Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O-])=O.[NH4+]>CCO.[OH-].[OH-].[Pd+2]>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[CH:2][CH:3]=2)[CH:12]=1
Reactant: Clc1cc(-c2cccnc2)c2nccn2n1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cncc(-c2ccnn3ccnc23)c1
Temperature: 50 °C
Yield: 73.1 %

Procedure:
To a suspension of 6-chloro-8-(pyridin-3-yl)imidazo[1,2-b]pyridazine (160 mg, 0.69 mmol) in EtOH (15 mL) was added ammonium formate (175 mg, 2.77 mmol) and palladium hydroxide on carbon (50 mg, 0.07 mmol) (20% wet) under nitrogen. The reaction mixture was heated to 50° C. for 20 min and cooled to room temperature. The reaction mixture was passed through a pad of CELITE® and washed with MeOH. The filtrate was concentrated and the residue was purified by BIOTAGE® (20-60% EtOAc/CH2Cl2, 1.5 L) to give the product (99 mg, 73%). LC (Condition B & C): >95% homogeneity index. LC/MS: Rt=0.31 min. LC/MS (Condition A): 197.21.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:36]=[CH:35][C:22]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[OH:40]/[N:39]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:35][CH:36]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCC(CC(=O)O)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCC(CC(=O)O)CC2)cc1

Procedure:
In analogy to example 151, step 3, (1-{4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoyl}-piperidin-4-yl)-acetic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=514.4 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:31])[CH:3]=1.[S:32](N)([NH2:35])(=[O:34])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCNCC3)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(S(N)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Yield: 82.3 %

Procedure:
A solution of (R)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)-3-(4-(piperidin-4-yl)phenyl)propan-1-one (60 mg, 0.14 mmol) and sulfamide (20 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was stirred for 17 h at 108° C., then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Flash chromatography (silica gel, 50% to 100% EtOAc in heptane) afforded the title compound (59 mg, 83%). White foam, MS (ESI+): m/z=512.3 ([M+H]+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.N1CCCC1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:27]1([CH2:33][CH2:34][CH:35]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=CCCc1ccccc1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1OC(=CCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.53 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of pyrrolidine was added. Next, an ethanol solution of 0.66 ml (5 mmol) of 3-phenylpropionaldehyde was added, followed by refluxing for 19 hours. Six hours later, 0.66 ml (5 mmol) of 3-phenylpropionaldehyde and 0.05 ml (0.5 mmol) of pyrrolidine were added. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/1) to yield 26 mg (1.2%, yellow oily substance) of the desired product.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[OH-].[Na+].[CH3:11][C:12]([CH:14]=O)=O.[Cl-].[Na+]>O>[CH2:2]([N:4]1[CH:11]=[C:12]([CH3:14])[N:7]=[CH:6][C:5]1=[O:8])[CH3:3]
Reactant: CC(=O)C=O
Reactant: CCNC(=O)CN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCn1cc(C)ncc1=O

Procedure:
A cold (0° C.) solution of N2-tert-butoxycarbonyl-N1-ethylglycinamide (68.0 g, 0.33 mol) in anhydrous dichloromethane (500 mL) was saturated with anhydrous hydrogen chloride gas. After stirring at the same temperature for 1.5 hours, the solution was recharged with more hydrogen chloride gas and stirred for additional 15 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in methanol, diluted with toluene, and concentrated under vacuum to afford the intermediate N-ethylglycinamide HCl salt. This was stored under vacuum overnight and used without further purification. A solution of N-ethylglycinamide HCl salt (44.2 g, 0.32 mol), aqueous sodium hydroxide (640 mL, 1M), water (350 mL), pyruvic aldehyde (20.9 mL, 40% solution in water) was heated in an oil bath at 120° C. for one hour. The reaction mixture was cooled and saturated with solid sodium chloride. The mixture was extracted with chloroform (4×250 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and passed through a plug of silica gel. The silica gel was rinsed successively with ethyl acetate and then 2% methanol in ethyl acetate. The eluted fractions were combined and concentrated under vacuum. The residual solid was recrystallized from diethyl ether to afford the title compound as pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[NH:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>[Pd]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)=[CH:6][C:5]=1[NH:19][C:20]([N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:21])([O-:3])=[O:2]
Reactant: Brc1cnccn1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(NC(=O)N3CCCC3)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Nc1cc(-c2cnccn2)ccc1[N+](=O)[O-])N1CCCC1
Yield: 69.6 %

Procedure:
To a solution of N-(2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxamide (0.20 g, 0.55 mmol) was added at room temperature sodium bicarbonate (0.09 g, 0.80 mmol, 1.45 equiv.), 2-bromopyrazine (0.14 g, 0.89 mmol, 1.6 equiv.) and palladium (0.07 g, 0.06 mmol, 0.1 equiv). The reaction was refluxed for fourteen hours. The crude reaction was filtered and concentrated. The residue was diluted into water and washed with ethyl acetate, the concentrated. The obtained was purified through column chromatography by eluting ethyl acetate and hexane to allow N-(2-nitro-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.12 g, 70% yield).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.[CH3:10][O:11][NH2:12].C([O-])(O)=O.[Na+]>C(O)C>[CH3:10][O:11][N:12]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[Cl:1]
Reactant: O=C1CCCCC1Cl
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCCCC1Cl
Temperature: 22.5 °C

Procedure:
3.0 g (22.6 mmol) of 2-chlorocyclohexanone were initially charged in 30 ml of ethanol, and 1.9 g (22.6 mmol) of O-methyl hydroxylamine hydrochloride were added with stirring at from 20 to 25° C. This mixture was stirred for about 20 hours at from 20 to 25° C., adjusted with sat. NaHCO3 solution to a pH between 7 and 8 and extracted with ethyl acetate. After washing with sat. NaCl solution, the combined organic phases were dried and then freed from the solvent. The title compound (3.4 g) was directly used further.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Bis-(4-chlorobenzyl)amine hydrochloride [prepared by reducing N-(4-chlorobenzyl)-4-chlorobenzamide with lithium aluminium hydride in tetrahydrofuran] was basified using sodium Carbonate in methylene dichloride solvent to give after rotary evaporation 3.16 g of the free base as an oil. This was then mixed with 4-bromobutyronitrile (1.19 ml), diisopropylethylamine (2.1 ml) and 25 ml of dry dimethylformamide and the mixture stirred at 80° C. under nitrogen for 24 hours. On cooling water (100cm3) was added and then the mixture was extracted with 1×50 ml and 2×25 ml of methylene dichloride. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give an oil. This was further purified by column chromatography (silica column eluted with toluene) to give 2.83 g of the title product as an oil. 2.8 g of the title compound was dissolved in 10 ml hot ethanol, acidified with 0.76 g (1 equiv,) of oxalic acid, diluted with ether and cooled to give, after filtration, the 1:1-ethanedioate salt (1.78 g) as colourless crystals, mp 124°-6° (dec).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].F[B-](F)(F)F.[CH3:20][N:21]([CH:23]([N:27]([CH3:29])[CH3:28])CO[CH2+])[CH3:22]>[Cl-].[NH4+]>[CH3:20][N:21]([CH3:22])[C:23]([N:27]([CH3:29])[CH3:28])=[C:9]([N+:7]#[C-:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [CH2+]OCC(N(C)C)N(C)C
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Product: [C-]#[N+]C(C(=O)OCC)=C(N(C)C)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
To a slurry of potassium t-butoxide (4.48 g, 40 mmol) in dry, distilled tetrahydrofuran (40 mL) in a 3-neck 250 mL flask at -78° C., under argon was added dropwise from an addition funnel a solution of ethyl isocyanoacetate (4.52 g, 40 mmol) in dry, distilled tetrahydrofuran (40 mL). The anion was allowed to form for 25 min at -78° C., then solid bis(dimethylamino)ethoxymethylium tetrafluoroborate [9.28 g, 40 mmol, prepared as described by von H. Meerwein, W. Florian, N. Schon, G. Stopp, Justus Liebigs Ann. Chem. 641, 1, (1960)] was added as quickly as possible through a powder funnel with a stream of argon. The reaction was allowed to warm to ambient temperature and stir for 4 hours. It was then poured onto water (200 mL) and saturated ammonium chloride (40 mL) and extracted three times with ethyl acetate (100 mL). The combined extracts were washed with water and saturated sodium chloride, dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting brown oil (6.9 g) was flash chromatographed, eluting with ethyl acetate, to give slightly impure D-36a as a brown oil (4.78 g, 57%). It was used without further purification
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[Cl:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:26](=[O:28])/[CH:25]=[CH:24]/[C:4]2[N:5]([C@@H:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)[C:6]3=[N:7][C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[C:11]3[C:3]=2[C:1]#[N:2])=[CH:38][CH:37]=1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccc(Cl)cc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03: ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-chloroaniline (123 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the objective product as a solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].O=[C:12]1[CH2:17][CH2:16][CH2:15][S:14][CH:13]1[C:18](OC)=[O:19].C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:18]([OH:19])[C:13]3[S:14][CH2:15][CH2:16][CH2:17][C:12]=3[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C1SCCCC1=O
Reactant: N=C(N)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2
Temperature: 85 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a solution of 3-chlorobenzimidamide (4.3 g, 27.7 mmol) in ethanol (120 mL) was added methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (4.82 g, 27.7 mmol) and sodium methoxide (1.8 g, 33.2 mmol). The mixture was stirred at 85° C. for 16 h. After this time, the mixture was concentrated after which ethanol (10 mL) was added and the suspension was chilled to 0° C. HCl (2 M, 50 mL) was added and the suspension was filtered and washed with water. The solid was dried under heat and vacuum to afford the title compound (5.2 g, 67%) as a light yellow solid. MW=278.75. 1H NMR (DMSO-d6, 500 MHz) δ 12.81 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.63-7.58 (m, 1H), 7.56-7.51 (m, 1H), 3.01-2.95 (m, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.12-2.04 (m, 2H); APCI MS m/z 279 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCN3C=CN=C3)[C@H]2[OH:42])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>CS(C)=O>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C@@H:12]2[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]2[N:8]2[C:9]3[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=3[N:6]=[CH:7]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](OCCCCn4ccnc4)[C@H]3O)c2n1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CS(C)=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
A mixture of the 2,6-diamino-9-[2'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine and 2,6-diamino-9-[3'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine isomers in 0.1 M tris buffer (pH 7.4), 0.1 M NaSO4 buffer (pH 7.4) and DMSO is treated with adenosine deaminase at RT for 5 days as per the procedure of Example 3. The product containing fractions are purified by silica gel chromatography and the product containing fraction evaporated to give the product.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[NH:5][CH2:4][C:3]1=[O:14].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([SH:38])[CH3:37]>ClCCl>[CH2:36]([S:38][C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][N:5]=1)[CH3:37]
Reactant: CCS
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCSC1=NCC(=O)N(C)c2ccccc21
Temperature: -51 °C
Reaction time: 0.03 h

Procedure:
A solution of 1.0 mmol of 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Tett. Lett. 1994, 50(30), 9051) in 8mL dry dichloromethane (Aldrich Sure Seal), in an oven-dried round bottom flask under nitrogen cover, is treated with 1.1 equivalents of anhydrous pyridine (Mallinkrodt). The reaction is cooled to −51° C. in a dry ice/acetone bath and treated, dropwise via syringe over three minutes, with 1.1 equivalents of trifluoromethanesulfonic anhydride (Aldrich; sealed ampules). The reaction mixture is allowed to stir twenty minutes while maintaining a reaction temperature between −47 and −35° C. The temperature is brought to 0° C. over 1-2 minutes and then maintained at that temperature for one hour. Ethanethiol (3.4 equivalents) is introduced via syringe and the mixture allowed to stir overnight, still immersed in an ice water-filled Dewar. The temperature had risen to 16° C. by morning. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The aqueous portion is further extracted three times with methylene chloride and the combined extracts dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification is effected by flash chromatography (silica gel; gradient elution using methylene chloride/ethyl acetate in 100/1, 95/5, 90/10 and 85/15. The title compound is obtained as a colorless oil which crystallizes on standing.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[CH2:11]O[CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[CH:7]1([CH:11]2[CH2:9][CH2:9][CH2:8][CH2:7][CH2:11]2)[CH2:11][CH2:7][CH2:8][CH2:9][CH2:8]1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: C1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
A stirred, ice-cooled (2° C.) solution of 1N lithium aluminum hydride/THF (3.43 mL, 3.43 mmol) under nitrogen was treated dropwise with a solution of the above diimide intermediate (140 mg, 0.55 mmol) in anhydrous tetrahydrofuran (20 mL), stirred for 1 h at room temperature and 7 h at reflux, then cooled on an ice bath. Water (0.30 mL), 15% NaOH (0.30 mL) and water (0.90 mL) were added dropwise together with more tetrahydrofuran to facilitate stirring. The mixture was stirred at room temperature for 15 minutes, filtered through celite, and the filtrate concentrated in vacuo. The residue was dissolved in methylene chloride, loaded onto a silica gel column, and eluted with 3:1 methylene chloride/ethyl acetate to afford 3-methyl-1-(1-methylindol-2-yl)-3-azabicyclo[3.1.0]bicyclohexane (100 mg, 80%), which was then converted to the hydrochloride salt by treating with 2N HCl/ether (82 mg, 80%). MS (M+1) 226.8 1H NMR (DMSO-d6) δ 11.35-11.12 (br s, 1H), 7.52-7.34 (m, 2H), 7.15-6.93 (m, 2H), 6.45-6.34 (m, 1H), 3.92-3.84 (m, 1H), 3.79-3.75 (s, 3H), 3.71-3.64 (m, 1H), 3.63-3.56 (m, 1H), 3.39-3.26 (m, 1H), 2.81 (d, 3H), 2.24-2.16 (m, 1H), 1.91-1.83 (m, 1H), 1.11-1.01 (m, 1H). 13C NMR (DMSO-d6) δ 138.06, 137.98, 127.38, 122.00, 14.21, 120.67, 119.98, 110.28, 102.01, 59.38, 56.47, 40.36, 30.96, 24.26, 22.51.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH3:19])[CH:7]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:6]([CH3:19])[CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: C1CCNCC1
Reactant: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CCl
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CN1CCCCC1
Yield: 81.4 %

Procedure:
A solution of 4 g (0.013 mole) of 2-chloro-1-[4-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-2-yl]-ethanone (11) and 4.08 mL (0.039 mole) of piperidine in 60 mL 2-PrOH was heated under reflux for 1 h. The solvent was evaporated in vacuo and the residue was taken up in diethyl ether/THF, washed with water, brine, and dried (MgSO4). Evaporation of the solvent gave a tan solid which was recrystallized from 2-PrOH to give 3.65 g of product: mp 129°-130° C.; mass spectrum (Cl--CH4) m/z=345 (M+1); NMR 300 MHz (CDCl3) d 7.8 (m, 2H); 7.6 (s, 1H); 7.45 (d, 2H); 7.35 (s, 1H); 4.0 (s, 3H); 3.6 (s, 2H); 2.5 (br s, 4H); 1.6 (m, 4H); 1.4 (m, 2H). Anal Calcd for C19H21Cl2N2O2 : C, 66.18; H, 6.14; N, 8.12. Found: C, 66.25; H, 6.16; N, 8.08.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([S:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[O:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:43]=[C:44]([NH2:49])[C:45]([NH2:48])=[CH:46][CH:47]=1.OS([O-])=O.[Na+]>CCO>[F:40][C:41]([F:50])([F:51])[C:42]1[CH:47]=[CH:46][C:45]2[NH:48][C:16]([C:15]3[CH:14]=[CH:13][C:12]([S:9]([CH:8]4[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([O:20][C:21]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:2]4=[O:1])(=[O:11])=[O:10])=[CH:19][CH:18]=3)=[N:49][C:44]=2[CH:43]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=Cc1ccc(S(=O)(=O)C2CCCCN(OC(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1C(S(=O)(=O)c2ccc(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-(2-Oxo-1-trityloxy-azepane-3-sulfonyl)-benzaldehyde prepared from step G (17.4 mg, 0.0322 mmol) and 4-Trifluoromethyl-benzene-1,2-diamine (23.6 mg, 0.13 mmol) in 5.0 ml of anhydrous EtOH was heated to reflux and a 1.2 ml aqueous solution of NaHSO3 (100.1 mg) was added in one portion. The resulting solution was stirred and heated to reflux for overnight. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc and water. The organic phase was washed sequentially with water and saturated NaCl solution, and then dried over anhydrous Na2SO4. The EtOAc solution was concentrated under reduced pressure to give a crude material, which was then purified by a column chromatography (0˜10% EtOAc in hexane and dichloromethane 1:1). MS: 696.2 (M+H)+.