Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21](=[O:42])[CH2:22][N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:33])=[CH:24]4)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].CO.O1CCCC1>C([O-])(=O)C.[NH4+]>[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH:21]([OH:42])[CH2:22][N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]([O:34][CH2:35][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[O:33])=[CH:24]4)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cn4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(C(O)Cn4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1

Procedure:
Sodium borohydride (4 mg) was added to a solution of benzyl 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-oxoethyl}indole-3-carboxylate in a mixed solvent of methanol (1 ml) and tetrahydrofurane (5 ml). After being stirred for several hours, the reaction mixture was diluted with aqueous ammonium acetate solution, which was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give benzyl 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-hydroxyethyl}indole-3-carboxylate (70 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[Sn](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(O)C>[NH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1cc(Br)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Br)c(C#N)cc1N
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-methyl-5-nitrobenzonitrile (500 mg, 2.07 mmol) in ethanol (20 mL) was added tin chloride (785 mg, 4.14 mmol). The mixture was refluxed for 5 h. After cooling to room temperature, triethylamine (1.01 g, 10 mmol) was added. The mixture was concentrated and purified by silica chromatography (30-50% ethyl acetate in hexanes gradient) to afford 5-Amino-2-bromo-4-methylbenzonitrile a as beige solid; ESMS m/z 211 (M+H+).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]([CH3:18])=[CH2:17]>CC(C)=O>[CH3:17][C:16](=[CH2:15])[CH2:18][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)CC(C(C)=O)C(C)=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
A mixture of acetylacetone (2.5 g, 25 mmol), K2CO3 (3.45 g, 25 mmol) and 3-bromo-2-methylpropene (2.5 mL, 25 mmol) in acetone (80 mL) is stirred at 50° C. for 3 days. The mixture is filtered, the filtercake washed with few acetone and the filtrate evaporated to give 2.48 g of 3-(2-methyl-allyl)-pentane-2,4-dione as a dark oil that is used without further purification in subsequent steps; LC-MS: tR=0.87 min, [M+1]+=155.26.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C[O-].[Na+]>CO>[Cl:13][C:14]1[C:15]([F:22])=[C:16](/[CH:17]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[O:11][CH3:12])\[C:7]#[N:8])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: COc1cc(Cl)ccc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Yield: 65.2 %

Procedure:
Step C In a manner similar to the method described in Example 1b, 4-chloro-2-methoxybenzyl cyanide (1.8 g, 10 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (2 g, 13 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50° C. for 2 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)-acrylonitrile as a white powder (2.1 g, 65%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)=[CH:10][N:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[C:30]([C:35]([F:38])([F:37])[F:36])=[N:31][CH:32]=[CH:33][CH:34]=2)O1.CC([O-])=O.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(O)CCC>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([C:29]2[C:30]([C:35]([F:38])([F:37])[F:36])=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:7]=[CH:6]3)=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: CC1(C)OB(c2cccnc2C(F)(F)F)OC1(C)C
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 57.1 %

Procedure:
A 500 mL flask is charged with 6-chloro-2-(4-methyl-3-nitro-phenyl)imidazo[2,1-f]pyridazine (10.104 g, 0.035 mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (Journal of Organic Chemistry, 2011, 76, 1062) (13.38 g, 0.049 mol), KOAc (6.869 g, 0.07 mol), bis(dibenzylideneacetone)palladium(0) (2.01 g, 3.5 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (3.34 g, 0.007 mol), butanol (112 mL) and water (20 mL). The reaction mixture is heated at 90° C. for 4 hr. The reaction is filtered through celite and washed with EtOAc. The liquid layers are combined, concentrated onto celite and purified by silica gel chromatography (0-75% EtOAc in CH2Cl2) to give the title compound (7.98 g, 60% yield). LCMS (m/z)=400.4 [M+H]+, tR=2.76 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-iodobenzoic acid (1.0 equiv) in dry DMF (0.5 M) under argon was added solid potassium carbonate (1.5 equiv) followed by benzyl bromide (1.1 equiv). The resulting mixture was stirred at rt for 4 h, acidified with 10% HCl, diluted with brine and ethyl acetate, and the layers were separated. The organic layer was washed with brine (5×), dried (MgSO4), filtered and concentrated in vacuo to afford a solid, benzyl 3-iodobenzoate (4), which was used without further purification.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5](N)[CH:4]=1.BrBr.N([O-])=O.[Na+].N([O-])=O.[OH-].[Na+]>>[Br:1][C:5]1[CH:4]=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(C)nc(Br)c1
Temperature: 20 °C
Yield: 49.3 %

Procedure:
A solution of 48% HBr (aq) (Aldrich, 65 mL, 1.2 mol, 10 eq) was cooled to −5° C. and treated with 4,6-dimethyl-pyridin-2-ylamine (Aldrich, 15.0 g, 0.12 mol. 1.0 eq). The thick white salt mixture was stirred with a mechanical stirrer while bromine (Aldrich, 19.7 mL, 0.38 mol, 3.1 eq) was added dropwise. The resultant red mixture was treated with an aqueous solution (32 mL H2O) of NaNO2 (Aldrich, 22.1 g, 0.32 mol, 2.6 eq) over one hour. The temperature was maintained below 5° C. during the nitrite addition, and then gradually warmed to 20° C. over 2 hours. The reaction mixture was adjusted to pH 14 with NaOH (aq), and extracted with MTBE. The organic extracts were washed with water, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product (29 g of a red oil) was purified by flash chromatography (silica, 350 g) and eluted with 2–7% ethyl acetate-cyclohexane, which gave an orange oil (11.0 g, 48%). 1H NMR (DMSO-d6, 300 MHz) δ 7.30 (1H, s), 7.13 (1H, s), 2.39 (3H, s), 2.26 (3H, s). 13C NMR (DMSO-d6, 75 MHz) δ 159.4, 151.3, 140.9,125.7,124.0, 23.7, 20.3. ESI m/z 186/188 (M +H)+.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])C.O[NH:26][C:27](=[NH:30])[CH2:28][CH3:29]>>[C:15]([O:14][C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([C:4]2[O:5][N:30]=[C:27]([CH2:28][CH3:29])[N:26]=2)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCC(=N)NO
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccccc1
Product: CCc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1

Procedure:
Prepared from 2-tert-butoxycarbonylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester and N-hydroxy-propionamidine.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:19]3[CH:24]4[CH2:25][CH2:26][CH:20]3[CH:21]=[C:22](OS(C(F)(F)F)(=O)=O)[CH2:23]4)=[O:18])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[Li+]>[Cl-].[Na+].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.COCCOC.O>[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:19]3[CH:24]4[CH2:25][CH2:26][CH:20]3[CH:21]=[C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23]4)=[O:18])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: O=C(c1ccc2c(c1)OCCO2)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Reactant: OB(O)c1ccccc1
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccc2c(c1)OCCO2)N1C2C=C(c3ccccc3)CC1CC2
Temperature: 25 °C

Procedure:
2 M aqueous Na2CO3 solution (1.0 mL) is added to a flask charged with a stir bar, trifluoro-methanesulfonic acid 8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester (0.40 g), phenylboronic acid (0.13 g), lithium chloride (87 mg), Pd(PPh3)4 (60 mg), water (2 mL), and 1,2-dimethoxyethane (10 mL) in argon atmosphere. The resulting mixture is stirred at reflux temperature for 4 h. After cooling to ambient temperature, brine is added and the mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0→2:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:8]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCNC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a solution of 3-methoxy-5-nitrobenzoic acid (1 g; 5.1 mmol; 1 eq) DCM (40 mL) is added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (972 mg; 5.1 mmol; 1 eq). After 5 min, 2-methoxyethylamine (381 mg; 5.1 mmol; 1 eq) is added and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture is then quenched with water and the expected product extracted with EtOAc. The organic phase is washed with an aqueous solution of Na2CO3 then dried over MgSO4. The solvent is evaporated to dryness to afford (1.3 g (100%) of the title compound as an orange oil. HPLC (max plot) 73.0%; Rt 2.98 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[CH2:6][C:7]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccc(F)cc2N1
Product: CC(=O)N1C(=O)Cc2ccc(F)cc21
Temperature: 25 °C

Procedure:
At 130° C., 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 ml acetic anhydride for 3 hours. After cooling to room temperature, the precipitate is filtered off with suction, washed with 100 ml of petroleum ether and dried.
Reaction SMILES: [C:1]([CH:4]([CH2:19][CH2:20][CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][O:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(C(CCCC(OC(=O)C)CCCCC)CCCC1C=CC(C(OCC)=O)=CC=1)(=O)C>>[C:1]([CH:4]([CH2:19][CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][O:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCOCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)C(C)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)C(C)=O)OC(C)=O
Product: CCCOCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
This compound is prepared by the method described in Example 1, Step F, except that the product of Step C of the present example replaces ethyl 4-(4-acetyl-8-acetoxytridecyl)benzoate. The title compound is purified by column chromatography on silica gel with 4% methanol in chloroform as the eluant. The title compound is a light yellow, viscous oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>C(OC(C)C)(C)C>[CH2:16]([NH:20][C:21]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: CC(C)OC(C)C
Product: CCCCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A solution of 6.5 g (0.03 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether was stirred under a blanket of nitrogen while 4 g (0.04 mole) of n-butyl isocyanate was added dropwise. The reaction was slightly exothermic and after 30 min, a solid separated. The solid was collected by filtration after 3 hr to give 3.85 g of crystalline product, m.p. 135°-136° C. After 24 hr, a second bath of crystals was obtained; 1.5 g; m.p. 132°-134° C. The two fractions were combined and recrystallized from cyclohexane to yield 3.6 g of product (38%), m.p. 136°-137° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Cl-].[OH:25][NH3+:26]>C(O)C>[OH:25][N:26]=[C:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1
Reactant: [NH3+]O
Reactant: O=C1CCC(Oc2ncnc3c2CCCC3)CC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCC(Oc2ncnc3c2CCCC3)CC1

Procedure:
A solution of 3.8 g (15.5 mmol) of 4-(cyclohexanone-4-oxy)-5,6,7,8-tetrahydroquinazoline in 50 ml of distilled ethanol is first treated with 2.9 g (34.2 mmol) of sodium acetate and then with 2.2 g (31.0 mmol) of hydroxyl ammonium chloride. The reaction mixture is refluxed for 4 hours, and the crystallized product (1.8 g) is subsequently removed by filtration with suction.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=O)[N:11]([CH3:17])[C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N1CC2N(C)C(CC2)C1)C1C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH3:17])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C2CCC(C1=O)N2Cc1ccccc1
Agent: CN1C2CCC1CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CC2CCC(C1)N2Cc1ccccc1

Procedure:
Reduction of 9.6 g (0.039 mole) of 8-benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione with lithium aluminum hydride in tetrahydrofuran by the procedure used for the preparation of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane, as described in Example 1, gave 8.3 g of crude desired product. Chromatography on 124 g alumina with chloroform elution gave 6.9 g (81%) of pure, oil 8-benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane. The hydrochloride salt, formed in diethyl ether by addition of three equivalents of ethanolic hydrogen chloride, melted at 263.5°-272° C (dec.) with sublimation above 180° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])(C)C.Cl[C:16](OCC=C)=O>ClCCl.C(N(C(C)C)CC)(C)C>[CH2:1]([O:5][C:6]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])[CH:4]=[CH2:16]
Reactant: CC(C)(C)OC(=O)C(N)CCCCN
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C(N)CCCCN
Temperature: 0 °C

Procedure:
Mono-t-butyloxycarbonyl (BOC) 1,5-pentanediamine was synthesized by using 1,5-diaminopentane (12.5 g, 122 mmol) in place of 1,3-diaminopropane in the synthesis of mono-allyloxycarbonyl-1,3-diaminopropane described in Example 1 above, yielding 10 g (49 mmol) of mono-tert-butyloxycarbonyl-1,5-diaminopentane (1). The mono-tert-butyloxycarbonyl-1,5-diaminopentane (1) (5.8 g, 28.7 mmol) was dissolved in 75 mL of dichloromethane with 7.5 mL of diisopropylethylamine and cooled to 0° C. A solution of allyl chloroformate (3.3 mL) in dichloromethane (25 mL) was added over five minutes. The reaction was allowed to warm to room temperature for one hour and then solvent was removed by rotary evaporation. The residue was dissolved in 100 mL of ethyl acetate and washed with three 100 mL portions of 10% citric acid, once with 100 mL saturated aqueous sodium bicarbonate and once with 100 mL of saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and solvent was removed by rotary evaporation. The resulting oil (2) was treated with 25 mL of trifluoroacetic acid for 30 minutes. The trifluoroacetic acid was removed by rotary evaporation and the resulting reside was twice dissolved in dichloromethane and then evaporated to remove residual solvent. The residue was dissolved in 50 mL of 3N hydrochloric acid and washed with two 50 mL portions of dichloromethane. The aqueous phase was cooled in an ice bath and the pH was adjusted to approximately 13 with 50% aqueous sodium hydroxide. The basic aqueous phase was extracted with three 100 mL portions of dichloromethane, the combined organics were washed with 100 mL of saturated aqueous sodium chloride and then dried over potassium carbonate. The mixture was filtered, the solvent removed first by rotary evaporation and then by high vacuum to yield 3.95 g of mono-allyloxycarbonyl-1,5-diaminopentane (3) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:20]([C:19]([OH:22])=[O:21])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 110 °C
Reaction time: 6.5 h

Procedure:
To 10.0 g of 3-(3-fluorophenyl)-1H-5-indazolecarbonitrile were sequentially added 50 ml of glacial acetic acid, 15 ml of water and 12 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 6.5 hours. After standing to cool, the reaction mixture was added with 150 ml of ice-water, and the resulting crystals were collected by filtration. The resulting crystals were dried in vacuo, to give 10.7 g of the title compound as beige orange-pink crystals.
Reaction SMILES: C(O)C.O.NN.[CH2:7]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:10]1=2)[CH3:8]>[Pd].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:10]2[N:9]([CH2:7][CH3:8])[C:15](=[O:16])[CH2:14][CH2:13][C:12]([CH3:17])([CH3:18])[C:11]=2[CH:19]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Yield: 73 %

Procedure:
Added 30 mL of ethanol, 10% Palladium on activated carbon, 50% wet with water for safety (273 mg), and hydrazine monohydrate (400 ul) to 1-Ethyl-5,5-dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (537 mg, 2.047 mmol). Heated reaction to 60° C. for 24 hours. Filtered reaction through Celite, and concentrated under reduced pressure. Purified with normal phase silica gel chromatography eluting with 40% to 60% ethyl acetate in hexane to obtain a yellow sticky solid, 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (347 mg, 73%). LCMS: m/z=233.07 (M+H+), 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, 1H, J=8.9 Hz), 6.59 (d, 1H, J=1.8 Hz), 6.48 (dd, 1H, J=8.3, 1.5 Hz), 5.08 (s, 2H), 3.58 (m, 2H), 1.96 (m, 4H), 1.17 (m, 9H).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:34])[CH2:23][C:24]=1[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[CH:20]([NH:35]C(OC(C)(C)C)=O)[C:19]2=[O:43])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[NH2:35][CH:20]1[C:19](=[O:43])[N:18]2[CH:21]1[S:22](=[O:34])[CH2:23][C:24]([CH2:25][C:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(=O)c3ccccc3)CS(=O)C12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(=O)c3ccccc3)CS(=O)C12
Temperature: 35 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (10.1 g) is added to a solution of p-toluenesulphonic acid monohydrate (8.15 g) in acetonitrile (170 cc), warmed to 35° C., and the mixture is left at 35° C. for 1 hour, whilst stirring. The reaction mixture is then poured into a stirred mixture of a saturated solution of sodium bicarbonate (150 cc) and ethyl acetate (300 cc). The organic phase is then washed with distilled water (100 cc), dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields crude 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (7 g) in the form of a thick oil which can be used without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Brc1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.98 g, 3.0 mmol) and commercially available 4-bromo-imidazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.78 g, 59%). MS (EI) 438.0 [(M)+]; mp 184.5° C.