Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13](N)[C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)[CH2:3]1.N1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[C:27]([F:35])[CH:26]=1>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:13]2[N:14]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:32])=[O:33])=[C:27]([F:35])[CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1S(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 38.8 %

Procedure:
6-[(3R,5S)-3,5-Dimethyl-1-piperazinyl]-3-(methyloxy)-2-pyridinamine (D7, Method D) (2.25 mmol) was dissolved in DCM (5 mL) and pyridine (5 mL) and then cooled to 0° C. 4-Bromo-2-fluoro benzenesulfonyl chloride (0.738 g, 2.706 mmol), dissolved in DCM (5 mL) was then added dropwise and the reaction then allowed to warm to rt overnight. The reaction was then evaporated to a minimum and redissolved in DCM (100 mL) and washed with water (2×75 mL), saturated sodium hydrogen carbonate (3×75 mL) and brine (75 mL). The organic layer was dried (MgSO4) and evaporated to give a brown oil which was triturated with methanol and dried at 50° C. under high vac to give the title compound as a pale brown powder (D18) (0.400 g). MS (ES+) m/e 473/475 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH2:3]([O:4][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13])[C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)CO
Product: CC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 80 %

Procedure:
Prepared as in Example 215c from 2,2-dimethylpropan-1-ol and 2,6-dinitrobenzonitrile in 80% yield. MS 235 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][C:7]=2[N:8]=1.Cl>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Agent: Cl
Product: CSc1ncc2c(n1)CNC2
Reaction time: 1 h

Procedure:
To 1.5 g of the product from Step A was added 15 mL (4.0 M in 1,4-dioxane) of hydrochloric acid and the solution stirred for 1 h and then concentrated in vacuo. The crude residue was chromatographed on a Biotage® system (silica gel, 0 to 50% methanol/ethyl acetate, 1% ammonium hydroxide) to give the title compound as a white solid. LC/MS 167.3 (M+1).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: N
Product: FC(F)(F)c1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3-(trifluoromethyl)benzene (Aldrich, 85 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.76 (m, 1H), 7.81-7.96 (m, 2H), 7.98 (s, 1H), 8.20-8.30 (m, 2H), 8.41 (dt, J=8.1, 1.9 Hz, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 9.17 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]3[C:17](=[O:32])[CH:18]=[C:19]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[O:20][C:15]=3[C:14]=2[CH2:35][CH2:36][CH3:37])=[C:6]([CH2:41][CH2:42][CH3:43])[C:5]=1[OH:44])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]3[C:17](=[O:32])[CH:18]=[C:19]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[O:20][C:15]=3[C:14]=2[CH2:35][CH2:36][CH3:37])=[C:6]([CH2:41][CH2:42][CH3:43])[C:5]=1[OH:44])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2ccc3c(=O)cc(-c4ccc(C(=O)OCC)cc4)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(OCC(O)COc2ccc3c(=O)cc(-c4ccc(C(=O)O)cc4)oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
This ester was hydrolysed by heating under reflux with 30 mls of 10% sodium carbonate solution and 30 mls of ethanol for one hour. The solution was acidified to give a solid which was crystallised from ethanol three times to give 1.4g of 4-(7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy] -4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoic acid, melting point, 204°-206°C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12].[CH3:19]O>>[F:6][C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH:10]([OH:14])[C:11]([O:13][CH3:19])=[O:12]
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
2 ml of sulfuric acid at 95% by mass are added to 2 g of 3,5-difluoromandelic acid in solution in 25 ml of methanol, and the mixture is kept under reflux for 6 hours. The medium is concentrated, the residue is taken up in ethyl acetate and washed with a sodium hydroxide solution (0.1 N). The organic phase is dried over anhydrous sodium sulfate and 2 g of oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1.O=[C:24]([CH3:38])[CH2:25][CH2:26][N:27]1C(=O)C2C(=CC=CC=2)C1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:38])[CH2:25][CH2:26][NH2:27])[CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(Cl)cc3)Oc3ccccc3O2)CC1

Procedure:
Using general procedure B with the above amine (221 mg, 0.70 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (305 mg, 1.40 mmol) and then using general procedure D afforded 3-{4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (185 mg, 68% over 2 steps).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCCN1CCC(c2ccccc2)CC1

Procedure:
1-(3-Chloropropyl)-4-phenylpiperidine can be obtained as follows: a solution of 4-phenylpiperidine (8 g) and of 1-bromo-3-chloropropane (20 cc) in acetonitrile (80 cc) is stirred at 25° C. for 24 hours with potassium carbonate (28 g). The mixture is filtered and is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.06-0.2-mm particle size, 3-cm diameter, 25-cm height) and eluted with a mixture of cyclohexane and ethyl acetate (50--50 by volume), 60-cc fractions being collected. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1-(3-Chloropropyl)-4-phenylpiperidine (8 g) is obtained in the form of oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[Na+].C(NC([N:43]1[CH2:49][CH2:48][C@@H:47]2[C@H:44]1[C:45](=[O:54])[N:46]2S([O-])(=O)=O)=O)C1C=CC=CC=1>O1CCCC1.ClCCl.CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9](/[CH:12]=[CH:13]/[C:14](=[O:16])[N:43]2[CH2:49][CH2:48][C@@H:47]3[C@H:44]2[C:45](=[O:54])[NH:46]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(O)/C=C/c1ccc(NC(=O)CCl)cc1
Reactant: O=C(NCc1ccccc1)N1CC[C@@H]2[C@H]1C(=O)N2S(=O)(=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc(/C=C/C(=O)N2CC[C@H]3NC(=O)[C@H]32)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(E)-3-(4-Chloroacetylaminophenyl)acrylic acid (1.44 g, 6.0 mmol) was suspended in 50 ml of tetrahydrofuran, treated with 0.66 ml (6.0 mmol) of N-methyimorpholine and cooled to -10° C. Subsequently, 0.8 ml (6.0 mmol) of isobutyl chloroformate was added dropwise thereto, the mixture was stirred for 30 minutes while cooling and then, at room temperature overnight. The solvent was removed in a vacuum, the residue was taken up in ethyl acetate and extracted twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated. The thus-obtained mixed anhydride was diluted in 25 ml of dichloromethane and added dropwise to a solution of 500 mg (4.5 mmol) of (1S,5R)-2,6-diazabicycio[3.2.0]heptan-7-one (Example 2) dissolved in 25 ml of dichloromethane and 4 ml of dimethylformamide. The mixture was left to react overnight and the product which separates was filtered off under suction. The latter was purified by chromatography (silica gel, 1. ethyl acetate, 2. ethyl acetate/ethanol=3:2). Yield: 1.0 g (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:32]\[OH:33])=[C:4]([F:30])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2cccc(S(C)(=O)=O)c2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2cccc(S(C)(=O)=O)c2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(3-(methylsulfonyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=463.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[F:29][C:26]1[CH:25]=[C:17]([CH:16]=[C:15]([F:14])[C:27]=1[F:28])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Nc1ccn(Cc2cc(F)c(F)c(F)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4cc(F)c(F)c(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3,4,5-trifluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil (yield=42%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([N+:20]([O-])=O)=[CH:12][C:3]=1[C:4]([N:6]([S:8]([CH3:11])(=[O:10])=[O:9])[NH2:7])=[O:5].O.O.[Sn](Cl)Cl.N>Cl>[NH2:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]([NH2:20])=[CH:12][C:3]=1[C:4]([N:6]([S:8]([CH3:11])(=[O:10])=[O:9])[NH2:7])=[O:5]
Reactant: CS(=O)(=O)N(N)C(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Product: CS(=O)(=O)N(N)C(=O)c1cc(N)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 80 mg (0.23 mmol) of N-(2-amino-5-nitro-4-trifluoromethyl-benzoyl)-methanesulfonhydrazide in 1.5 ml of conc. hydrochloric acid, 270 mg (1.17 mmol) of tin(II) chloride dihydrate is added and the mixture is stirred at room temperature for 20 min. The mixture is neutralized at 0° C. with an aqueous solution of ammonia. The product is extracted with ethyl acetate. The combined organic fractions are dried, evaporated and purified by flash-master chromatography (0-70% gradient cyclohexane/ethyl acetate) to yield N-(2,5-diamino-4-trifluoromethyl-benzoyl)-methanesulfonhydrazide as hydrochloride salt. M.p. 220.8 -225.5° C.; 1H-NMR ; DMSO-d6 (400 MHz, ppm): 6.98 (s, 1H, aromatic); 6.88 (s, 1H, aromatic); 2.98 (s, 3H, S02-CH3). LC-MS: 313 [M+H]+; Agilent LCIMSD 1100 Series; LC-MS method: Column: SunFireC 18, 4.6*50 mm, 3.5 μm; positive MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][OH:8])[CH3:5].[CH3:9][O:10][C:11]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:12]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=1)=[O:14]>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:12]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([O:8][CH2:7][CH2:6][N:4]([CH3:5])[CH3:3])=[O:22])[N:20]=1)=[O:14]
Reactant: CN(C)CCO
Reactant: COc1cc(OC)c(C(=O)Nc2nc(C(=O)O)cs2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Nc2nc(C(=O)OCCN(C)C)cs2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In 10 ml of N,N-dimethylformamide, 278 mg of sodium hydride was suspended. To the resulting suspension, 620 mg of N,N-dimethylaminoethanol was added dropwise, followed by stirring at room temperature for one hour. In another 10 ml portion of N,N-dimethylformamide, 1.57 g of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(hydroxycarbonyl)-1,3-thiazole was suspended. To the resulting suspension, 827 mg of carbonyl diimiazole was added, followed by stirring at room temperature for one hour. Two reaction mixtures so obtained were combined and were stirred at 100° C. for one hour. The reaction mixture was poured into an ice water and the crystals so precipitated were collected by filtration. The crystals so obtained were recrystallized from isopropyl alcohol, whereby 1.4 g of the title compound was obtained. Yield: 74%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[C:10]1(=[O:36])[N:14]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:13](=[O:31])[C:12]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:11]12.C(N(CC)CC)C>CN(C=O)C>[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]([CH2:16][CH2:15][N:14]1[C:13](=[O:31])[C:12]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:11]2[C:10]1=[O:36])[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])#[N:9]
Reactant: N#CCCCCCCBr
Reactant: O=C1c2ccccc2C(=O)N1CCNCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCCCCCCN(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 40.9 %

Procedure:
A mixture of 6-bromohexylcyanide (13.88g, 0.073 mol), bis(2-phthalimidoethyl)amine (26.52g, 0.073 mol), and triethylamine (7.37g, 0.073 mol) in DMF (120 ml) was heated at 100° C. for 20 hours. After cooling, the precipitate which had formed was removed by filtration and the filtrate was poured into ice (1000 ml). The aqueous solution was extracted with dichloromethane (3×200 ml). The combined organic extracts were washed with brine and dried over Na2SO4. Removal of the solvent under reduced pressure gave crude product which was chromatographed on silica gel (hexanes - 30% ethyl acetate/hexanes gradient elution). Impure fractions were rechromatographed to provide a total of 14.1g of (6-cyanohexyl)bis(2-phthalimidoethyl)amine (41%) as an oil. The produce was one spot on tlc. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[N:3]=1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[CH:10]1([C:9]2[C:2]([O:29][C:27]3[CH:26]=[CH:25][C:24]4[B:20]([OH:30])[O:21][CH2:22][C:23]=4[CH:28]=3)=[N:3][C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[C:5]([CH:8]=2)[C:6]#[N:7])[CH2:12][CH2:11]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(C2CC2)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinonitrile (360 mg, 1.29 mmol), compound benzo[c][1,2]oxaborole-1,5(3H)-diol (232 mg, 1.55 mmol) and Cs2CO3 (505 mg, 1.55 mmol) in DMSO (20 mL) was stirred at 40° C. overnight. The mixture was diluted by water, extracted by EtOAc, the separated organic layer was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether:EtOAc=10:1-3:1) to afford 5-cyclopropyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(4-oxopentyloxy)nicotinonitrile. (200 mg, 40%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.20 (s, 1H), 7.86 (s, 1H), 7.75 (d, J=8.0, 1H), 7.24 (d, J=2.0, 1H), 7.16 (dd, J=8.0, 2.0, 1H), 4.97 (s, 2H), 3.94 (t, J=7.8, 2H), 3.29 (t, J=7.8, 2H), 2.02 (m, 4H), 1.65 (t, J=7.8, 2H), 0.92 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH:8]=1)(=O)=O.[C-:31]#[N:32].[Na+]>C(#N)C.[Cu]I.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:31]([C:7]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:9][CH:8]=1)#[N:32]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(OS(=O)(=O)C(F)(F)F)c3ccccc32)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC=C(C#N)c3ccccc32)CC1
Yield: 92.5 %

Procedure:
A mixture of the triflate (A2) (447 mg, 1 mmol), sodium cyanide (100 mg, 2 mmol), copper (I) iodide (19 mg, 0.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) in acetonitrile (10 ml) was degassed and heated under reflux under nitrogen for 4 h. After concentration, the residue was directly purified by flash chromatography (hexane/EtOAc 8:2) to give tert-butyl 4-cyano-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A3) (300 mg). LC-MS: m/e=269.0 (M+H−C(CH3)3. Rt=3.75 min. 1H-NMR (500 MHz, DMSO-d6): 7.49 (d, 1H), 7.42-7.36 (m, 3H), 7.09 (t, 1H), 3.81 (br. d, 2 H), 3.03 (br. s, 2H), 2.67 (d, 2H), 1.70 (td, 2H), 1.62 (d, 2H), 1.41 (s, 9H),
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([O:8]C)=O)=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17].[CH2:18]([NH2:21])[CH2:19][CH3:20]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([NH:21][CH2:18][CH2:19][CH3:20])=[O:8])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17]
Reactant: CCCN
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 92 %

Procedure:
The acid 2-2 (1.41 g, 5.3 mmol) was heated to reflux in thionyl chloride (20 mL) for 2 h. After cooling, the volatiles were removed in vacuo and the residue was azeotroped with toluene. The resulting acid chloride was dried at high vacuum and then dissolved in anhydrous CH2Cl2 (50 mL), cooled to 0° C. then treated with propylamine (2.45 mL, 29.9 mmol). The reaction was warmed to room temperature for 2 h. The solvent was removed in vacuo and the residue was taken up in EtOAc and brine. The aqueous layer was extracted three times into EtOAc and the combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to provide the amide in which R is propyl 4-5 as a light orange solid. (1.5 g, 92% yield). 1H NMR (400 MHz, d6-DMSO) δ 0.91 (t, J=7.0 Hz, 3H), 1.40 (q, J=7.0 Hz, 2H), 3.07 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 8.13 (s, 1H), 8.84 (br s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]>C(O)(C)C.[Ni]>[C:1]([O:4][C@@H:5]1[C@@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[NH2:19])[CH2:8][C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C[C@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ni]
Solvent: CC(C)O
Product: CC(=O)OC[C@@H]1C[C@H](Nc2cc(Cl)c(Cl)cc2N)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (4.30 g, 9.28 mmol) in isopropanol (250 mL) was shaken with Raney nickel (Aldrich, slurry in water, 400 mg wet) under hydrogen (50 psi) on a Parr shaker for 2.75 hours. Catalyst was filtered off with Celite and the filtrate-wash (350 mL) stored at -5° C. Yellow crystals of title compound formed slowly (2.35 g, 58%), m.p. 124°-125° C.; 1H-NMR(DMSO-d6) δ: 6.70 and 6.57 (both s, 1 each, 2 aromatic CH), 5.15-4.9 (m, 5, NH2, NH, and 2 OCH), 4.2-4.0 (m, 2, CH2O ), 3.9-3.75 (m, 1, NCH), 2.5-2.4 (m overlapping solvent, CH2), 2.07, 2.04, and 2.01 (all s, 9,3 CH3), 1.4-1.2 (m, 1, CH); mass spectrum(CI): 433(M+1)
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)(=O)C.[OH-].[Na+]>C(O)C>[C:17]1([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][OH:4])[CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OCc1ccccc1-c1cc(-c2ccccc2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccccc1-c1cc(-c2ccccc2)on1

Procedure:
A mixture of o-(5-phenyl-3-isoxazolyl)benzyl acetate, 35.2 ml. (0.352 mole) of 1 N sodium hydroxide solution and 95 ml. of ethanol is stirred for 4 days at room temperature. The ethanol is removed in vacuo and the aqueous material extracted with methylene chloride. The methylene chloride is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether/petroleum ether to give o-(5-phenyl-3-isoxazolyl) benzyl alcohol; m.p. 68° to 70° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:31][O:32][CH2:33][CH2:34][C:35]([NH:37][NH2:38])=O>>[CH3:31][O:32][CH2:33][CH2:34][C:35]1[O:30][C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)=[N:38][N:37]=1
Reactant: COCCC(=O)NN
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: COCCc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)o1

Procedure:
100 mg (0.15 mmol) of the compound from Example 108A and 36 mg (0.31 mmol) of 3-methoxypropanehydrazide were reacted according to the General Method 4. Yield: 5 mg (7% of theory).