Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(CC)CC.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([S:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:38])=[O:37])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(S(=O)(=O)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.129 g, 0.43 mmol) in dichloromethane (8 mL) and Et3N (0.13 mL, 0.86 mmol) was added benzenesulfonyl chloride (62 μL, 0.47 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was partitioned between EtOAc and aqueous NaOH. The organic layer was then separated, washed with brine (2×10 mL), concentrated under reduced pressure. The crude product was purified using either flash column chromatography (SiO2, 33% EtOAc in hexane) to give 3-(4-methoxybenzyl)-7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (0.147 g, 77%) or used in the next step without any further purification. M.p.=136-138° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.39 (s, 1H), 8.12 (s, 1H), 7.88-7.83 (m, 2H), 7.72-7.59 (m, 3H), 7.18-7.13 (m, 2H), 6.86-6.8 (m, 2H), 5.55 (s, 2H), 4.36 (s, 2H), 3.68 (s, 3H), 3.43, t, J=6.4 Hz, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54-2.48 (m, 2H); LCMS [M+H]: 435.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[CH2:10]=O>>[OH:9][CH:2]([CH3:1])[CH2:3][N:4]1[CH2:5][CH:6]([CH3:7])[O:8][CH2:10]1
Reactant: C=O
Reactant: CC(O)CNCC(C)O
Product: CC(O)CN1COC(C)C1

Procedure:
133 g of diisopropanol amine and 33 g of paraformaldehyde are reacted as described under (a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C[O:14][C:15]([C:17]1[C:26]2[C:25]3[N:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH2:23][NH:22][CH2:21][C:20]=2[NH:19][CH:18]=1)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:17]2[C:26]3[C:25]4[N:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH2:23][NH:22][CH2:21][C:20]=3[NH:19][CH:18]=2)=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c[nH]c2c1-c1ncccc1CNC2
Reactant: Nc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)c1c[nH]c2c1-c1ncccc1CNC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.38 mL (4 mmol) of 3-fluoroaniline in 2 mL of methylene chloride under a nitrogen atmosphere is added dropwise 1.5 mL (3 mmol) of trimethyl aluminum (2M solution of toluene). This mixture is stirred at room temperature for 30 minutes. To this mixture is added a solution of 0.12 g (0.5 mmol) of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid methyl ester dissolved in 8 mL of methylene chloride. The reaction mixture is heated to 40° C. for 24 hours; cooled to room temperature and quenched with 0.5 mL of saturated NaCl. After stirring for 30 minutes an additional 5 mL of methylene chloride and 2 grams of anhydrous sodium sulfate is added. The reaction mixture is filtered. The filtrate is evaporated and chromatographed on 10 grams of silica gel using 10/1/0.5 chloroform/methanol/ammonium hydroxide as the eluant. Appropriate fractions are combined and evaporated to 23 mg of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid (3-fluoro-phenyl)-amide. 1H NMR (CD3OD) δ8.70 (m, 1H), 7.90 (m, 1H), 7.80 (m, 1H), 7.60 (s, 1H), 7.30 (m, 3H), 6.90 (m, 1H), 3.87 (s, 2H), 3.70 (s, 2H). Mass spectrum: m/e=323.2 (p+1). TLC (10/1/0.1 chloroform/methanol/ammonium hydroxide) Rf=0.3.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][N:18](C)[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[C:1]1([C:7]2([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCC1(c2ccccc2)COc2ccccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 6.0 g (22.5 mole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine, 3.72 ml (27 mmole) beta,beta,beta-trichloroethyl chloroformate, 12.4 g (90 mmole) anhydrous K2CO3, and 100 ml anhydrous CH2Cl2 was stirred at room temperature overnight. Water was then added to dissolve the inorganics and the layers were separated. The organics were washed with water and dried over MgSO4. Filtration and evaporation gave an oil, which was chromatographed with HPLC using 80% CH2Cl2 /hexane as an eluent to give 6.4 g (66%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Br:7]/[C:8](=[CH:11]\N(C)C)/[CH:9]=O.C(O)C>C(O)(=O)C>[Br:7][C:8]1[CH:9]=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: Nc1cc[nH]n1
Reactant: CN(C)/C=C(\Br)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1cnc2ccnn2c1

Procedure:
3-Aminopyrazole (0.75 g, 9.04 mmol) was mixed with (2Z)-2-bromo-3-(dimethylamino)acrylaldehyde obtained at the previous step (1.85 g, 10.4 mmol). Absolute ethanol (20 mL) and glacial acetic acid (2 mL) were added. The reaction mixture was stirred under reflux for 16 h and evaporated to dryness. The residue was washed on a filter with cold ethanol/hexane mixture (3:1) and dried in a vacuum oven at 30° C. to give 6-bromopyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:20]=[N+:21]=[N-:22].[Na+].Cl>CN1CCCC1=O>[N+:9]([C:5]1[CH:4]=[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Temperature: 160 °C
Yield: 88.9 %

Procedure:
To a solution of 3-cyanonitrobenzene (20 g, 0.13 mol) in 1-methyl-2-pyrrolidinone (200 mg) was added triethylamine hydrochloride (27.9 g, 0.20 mol) followed by sodium azide (26.4 g, 0.40 mol). The mixture was heated at 160° C. for 1.5 h, then cooled to ambient temperature, poured into ice water (100 mg) and acidified using 5M HCl. The solid which precipitated from the mixture was filtered, washed with water and dried under vacuum at 50° C. to afford the title tetrazole (22.1 g, 86%) as a beige powder, mp 154°-156° C. 1H NMR (360 MHz, CDCl13) δ 7.59 (1H, t, J=8 Hz), 8.19 (1H, d, J=8 Hz), 8.36 (1H, d, J=8 Hz), 8.86 (1H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=2)[CH:11]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([O:1][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]3[CH:13]=[CH:14][C:15]([OH:16])=[CH:10][CH:11]=3)=[CH:19][CH:20]=1)[CH2:3]2
Reactant: O[C@@H]1CN2CCC1CC2
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Product: Oc1ccc(Oc2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
3-(S)-Hydroxy-quinuclidine (the product of Reference Example 2D, 127 mg, 1 mmol) was treated with 4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.2) as oil (48 mg, yield, 15%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.55 (m, 1H), 1.60–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.75–2.98 (m, 5H), 3.20–3.30 (m, 1H), 4.45 (m, 1H), 6.62–6.96 (m, 8H) ppm. MS (DCl/NH3) m/z 312 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.CN(C=O)C>O>[Si:14]([O:8][C:5]1[CH:4]=[C:3]([F:9])[C:2]([Cl:1])=[N:7][CH:6]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1cnc(Cl)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-fluoropyridin-3-ol (13.1 g), tert-butyl (chloro)diphenylsilane (27.7 mL), 1H-imidazole (7.25 g) and DMF (100 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (29.5 g).
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[CH2:5]([OH:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[CH3:1][S:2]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3]
Reactant: CCCCCCCCCCO
Reactant: CS(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCOS(C)=O
Temperature: 50 °C

Procedure:
Into a 50 ml three-necked flask equipped with a magnetic stirrer, thermometer, nitrogen purge and dropping funnel is added 9.9 gms (0.10 moles) of methanesulfinyl chloride. The methane sulfinyl chloride is cooled to -10°C and 17.4 gms (0.11 moles) of decanol is added dropwise while maintaining the temperature of -5° to -10°C. When the addition of the decanol is complete, the reaction mass is warmed to 50°C under 20 mm of vacuum. The resulting product is then cooled and dissolved in 100 ml of diethyl ether admixed with 2 gms. of pyridine. The reaction mass is then extracted with two 10 ml portions of water. A drop of pyridine is added to the ether layer in order to remove additional chloride. In the event that no precipitation occurs the ether layer is then extracted with two 10 ml portions of 3% aqueous hydrochloric acid. The ether layer is then dried over anhydrous sodium sulfate and is then evaporated by means of rotary evaporation yielding an oil which is then subjected to a distillation operation. The resulting product is distilled at 98°C at 0.50-0.65 mm Hg pressure. (Yield 16 gms). GLC, mass spectral and infrared analysis yield the information that the structure of this material is as follows: ##EQU13##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)(=[O:42])=[O:43])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.4 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and 4-nitro-benzene sulfonyl chloride (49.0 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 21 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(4-nitro-benzenesulfonylamino)-phenyl]-N-thiazol-2-yl-propionamide (47.5 mg, 47.5%) as a yellow solid: mp 120-125° C.; FAB-HRMS m/e calcd for C23H24N4O5S2 (M+H)+ 501.1266, found 501.1264.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:18])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)cc1

Procedure:
A solution of 25.3 g (152 ml) of (4-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of conc. sulfuric acid and heated under reflux for 16 h. The cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo.
Reaction SMILES: CS[C:3]([N:6]1[N:10]=[CH:9][C:8]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7]1)=[N:4][CH3:5].[Cl:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:21][S:20]2>C(#N)C>[CH3:5][NH:4][C:3]([N:6]1[N:10]=[CH:9][C:8]2([CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH2:7]1)=[N:28][S:25]([C:24]1[N:23]2[C:19]([S:20][CH:21]=[CH:22]2)=[N:18][C:17]=1[Cl:16])(=[O:27])=[O:26]
Reactant: NS(=O)(=O)c1c(Cl)nc2sccn12
Reactant: CN=C(SC)N1CC2(C=N1)CCOCC2
Solvent: CC#N
Product: CNC(=NS(=O)(=O)c1c(Cl)nc2sccn12)N1CC2(C=N1)CCOCC2
Yield: 0.1 %

Procedure:
0.42 g (1 mol equiv.) N-Methyl-8-oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carboximidothioic acid methyl ester and 0.46 g (1.05 mol equiv.) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid amide were added to 7 mL acetonitrile and the reaction mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was taken up in ethylacetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (EtOAc) afforded 0.56 g (69%) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid methylamino-(8-oxa-2,3-diaza-spiro[4.5]dec-3-en-2-yl)-methylene-amide. 1H NMR (400 MHz, CDCl3) δ 1.51-1.57 (m, 2H), 1.80-1.89 (m, 2H), 3.10 (d, J=5.0 Hz, 3H), 3.51-3.59 (m, 2H), 3.83-3.90 (m, 4H), 3.89 (s, 2H), 6.89 (s, 1H), 6.99 (d, J=4.6 Hz, 1H), 7.12 (br.s., 1H), 8.01 (d, J=4.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:26]=1)[C:10]([O:12][C@H:13]([CH3:23])[CH2:14][O:15][Si](C(C)(C)C)(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:26]=1)[C:10]([O:12][C@H:13]([CH3:23])[CH2:14][OH:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](CO)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
(1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (16) (4.7 g, 7.2 mmol) was dissolved in anhydrous tetrahydrofuran. Triethylamine trihydrofluoride (9.4 mL, 57.0 mmol) was slowly added. The mixture was stirred at room temperature for 4 hours. Removal of solvent under reduced pressure gave 3.8 g (98% yield) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J=6.4 Hz, 3H), 1.41 (s, 9H), 2.78 (s, 1H, br), 2.96 (m, 2H), 3.51 (m, 1H), 3.68 (m, 1H), 4.36 (dd, J=14.0, 6.4 Hz, 1H), 4.98 (m, 1H), 5.05 (d, 1H, NH), 5.10 (s, 4H), 6.66 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 7.26-7.43 (m, 10H).
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:26][N:27]([CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1)[CH3:28]
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1nc2cc3c(cc2c(-c2ccc4c(c2)OCO4)[n+]1[O-])OCO3
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (200 mg, 0.55 mmol), in THF (6 mL), was added dimethylamine (2M in THF 2 mL, 4 mmol). The mixture as stirred at 65° C. for 2 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane:acetone 4:1); mp 205-210° C. 1H NMR (CDCl3) 7.41 (s, 1H), 6.90-7.06 (m, 4H), 6.78 (s, 1H) 6.11 (s, 2H), 6.08 (s, 2H), 4.05 (s, 2H), 2.52 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:11][C:10]=2[F:29])[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CCCCO>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][C:9]=1[O:8][C:4]1[CH:3]=[C:2]([NH:31][CH3:30])[N:7]=[CH:6][N:5]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: CN
Solvent: CCCCO
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ncn1
Yield: 34 %

Procedure:
A solution of N1-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (100 mg, 0.42 mmol, Example 4) in n-BuOH (3 mL) was treated with 2 M methylamine/THF (0.2 mL) and heated in a screw cap vial at 80° C. for 12 h. The mixture was concentrated and the residue purified by preparative HPLC using a gradient of MeOH—H2O containing 0.1% TFA. The fraction containing the product was lyophilized to give the title compound as a pale yellow solid (60 mg, 34%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.36 (br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, J=12.1 Hz), 7.64-7.62 (m, 2H), 7.36-7.27 (m, 2H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 5.95 (br s, 1H), 3.49 (s, 2H), 2.80 (s, 3H); MS(ESI+) m/z 414.16 (M+H)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaB(OAc)3H (6.6 mmol, 1.4 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (6.0 mmol, 0.9 g), piperidine Compound 5a (9.0 mmol, 0.9 mL) and glacial acetic acid (5 drops) in CH2Cl2 (50 mL) and the resulting suspension was stirred at r.t. overnight. The reaction mixture was made basic with a 2N NaOH solution and extracted with CH2Cl2. The organic layer was washed with brine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo. The product was purified by flash column chromatography (10:1 EtOAc:MeOH) to yield 1-(4-nitro-benzyl)-piperidine Compound 5b as a yellow oil (0.89 g, 67% yield). MS m/e 221 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([NH2:23])=O)=[C:8]2[CH3:25])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21](=[S:37])[NH2:23])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)c(CC(C)CC(N)=O)c(C)n2Cc1ccc(Br)cc1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(CC(C)CC(N)=S)c(C)n2Cc1ccc(Br)cc1

Procedure:
To the amide (530 mg, 1.30 mmol) of Example 90 in 1,4-dioxane (10.0 mL) was added the Lawesson reagent (310 mg, 0.767 mmol). After refluxing for 2 min, the solvent was evaporated in vacuo and the title product was purified by flash chromatography (30% EtOAc in hexane).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:28]=[CH:29][C:30]([NH:31][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:32][CH:33]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 76 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-(trifluoromethyl)aniline gave the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 6.54 (d, J=8.3 Hz, 2H), 4.40 (s, 2H), 2.71 (t, J=7.5 Hz, 2H), 1.80-1.65 (m, 2H), 1.40-1.07 (m, 16H), 0.80 (t, J=6.8 Hz, 3H). M−(LC/MS(ESI)): 472.5; M+(LC/MS(ESI)): 474.2. HPLC (Condition A), Rt: 6.78 min (HPLC purity: 97.5%).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1.[NH:44]1[C:48]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:46]=[N:45]1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]2[N:31]([C:27]([CH2:26][N:44]3[C:48]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:46]=[N:45]3)=[C:28]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:29]=2)[CH:32]=1
Reactant: Fc1ccc(-c2nc3ccc(F)cn3c2CCl)cc1
Reactant: COC(=O)c1ncn[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and methyl 1H-1,2,4-triazole-5-carboxylate. The two isomers were separated by silica gel chromatography eluted with 20% acetone to flash out the less polar spot and 50% acetone to flash out the second spot (more polar spot). m/e− 370 for C18H14F2N5O2 (M+H)−.