Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:26]([C:2]1[N:3]=[C:4]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccc(F)cc23)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(F)cc23)C1
Temperature: 160 °C
Yield: 65 %

Procedure:
To a solution of (S)-tert-butyl 3-((3-chloro-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1 g, 2.73 mmol) in DMF (10 mL) was added Zn(CN)2 (0.64 g, 5.46 mmol) and Pd(PPh3)4 (0.316 g, 0.273 mmol) under N2. The mixture was heated at 160° C. for 30 minutes in a microwave reactor and was subsequently partition between EtOAc (50 mL) and water (50 mL). The aqueous phase was back-extracted with EtOAc (3×50 mL) and the organic layers were combined and washed with saturated aqueous NaCl (3×50 mL) and concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=20:1-5:1 gradient) to give the title compound (0.65 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 8.19-8.16 (dd, J1=5.2 Hz, J2=3.6 Hz, 1H), 7.97-7.95 (m, 2H), 5.73-5.69 (d, J=16 Hz, 1H), 3.71-3.67 (m, 1H), 3.58-3.50 (m, 3H), 2.25-2.24 (d, J=4 Hz, 2H), 1.42-1.39 (d, J=12 Hz, 9H).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:16])=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:30])[C:19]1[S:20][C:21]([CH:28]=O)=[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=12.N1CCCCC1>C(O)C>[C:1]([C:5]1[O:6][C:7]([CH:16]=[CH:28][C:21]2[S:20][C:19]([N:18]([CH3:17])[CH3:30])=[C:23]3[C:22]=2[O:27][CH2:26][CH2:25][O:24]3)=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C(C)(C)C)O1
Reactant: CN(C)c1sc(C=O)c2c1OCCO2
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1sc(C=CC2=CC(=C(C#N)C#N)C=C(C(C)(C)C)O2)c2c1OCCO2
Temperature: 75 °C
Yield: 48.8 %

Procedure:
As shown in the following reaction 1, 2.14 g (10 mmol) of 2-(2-tert-butyl-6-methyl-pyran-4-ylidene)-malononitrile and 2.13 g (10 mmol) of 7-dimethylamino-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5-carbaldehyde were added into 100 ml of ethanol, and 0.93 g (11 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours. After cooling the reaction solution, the precipitated red solid was filtered, and recrystallized with ethanol to obtain 2 g of the target compound (Yield 48%).
Reaction SMILES: N.[F:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C(OC)=O)=[CH:6][C:4]=1[NH2:5]>CO>[F:2][C:3]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=1[NH2:5]
Reactant: COC(=O)Oc1ccc(F)c(N)c1
Agent: N
Solvent: CO
Product: Nc1cc(O)ccc1F
Reaction time: 2 h
Yield: 72.8 %

Procedure:
Concentrated aqueous ammonia (15 ml) was added to a solution of 2-fluoro-5-methoxycarbonyloxyaniline (400 mg, 2.16 mmol) in methanol (10 ml). The mixture was stirred for 2 hours and most of the solvent was removed by evaporation. The resulting suspension was diluted with water, acidified to pH7 and extracted with ethyl acetate. The organic extracts were washed with water, dried (MgSO4) and solvent removed by evaporation to give 2-fluoro-5-hydroxyaniline (200 mg, 73%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32]O)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.C1(P([N:57]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:57][CH2:32][C:21]1[C:20]([C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:19])=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[O:23][N:22]=1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1)c1c(CO)noc1-c1ccccc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: NCc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reaction time: 8 h
Yield: 47.1 %

Procedure:
Combine [1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone (0.30 g, 0.49 mmol), diphenyl phosphoryl azide (0.13 mL, 0.59 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL, 0.59 mmole) in THF (2 mL) and stir at RT overnight. Filter off the solid and concentrate the filtrate. Dissolve the crude product in THF (2 mL), add triphenylphosphine (0.16 g, 0.59 mmole), and a few drops of water. Stir the mixture overnight. Purify the resulting amine by sequentially passing through a short silica gel column (gradient elution with EtOAc, 2% MeOH in EtOAc, 5% MeOH/2% NH4OH(aq) in EtOAc), a SCX column (elution with 1:1 MeOH/CH2Cl2 and then 3.5 M NH3 in MeOH) and again a short silica gel column (gradient elution with EtOAc, 5% MeOH/2% NH4OH (aq) in EtOAc) to provide a yellow oil (0.14 g, 47%). 1H NMR (400 MHz, CDCl3) δ 4.07 (s, 2H), 5.45 (s, 2H), 7.18–7.25 (m, 3H), 7.30–7.40 (m, 3H), 7.44 (t, J=7.42 Hz, 1H), 7.74 (d, J=7.62 Hz, 1H), 7.87 (s, 1H), 8.81 (m, 2H); MS (ESI) m/z 607.1 (M+1).
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH2:13]([N:20]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([NH:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC(NCc1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
In a dry Schlenk tube under argon was placed (R,R)-Ethylene-1,2-bis(η5 -4,5,6,7-tetrahydroindenyl) titanium (R)-1,1'-binaphth-2,2'-diolate (25 mg, 0.042 mmol) and THF (4 mL). A solution of n-butyllithium (53 μL, 0.084 mmol, 1.6M in hexane) was added and the mixture was stirred for 10 minutes, at which time the color was a dark shade of brown. Phenylsilane (13 μL, 0.105 mmol) was then added and the mixture was stirred for another 10 minutes, the color changing to a darker shade of brown. Acetophenone N-benzyl imine (87 mg, 0.42 mmol) was then added and the reaction vessel was sealed and moved to a dry box. The reaction mixture was transferred to a Parr high pressure reactor, which was sealed and removed from the dry box. The reactor was charged with hydrogen to 1900 psi and heated to 65° C. After stirring for 48 hours the mixture was opened to air and concentrated. The residue was diluted with diethyl ether (20 mL) and extracted with 1N HCl (3×10 mL). The combined aqueous layers were basified with NaOH until strongly basic to pH paper and extracted with diethyl ether (4×25 mL). The organic layers were combined, dried over sodium sulfate and concentrated to produce 82-89% yield of N-benzyl-1-phenylethylamine. The enantiomeric excess (ee), as determined by HPLC analysis of the free amine using a Chiralcel OD column, was 89-92% in favor of the (R)enantiomer.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C>CO>[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a mixture of L-phenylalanine (8.88 g, 53.7 mmol) and 1-fluoro-2,4-dinitrobenzene (3.24 ml, 26.9 mmol) was added triethylamine (7.86 ml, 56.4 mmol). The resulting mixture was warmed using a Biotage Initiator microwave to 100° C. for 4 min. The solid was diluted with MeOH and the slurry was dropped into distilled water. Dichloromethane was added to the slurry and the organic phase was separated. The organic phase was further extracted with 1.2 M hydrogen chloride solution and brine. The organic phase was dried over Na2SO4, filtered and the solvents were evaporated. The residue was diluted with dichlormethane and the slurry was filtered. The precipitate was then washed with a small amount of dichlormethane. The combined filtrates were evaporated and the residue was purified by flash chromatography using a dichloromethane/methanol gradient (0% to 5%) to afford the title compound.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:8][CH:7]=1.O.Cl>O1CCCC1.CO>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9](/[C:12](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:11]=1
Reactant: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(/C(CCCCCCC(=O)O)=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Lithium hydroxide monohydrate (128 mg) was added to a solution of methyl E-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (580 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (528 mg, yield 93%) as colorless crystals. m.p. 69-70° C.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][C:6]([CH3:10])([OH:9])[C:7]#[N:8].N1C=CC=CC=1.C(=O)=O.CC(O)C>CCOCC>[Cl:3][C:1]([O:9][C:6]([C:7]#[N:8])([CH3:10])[CH3:5])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(O)C#N
Agent: O=C=O
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)(C#N)OC(=O)Cl
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Into a one liter round bottom flask equipped with a phosgene inlet tube, a dry ice cooled condenser, a Teflon blade stirrer and a dropping funnel were added 200 milliliters (ml) of anhydrous ether. The flask was cooled in a dry ice/2-propanol bath and 100 ml of liquid phosgene (1.5 moles) were introduced. A mixture of acetone cyanohydrin (85 grams, 1 mole) and pyridine (80 ml, 1 mole) in 400 ml of anhydrous ether was added dropwise to the pool of phosgene, through the dropping funnel. When the addition was completed, the dry ice/2-propanol bath was replaced by an ice bath and stirring was continued for two hours. The reaction mixture was then stirred at room temperature for an additional two hours. Nitrogen was introduced into the reactor through the reactor inlet tube to remove the excess phosgene. The phosgene containing nitrogen gas stream removed from the reactor was forwarded to a packed column into the top of which was sprayed a solution of 15 weight percent sodium hydroxide and 0.8 weight percent pyridine. After degassing, the reaction mixture was filtered and dried over anhydrous magnesium sulfate. The ether solvent was evaporated and 123 grams (72% yield) of 1-cyano-1-methylethyl chloroformate as a light yellow liquid was obtained. Identification of the product as 1-cyano-1-methylethylchloroformate was confirmed by infrared and nuclear magnetic resonance (NMR) spectroscopy.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+]>O>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
A batch type process wherein the catalyst compositions are stirred in from 0.1 to 5.0 molar (preferably 0.5 to 2.0 molar) solutions of ammonium fumarate in water at 5.0 to 10.0 pH (preferably 7.5 to 9.5 pH) for periods of 1.0 to 100 hours (preferably 8 to 48 hours) at temperatures below 60° C. (preferably 20° to 45° C.). Broadly from 0.05 to 50 g of immobilized cells, preferably from 1.0 to 15 g, are used per 1.0 mole of starting ammonium fumarate. After the conversion, the catalyst compositions may be removed by filtration or the equivalent for reuse in converting fresh batches of fumarate solutions. The product solutions are obtained in a form suitable for conventional processing to isolate the L-aspartic acid (acidification, precipitation, filtration, washing, recrystallization, drying).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CCS(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(Br)c(C#N)c1
Yield: 80 %

Procedure:
To 2-bromo-5-(ethylsulfonyl)benzamide (Preparation 74, 2.20 g, 7.53 mmol) in THF (50 mL) with triethylamine (1.57 mL, 11.3 mmol) was added trifluoroacetic anhydride (1.26 mg, 9.04 mmol) dropwise under nitrogen. The reaction was left to stir for 16 hours, before dilution with EtOAc (100 mL) and washing with sodium bicarbonate solution (saturated 100 mL), HCl (1M, 100 mL) and brine (100 mL). The organic phase was dried over MgSO4 and the solvent removed under reduced pressure to give the title compound as a colourless solid in 80% yield, 1.64 g.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1>O1CCCC1.[Ni]>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)C(=O)C=Cc1cccnc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CCc1cccnc1
Yield: 76.9 %

Procedure:
154.2 g (0.814 mol) of 4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one were dissolved in 750 ml of tetrahydrofuran and the solution was stirred with about 20 g of Raney nickel. The solution was filtered, a further 20 g of Raney nickel were added and hydrogenation was carried out under the usual pressure and at room temperature until, according to the thin layer chromatogram, no further starting material was present. The Raney nickel was filtered off from the solution, the filtrate was concentrated and the residue was distilled. 119.8 g (78% of theory) Of 4,4-dimethyl-1-pyridin-3-yl-pentan-3-one of boiling point 123°-130° C./2.3 mm Hg were obtained. ##STR118##
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:9]=2[N:10]=1)(=O)=O.[C:16]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:5]3[N:6]=[CH:7][C:8]4[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:9]=4[N:10]=3)[CH2:30][CH2:31]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)c1ncc2ccc(=O)[nH]c2n1
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Product: O=c1ccc2cnc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2[nH]1

Procedure:
Following the same procedure as in Example H12 and starting from 2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg, 1.332 mmol, U.S. Pat. No. 6,498,163) and 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (416 mg, 1.465 mmol), the title compound was made as a solid (300 mg, 0.683 mmol, 51.3%). MS: APCI: M+1: 430.2 (Exact Mass: 429.22).
Reaction SMILES: [I-].[K+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:26]=1.C(N[CH:31]1[CH2:33][CH2:32]1)CC>O1CCCC1>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][NH:11][CH2:10][CH2:9][CH2:8][CH:31]4[CH2:32][CH2:33]4)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:26]=1
Reactant: CCCNC1CC1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CNCCCC3CC3)n1-2

Procedure:
In the manner given in Example 2, potassium iodide and 8-(methylthio)-1-(chloromethyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with propylcyclopropylamine to give 8-(methylthio)-1-[(cyclopropylpropylamino)methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.[O:24]1[CH2:29][CH2:28]O[CH2:26][CH2:25]1.O1C=CC=C1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[O:24]1[CH:29]=[CH:28][CH:26]=[C:25]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: C1COCCO1
Reactant: O=S(=O)(Oc1ccc(-c2cc3nccnc3[nH]2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccco1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1coc(-c2ccc(-c3cc4nccnc4[nH]3)cc2)c1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-trifluoromethanesulfonyloxyphenyl)-5H-pyrrolo[2,3-b]pyrazine [20 mg, Reference Example 18(e)], dioxane (2.5 mL), furan-2-boronic acid (9.8 mg), sodium carbonate solution (0.06 mL, 2N), and tetrakis(triphenylphosphine)palladium[0] (4 mg) was heated at 180° C. in a microwave oven for 40 minutes. The reaction mixture was then evaporated and the residue was subjected to chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give, after trituration with a mixture of ethyl acetate and methanol, the title compound (7 mg) as a yellow solid. MS: 262.1 (MH+). RT=3.05 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:22][Si](C)(C)C)([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CO.Cl>O>[OH2:22].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[Si](C)(C)OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CO
Product: OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Yield: 186.9 %

Procedure:
A mixture of 7.50 g (0.02 mol) of 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 25 ml of methanol, 2 ml of water and 1.0 ml of concd. hydrochloric acid was stirred at 30° C. for 1 h. The reaction mixture was concentrated to a volume of 10 ml and after adding 50 ml of water the pH of the hot solution was adjusted to 8 with 10% aqueous sodium hydroxide. After cooling the precipitated crystals were filtered off, and dried at 40° C. until the weight was constant to yield 6.06 g (93.5%) of the title compound. M.p.: 139–140° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(C)([O-])C.[K+].Br[CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[C:41]1([O:47][CH3:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:48][O:47][C:41]1([C:32]2[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:40])[F:39])=[CH:36][C:31]=2[CH2:30][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CBr)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26 mg; 0.079 mmol) in tetrahydrofuran (0.3 mL) was added potassium t-butoxide (80 uL; 0.08 mmol; 1.0M in tetrahydrofuran). A solution of 2-(bromomethyl)-1-(1-methoxycyclohexyl)-4-(trifluoromethyl)benzene (25 mg; 0.071 mmol) in tetrahydrofuran (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours. The reaction was quenched with 2 drops of water. The mixture was diluted with ethyl acetate and filtered through a column containing silica and sodium sulfate and concentrated. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-45% ethyl acetate in heptane) to give 25 mg (59%) of a colorless gum. MS (ES+): Calc: 595.5, Found: 596 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.73 (s, 2H), 7.48 (d, J=7.47 Hz, 2H), 7.42 (d, J=8.30 Hz, 1H), 5.14 (s, 2H), 4.79 (s, 2H), 4.20 (s, 3H), 2.92 (s, 3H), 2.12 (d, J=11.62 Hz, 2H), 1.77-1.52(m, 8H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].Cl>ClCCl>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl alcohol (1 mL) and triethylamine (2.69 mL) in dichloromethane (15 mL) was added 4-bromobutyryl chloride (1.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1) to give benzyl 4-bromobutyrate (2.45 g). To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.17 g) in acetone (3 mL) were added cesium carbonate (0.16 g), benzyl 4-bromobutyrate (0.1 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−3/1) to give 1-(3-benzyloxycarbonylpropyl)-3-(β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.14 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-dichloromethane/methanol=15/1) to give the title compound (95 mg).