 g of 2-(2,2-diphenyl ethyl)-2-imidazoline and 50 ml of ethylformate was refluxed for 5 hours. After the reaction, unreacted ethylformate was removed by distillation. The resulting residue was subjected to silica gel column chromatography and eluted with methylene chloride. The solvent was removed by distillation from the eluate to give 1.2 g of 1-formyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 105° to 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][NH:7]1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][N:7]1[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: F[C@@H]1CN[C@@H](COc2ccccc2Cl)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: F[C@H]1C[C@H](COc2ccccc2Cl)N(c2ncnc3[nH]cnc23)C1

Procedure:
7.8 780 mg of (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine and 525 mg of 6-chloropurine are irradiated at 120° C. in the microwave for 6 h together with 1.2 ml of N-ethyldiisoproylamine and 40 ml of 1-butanol, during which a pressure of 10 bar arises. After conventional aqueous work-up, the residue obtained is crystallised from ether, giving 350 mg of 6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine (“A7”) as beige crystals; Rt.: 1.790 min; [M+H]+348.2; m.p. 143-144°;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.[Cl:22]C1C=C2C(=CC=1)NC=C2C(Cl)=O>>[Cl:22][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[C:10]([O:12][CH2:13][C:14]12[CH2:15][CH2:16][N:17]([CH2:20][CH2:21]1)[CH2:18][CH2:19]2)=[O:11]
Reactant: O=C(Cl)c1c[nH]c2ccc(Cl)cc12
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccc(Cl)cc12

Procedure:
Quinuclidin-4-ylmethyl 5-chloro-1H-indole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 5-chloro-1H-indole-3-carbonyl chloride as the electrophile.