Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32]O)=[CH:25][CH:24]=1.N1C=CN=C1>C(Cl)Cl>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][Br:20])=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: OCCCCc1ccc(O)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(CCCCBr)cc1
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
A solution of triphenylphosphine (144.1 mmole, 37.80 g) in methylene chloride (556 ml) was treated with bromine (144.1 mmole, 23.03 g) until a pale yellow color persisted. After stirring approximately 15 minutes, a solution of 4-(4-hydroxyphenyl)butanol (96.1 mmole, 15.97 g) and imidazole (192.2 mmole, 13.08 g) in methylene chloride (355 ml) was added over a 15 minute period. Approximately 4 hours later, the reaction suspension was filtered and the filtrate was reduced in volume. To the reduced filtrate was added silica gel and the suspension was reduced to dryness. This material was filtered and the first six fractions were eluted with 10% ethyl acetate: hexane. Fractions 7 through 12 were eluted with 20% ethyl acetate: hexane. Fractions 7 through 10 were combined, reduced in volume, dried over sodium sulfate, filtered and concentrated in vacuo to afford 19.32 g (88%) of the title compound as an oil.
Reaction SMILES: IC1C=CC(N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=CC=1.[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][N:9]=[C:10]2[C:11]([NH2:12])=[N:30][N:29]=[C:13]2[NH2:14])=[CH:18][CH:17]=1
Reactant: Nc1ccc(I)cc1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc(I)cc1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(I)cc1

Procedure:
4-[(4-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 148 mg (0.5 mmol) of 2-[(4-iodophenyl)hydrazono]malononitrile, which was derived from 4-iodoaniline (219 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 114 mg (70%) of the compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][OH:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C[N+]1([O-])CCOCC1.CC(O)C>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH:13]=[O:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CO)cccn2n1
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CC#N
Product: Cc1cc2c([C@@H]3C[C@H]3C=O)cccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Trans-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanol (2000 mg, 9.89 mmol), 4 Å molecular sieves (800 mg), 4-methylmorpholine N-oxide (1.74 g, 14.8 mmol) and tetra-n-propylammonium perruthenate(VII) (174 mg, 0.494 mmol) were dissolved in acetonitrile (100 mL), and the mixture was stirred at room temperature for 2 hr. 2-Propanol was added and the mixture was stirred for 30 min, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.62 g, yield 82%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([S:13](Cl)(=O)=O)[CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.C(O)C.Cl.O>[Zn].C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([SH:13])[CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1nc(C(F)(F)F)nc1N
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(-n2nc(C(F)(F)F)nc2N)cc1S
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer was placed 3.3 g (9.3 mmol) of 5-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-2,4-dimethylbenzenesulfonyl chloride, followed by addition of 3.27 g (50 mmol) of zinc, 10 ml of ethanol and 5 ml (50 mmol) of 35% hydrochloric acid. The mixture was stirred at room temperature for 15 minutes. Then, the mixture was refluxed with heating, for 3 hours. The mixture was cooled to room temperature. Thereto were added 30 ml of water and 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Vacuum distillation was conducted to distil off ethyl acetate to obtain a title compound as 1.9 g of oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9]S(C)=O.[CH:14](=O)[CH3:15].N1CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][C:15]1[O:1][C:2]2[C:3]([C:8](=[O:13])[CH:9]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CS(=O)CC(=O)c1ccccc1O
Reactant: CC=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(=O)c2ccccc2o1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
In an atmosphere of argon, 19.5 g (107.0 mmols) of 2'-hydroxy-2-(methylsulfinyl)acetophenone, 5.65 g (3.4 equivalent) of acetaldehyde and 5.0 ml (0.05 equivalent) of piperidine were dissolved in 500 ml of toluene, and the mixture obtained was refluxed with heating for 1 hour and 45 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the toluene. The residue thus obtained was dissolved in 300 ml of ethyl acetate and washed twice with 200 ml of water. The organic layer thus formed was dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing system: hexane/ethyl acetate=4/6) to obtain 14.7 g of 2-methylchromone (yield: 86%; a pale-white pink solid). 1H-NMR Spectrum [δ(ppm)]: 2.39(s, 3H), 6.17(s, 1H), 7.37(m, 2H), 7.64(dt, 1H, J=1.7 Hz, 8.1 Hz), 8.18(dd, 1H, J=1.7 Hz, 8.1 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[F:32][C:33]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:35]3[CH2:36][CH2:37][C:33]([F:38])([F:32])[CH2:34]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: FC1(F)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCC(F)(F)C3)ccc2n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 104 mg of 3,3-difluoropyrrolidine hydrochloride are added, and the mixture is stirred at 40° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C:12]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.[NH2:36][CH2:37][CH2:38][OH:39].O1CCOC[CH2:41]1>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:6]5[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=5[O:4][CH2:3][CH2:2][NH:36][CH2:37][C@H:38]([OH:39])[CH3:41])[CH2:14][CH2:13]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cccc(F)c3OCCCl)CC2)c1=O
Reactant: C1COCCO1
Reactant: NCCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cccc(F)c3OCCNC[C@@H](C)O)CC2)c1=O

Procedure:
3-[3-({1-[2-(2-chloroethoxy)-3-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide (Example 283f) (0.3 g) and 2-aminoethanol (0.147 g) were stirred together at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification by preparative HPLC (Xterra column 0.2% ammonia/MeCN eluent) give the title compound (0.094 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.O[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([O:14][CH2:13][CH:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4][O:5]3)=[CH:10][CH:9]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:23][CH:24]=1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Yield: 87.5 %

Procedure:
A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.366 g, 1.32 mmole) in 27 mL of THF was treated with 0.222 g of methyl 4-hydroxybenzoate, 0.382 g of triphenylphosphine and 0.23 mL of diethyl azodicarboxylate (DEAD). The reaction mixture was heated at reflux for two hours, diluted with 50 mL of ether and then washed with two 25 mL portions of water and 25 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 7% ethyl acetate in hexanes) to yield 0.474 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid methyl ester, as a pale yellow oil.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.[O-][Mn](=O)(=O)=O.[K+].C[OH:20]>O.C(Cl)Cl>[NH:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:4]([C:3]([OH:20])=[O:1])=[N:5]1
Reactant: Cc1n[nH]c2ncccc12
Reactant: CO
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1n[nH]c2ncccc12
Temperature: 80 °C
Yield: 81 %

Procedure:
To a solution of NaOH (0.88 g, 22 mmol) in water (20 mL) was added 3-methyl-1H-pyrazolo[3,4-b]pyridine (IV) (0.4 g, 3 mmol). The suspension was heated at 80° C. until a clear solution was obtained. A solution of KMnO4 (1.73 g, 11 mmol) in water (180 mL) was added slowly over 2 h while heating the solution at 80° C. The solution was heated at 90° C. for an additional 2 h until the complete disappearance of starting material was observed by TLC. The solution was cooled to 70° C. and filtered through a pad of Celite. The solids were washed by boiling water. The combined filtrate was cooled to 0° C., acidified with conc. H2SO4 to pH=2 and extracted with n-butanol (2×10 mL). The n-butanol layer was concentrated under reduced pressure to get a white residue which was dissolved in DCM by adding minimum amount of MeOH and then filtered. The filtrate was concentrated to give 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (V) as a white solid (390 mg, 2.39 mmol, 81% yield). 1H NMR (CDCl3) δ ppm 7.37 (dd, J=8.10, 4.52 Hz, 1 H), 8.47 (dd, J=7.54, 1.88 Hz, 1 H), 8.62 (dd, J=4.52, 1.32 Hz, 1 H), 14.37 (brs, 1 H).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].C(N(CC)CC)C.FC(F)(F)S(O[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][C:44]([F:50])=[CH:45][CH:46]=2)[N:41]=1)(=O)=O>CS(C)=O.O>[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][C:44]([F:50])=[CH:45][CH:46]=5)[N:41]=4)[CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: O=S(=O)(Oc1ccc2ccc(F)cc2n1)C(F)(F)F
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4ccc(F)cc4n3)CC2)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
To a RT solution of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (1.00 g, 3.18 mmol, prepared according to Step 2 of Example 1) and triethylamine (2.00 ml, 14.35 mmol) in DMSO (10 ml) was added a solution of 7-fluoroquinolin-2-yl trifluoromethanesulfonate (1.10 g, 3.73 mmol, prepared according to Step 3 of Example 2) in DMSO (2 mL). The reaction mixture was heated at 60° C. for 2.5 h. The reaction was cooled RT and diluted with water. The mixture was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered and the solution was evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→3:1). The fractions containing product were concentrated in vacuo and the residue was stirred vigorously over Et2O for 3 h. The solid was filtered, washed with Et2O and dried to give 674 mg (46%) of the desired product. m/z=460 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (d, J=2.34 Hz, 1 H), 8.59 (d, J=2.34 Hz, 1 H), 8.39 (br. s., 1 H), 8.04 (d, J=9.21 Hz, 1 H), 7.69-7.83 (m, 2 H), 7.45-7.58 (m, 2 H), 7.18-7.28 (m, 2 H), 7.08 (td, J=8.77, 2.63 Hz, 1 H), 4.66 (d, J=13.30 Hz, 2 H), 3.13-3.29 (m, 1 H), 2.86-3.03 (m, 2 H), 2.82 (d, J=4.68 Hz, 3 H), 1.72-1.97 (m, 4 H).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=2)[C:3]=1[OH:17].C(N(CC)CC)C>[Pd].C(O)C>[CH3:12][C:11]1[CH:2]=[C:3]([OH:17])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(S(C)(=O)=O)ccc2c(O)c1Br
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)c2ccc(S(C)(=O)=O)cc2c1
Reaction time: 1.5 h

Procedure:
A mixture of 2-bromo-3-methyl-6-(methylsulfonyl)naphthalen-1-ol (0.500 g, 1.59 mmol), 10% palladium on carbon (0.050 g) and triethylamine (0.331 mL, 2.38 mmol) in ethanol was stirred under a hydrogen atmosphere for 1.5 hours. Celite was added and the mixture was stirred for 10 minutes, filtered through a pad of Celite and the filtrate concentrated. The residue was dissolved in ethyl acetate, washed with dilute HCl/brine, dried (MgSO4), filtered, concentrated, and purified by flash column chromatography (silica gel, 20 to 50% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M−H]− calcd for C12H11O3S: 235.3. Found: 235.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]Cl)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)(=[O:16])=[O:15])=[CH2:13].C(Cl)(Cl)(Cl)[Cl:27]>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10][CH:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)(=[O:15])=[O:16])[CH2:13][Cl:27])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(SCl)c1
Reactant: C=CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(SC(CCl)S(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 36 %

Procedure:
To a solution of 0.161 mole of m-nitrobenzenesulfenyl chloride in enough carbon tetrachloride to make 265 ml was added 34.1 g (0.160 mole) of m-nitrophenyl vinyl sulfone. The reaction mixture was allowed to stand at room temperature in a closed flask for several weeks. Evaporation of the solvent under reduced pressure gave 44 g (68%) of crude product m.p. 98°-110°. Recrystallization from 120 ml of toluene gave 23 g (36%) of pure product, m.p. 105.0°-106.5°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH4+].[Cl-].[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C)C=O.C(OC(=O)C)C>[NH:22]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][CH2:11]3)=[CH:7][CH:8]=2)=[N:2][N:24]=[N:23]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nnn[nH]3)cc2)CC1
Temperature: 100 °C
Yield: 47.4 %

Procedure:
To a solution of tert-butyl (1-(4-cyanophenyl)cyclopropyl)carbamate (D15) (1.5 g, 5.81 mmol) in dimethylformamide (15 ml), NH4Cl (530 mg, 9.90 mmol) was added under nitrogen atmosphere, followed by addition of sodium azide (650 mg, 9.9 mmol). The reaction mixture was heated to 100° C. overnight, then cooled to room temperature with ice-water bath. Water and ethylacetate (100 ml) was added. The organic layer was separated and the solvent was removed. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate (1:1). Collected fractions after solvent evaporation afforded the title compound (D16) (830 mg) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21]>>[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-alanine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=140.5-142° C.). The reaction was monitored by tlc (Rf=0.17 in 50% EtOAc/hexanes).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:24](O)=[O:25])=[CH:18][CH:17]=1>>[CH2:31]([O:30][C:28]([NH:27][C@H:23]([C:24]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]1)=[O:25])[CH2:22][C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1)=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)CC1
Yield: 96.8 %

Procedure:
By reacting 2.15 g of t-butyl 4-piperidinyloxyacetate with 3.0 g of Z-L-phenylalanine, as described in Example 2b), there are obtained 4.8 g of t-butyl [[1-(N-benzyloxycarbonyl-3-phenyl-L-alanyl)-4-piperidinyl]oxy]acetate MS (FAB): 497 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.Cl>C(#N)C>[O:28]1[CH2:29][CH2:30][O:31][CH:27]1[CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: BrCCC1OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(C2CCN(CCC3OCCO3)CC2)c1F

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.42 g, 1.63 mmol), acetonitrile (20 ml), potassium carbonate (0.45 g, 3.2 mmol) and 2-(2-bromoethyl)-1,3-dioxolan (0.205 ml, 1.65 mmol). Yield: 0.18 g (31%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 224-225° C. MS m/z (relative intensity, 70 eV) 357 (M+, 3), 270 (bp), 257 (59), 256 (27), 178 (90).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([C:28]([OH:30])=O)[CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]>ClCCl.CN(C=O)C>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([C:28]([Cl:4])=[O:30])[CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)Cl)CC1
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.6 mL, 18 mmol) was added dropwise over a period of 5 minutes to a suspension of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-C]quinolin-1-yl]methyl}cyclopropanecarboxylic acid (2.0 g, 6.2 mmol) in dichloromethane (50 mL) containing one drop of DMF. The reaction mixture was stirred for two hours and then concentrated under reduced pressure to provide 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarbonyl chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.24 g (0.01 mole) of 4-hydroxymethylphenol, 1.8 g (0.012 mole) of tert-butyldimethylsilyl chloride, 1.7 g (0.025 mole) of imidazole and 3 ml of dimethylformamide was stirred under nitrogen at room temperature for 12 h. The reaction mixture was poured into water and extracted with three portions of ether. Ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (Na2SO4). The ether solution was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a colorless oil.