Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[O:14]1[C:18]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)=[CH:17][N:16]=[CH:15]1.N1C=CC=CC=1>ClCCCl.O1CCOCC1>[O:14]1[C:18]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)=[CH:17][N:16]=[CH:15]1
Reactant: Nc1ccc(Oc2ccnc(-c3cnco3)c2)cn1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(N)=O
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3cnco3)c2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.044 g, 0.431 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.038 mL, 0.431 mmol), stirred at RT for 5 min, then heated at 80° C. for 0.5 h. The mixture was cooled to RT, added to a mixture of 5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.073 g, 0.287 mmol) and pyridine (0.186 mL, 2.297 mmol) in dioxane (4 mL) and stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN and the solid collected via filtration to afford N-((5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (44 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.45 (s, 1H), 8.52 (d, J=5.7 Hz, 1H), 8.49 (s, 1H), 8.31 (d, J=2.9 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.81-7.77 (m, 2H), 7.27 (d, J=2.5 Hz, 1H), 6.95 (dd, J=5.7, 2.5 Hz, 1H), 1.21 (s, 9H); MS (ESI) m/z: 382.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Fc1ccccc1-c1nnc2cc(C3CCC3)c(Cl)nn12
Yield: 49 %

Procedure:
A mixture of 3,6-dichloro-4-cyclobutylpyridazine from above (3.0 g, 14.7 mmol), 2-fluorobenzhydrazide (3.0 g, 19.5 mmol) and triethylamine hydrochloride (3.0 g, 21.8 mmol) in p-xylene (50 ml) was stirred and heated at reflux under a stream of nitrogen for 20 hours. Upon cooling the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous was basified by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at, this stage. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 20%→30% ethyl acetate/dichloromethane to give the title compound (2.2 g, 49%) as a light-brown solid. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.85-2.08 (1H, m), 2.08-2.30 (3H, m), 2.38-2.64 (2H, m), 3.62-3.84 (1H, m), 7.19-7.46 (2H, m), 7.46-7.67 (1H, m), 7.80-7.96 (1H, m), 7.99 (1H, s), MS (ES+) m/e 303 [MH]+, 305 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:38]1[CH2:40][CH:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:30]4[O:31]C(C)(C)[O:33][CH:29]4[CH:28]([CH2:36][OH:37])[CH2:27]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.CO.C(OCC)(=O)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:38]1[CH2:40][CH:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:27][CH:28]([CH2:36][OH:37])[CH:29]([OH:33])[CH:30]3[OH:31])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO)C4OC(C)(C)OC43)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO)C(O)C3O)c2n1
Yield: 85.1 %

Procedure:
A solution of the product from Example 36, step (a) (1.39 g) in trifluoroacetic acid (1.5 ml)/methanol (15 ml) was stirred for two days. Ethyl acetate was added and the mixture was concentrated. Sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic extracts were dried, concentrated and purified (SiO2, petrol:acetone 1:1 as eluant) to give the subtitle compound (1.11 g).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C([O:13][C:14](=O)[CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:19]2[CH:18]=[C:17]([C:16]3[CH2:15][C:14](=[O:13])[NH:8][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[N:7]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccccc2N1

Procedure:
The title compound was prepared from 1,2-phenylenediamine (81 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) by refluxing in xylene according to the general procedure M. Obtained as a white solid (204 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][NH2:29])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: NOc1ccc(F)cc1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 81 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (386 mg, 1.22 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (110 mg, 1.34 mmol) in EtOH (18 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:4) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)propyl]phenyl}trifluoromethanesulfonamide 130 (420 mg, 81%), as a pale yellow solid. M.p. 47-48° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.25, br s, 1H, 7.71, d, J=8.8 Hz, 1H, 7.58, d, J=2.4 Hz, 1H, 7.40, dd, J=2.4 and 8.8 Hz, 1H, 7.18-7.02, m, 4H, 3.02, q, J=7.6 Hz, 2H, 1.31, t, J=7.6 Hz, 3H.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[CH:12]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[S:8][C:9]([C:23]2([OH:25])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:24]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:10][CH:11]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Cc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)c3ccccc3-c3ccccc32)s1
Temperature: 0 °C

Procedure:
A 2.5M solution of butyllithium in hexanes (9.6 mL, 24 mmol), (Aldrich) was added dropwise to a solution of 2-methylthiophene (1.96 g, 20 mmol) in anhydrous tetrahydrofuran (10 mL) with stirring under argon at 0° C. The mixture was stirred at room temperature for 0.5 h and then cooled to 0° C. A solution of 9-fluorenone (3.6 g, 20 mmol), (Aldrich) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture with stirring and cooling at 0° C. The reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride (5 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were washed with brine (10 mL), dried (MgSO4), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:28])(=O)[CH2:2][CH3:3].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:30]([O:32][NH:33][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:28])[CH2:2][CH3:3])[CH3:31]
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(OC(F)(F)C(F)F)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCONC(CC)=C1C(=O)CC(CCSc2ccc(OC(F)(F)C(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.21 Gram of 2-propionyl-5-[2-(4-α,α,β,β-tetrafluoroethoxyphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethanol, and 0.06 g of ethoxyamine hydrochloride and 0.06 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. Chloroform was removed and the residue was purified by thin layer chromatography (developing solvent, hexane:ethyl acetate=5:1) to obtain 0.07 g of 2-(1-ethoxyaminopropylidene)-5-[2-(4-α,α,β,β-tetrafluoroethoxyphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1.[CH3:36][O:37][C:38]1[CH:50]=[CH:49][C:41]([CH2:42][NH:43][C:44]2[CH:48]=[CH:47][O:46][N:45]=2)=[CH:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:43]([C:44]4[CH:48]=[CH:47][O:46][N:45]=4)[CH2:42][C:41]4[CH:40]=[CH:39][C:38]([O:37][CH3:36])=[CH:50][CH:49]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1
Reactant: COc1ccc(CNc2ccon2)cc1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(Br)ccc3OC)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.1 %

Procedure:
A flask containing perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.65 g, 6.33 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (1.358 g, 6.65 mmol) was flushed with nitrogen and then charged with THF (63.3 ml) and cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0M in THF) (6.97 ml, 6.97 mmol) was added slowly, and the solution was stirred at 0° C. for 45 minutes until complete consumption of starting material. The reaction was quenched with water and extracted (×3) with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was triturated in IPA and filtered, washing well with IPA, to yield 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.65 g, 4.44 mmol, 70.1% yield) as a white solid. m/z (ESI) 596.0 (M+H)+.
Reaction SMILES: C(O)(=O)C.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:10]#[C:11][CH2:12][OH:13].N(C([O-])=O)=NC([O-])=O.[K+].[K+]>N1C=CC=CC=1>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCC#Cc1nccs1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: OCCCc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Glacial acetic acid (16 ml) was added dropwise during 0.25 h to a stirred solution of 3-(2-thiazolyl)-2-propynol (2.4 g) and dipotassium azodicarboxylate (50 g) in pyridine (200 ml). The mixture was stirred at room temperature for 1 h and additional glacial acetic acid (40 ml) added during 0.5 h. The mixture was stirred at room temperature for 2 days. The solvent was removed by azeotropic distillation with toluene (2×100 ml) and the residue partitioned between (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined extracts dried and evaporated to leave a brown oil. This was purified by FCC eluting with toluene:ethyl acetate:triethylamine (50:50:1) to give the title compound as an orange oil (1.45 g), t.l.c. (toluene:ethyl acetate:triethylamine 50:50:1) Rf 0.15.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(#N)C.C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2](=[O:48])[O:1][CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC(=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (262 mg) in acetonitrile (10 mL) was added m-chloroperbenzoic acid (129 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=40/60→0/100 (volume ratio)] and crystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound as colorless crystals (204 mg, 75%).
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH3:24]
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
5-Benzyloxycarbonylamino-2-(2-methylimidazol-1-yl)fluorobenzene (54 g, 0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and 1,3-dimethyl-tetrahydropyrimidin-2-one (100 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6M in isohexane, 114 ml), over 30 minutes. After stirring for 30 minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M) in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated with aqueous sodium bicarbonate (5%, 500 ml) and ethyl acetate (800 ml), the organic layer separated, and the aqueous extracted with further ethyl acetate (3×750 ml). The combined extracts were dried (magnesium sulfate) and evaporated, and the resulting oil triturated with diethyl ether. The resulting solid was recrystallisd from isopropanol to give the title compound (21.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([OH:25])=[O:24])[CH2:18]1.C(N(C(C)C)CC)(C)C>>[NH2:8][C:6]1[N:7]=[C:2]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([OH:25])=[O:24])[CH2:18]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine in N,N-dimethylformamide (70 mL, 12.25 mmol, 0.175M) was added to (R)-piperidine-3-carboxylic acid (12.25 mmol) followed by diisopropylethylamine (4.55 mL, 24.5 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to afford (R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:35]1[CH2:41][O:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:37]4[CH2:36][CH2:35][CH2:41][O:40][CH2:39][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: C1CNCCOC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCCOCC4)c23)ccc1OCc1cccc(F)c1
Yield: 25 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 21) and homomorpholine to give the title compound in 25% yield; NMR Spectrum: 1.74-1.79 (m, 2H), 2.23 (s, 3H), 2.76-2.79 (m, 4H), 2.98 (t, 2H), 3.57-3.59 (m, 2H), 3.62-3.64 (m, 2H), 4.40 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.28-7.33 (m, 2H), 7.44-7.47 (m, 3H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 493 (MH+).
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1.[CH3:23]I>C1COCC1>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1
Reactant: CI
Reactant: CCOC(=O)Cc1ccncc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccncc1
Reaction time: 1 h

Procedure:
To a solution of LiN(TMS)2 (Aldrich, 1.0 M solution in THF, 30 mL, 30 mmol) in THF (30 mL) was added ethyl 4-pyridylacetate (Aldrich, 4.7 mL, 30 mmol)) at 0° C. Methyl iodide (Aldrich, 2.4 mL, 38 mmol) was added 30 min later. After 1 h, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography. Mass Spec. m/z+ion 180 (M+1).
Reaction SMILES: [CH3:1]I.[CH:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][C:11]=2[OH:12])[CH2:5][CH2:4]1>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][C:11]=2[O:12][CH3:1])[CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc(C2CC2)c(O)n1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C2CC2)c(OC)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Silver carbonate (70 g) and methyl iodide (11.2 mL) were added to a solution of ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g) in chloroform (250 mL), and the mixture was stirred at 60° C. for eight hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 5-cyclopropyl-6-methoxypyridine-2-carboxylate (13.05 g, 99%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH:5]=1)([CH3:3])=[CH2:2].[C:10]([O:13][CH:14]=[CH2:15])(=[O:12])[CH3:11]>CC(OC)(C)C>[C:1]([C:4]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH:5]=1)([CH3:3])=[CH2:2].[C:1]([C:4]1[CH2:5][CH2:6][C@@H:14]([O:13][C:10](=[O:12])[CH3:11])[CH:15]=1)([CH3:3])=[CH2:2]
Reactant: C=C(C)C1=CC(O)CC1
Reactant: C=COC(C)=O
Solvent: COC(C)(C)C
Product: C=C(C)C1=C[C@@H](O)CC1
Product: C=C(C)C1=C[C@H](OC(C)=O)CC1
Temperature: 40 °C

Procedure:
Compound (1a*) (63.9 mg, 0.5146 mmol) was dissolved in anhydrous MTBE (1.7 mL) and lipase PS (20 w %, 12.9 mg) and vinyl acetate (31 μL, 0.3363 mmol) were added before the resulting mixture was heated to 40° C. for 18 hours. Solids were removed by filtration and the filtrate concentrated in vacuo. Purification by chromatography (hexane/EtOAc 10/1 to 5/1 to 3/1 to 1/1) using Merck aluminium oxide 90 (0.063-0.200 mm, 70-230 mesh) furnished 25.7 mg of compound 7a as white solid with 40% yield and 43.4 mg of the enantioenriched acetic acid (R)-3-isopropenyl-cyclopent-2-enyl ester as slightly yellow oil with 51% yield.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:19][Br:20]>C(OCC)C>[Br-:20].[CH3:1][N+:2]([CH3:19])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CBr
Reactant: CCCCCCCCN(C)CCCCCCCC
Solvent: CCOCC
Product: CCCCCCCC[N+](C)(C)CCCCCCCC
Product: [Br-]

Procedure:
Following the general procedure of Example 1, 5.0 g. of N-methyl-N,N-dioctylamine was reacted with methyl bromide in diethyl ether to provide, after crystallization from diethyl ether, 6.89 g. of N,N-dimethyl-N,N-dioctylammonium bromide.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18]/[CH:19]=[CH:20]/[CH3:21]>C(O)C>[C:2]([NH:5][C:6]([CH2:18]/[CH:19]=[CH:20]/[CH3:21])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C/C=C/CBr
Agent: [Na]
Solvent: CCO
Product: C/C=C/CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reaction time: 8 h
Yield: 87.8 %

Procedure:
3.86 g (168 mmol) of sodium metal were dissolved in 106 ml of anhydrousethanol. 36.35 g (168 mmol) of diethyl acetamidomalonate dissolved in 225 ml of anhydrous ethanol were added and the mixture was heated under refluxfor 10 minutes. 22.66 g (168 mmol) of (E)-1-bromo-2-butene were added dropwise at room temperature and the mixture was stirred overnight and then evaporated to dryness under a vacuum. The residue was partitioned between ethyl acetate and 0.1M hydrochloric acid. The organic phase was washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The solvent was evaporated to give 40 g of diethyl (E)-2-acetamido-2-(2-butenyl)malonate as a colourless oil; 1H NMR (250 MHz, CDCl3) δ: 1.25 (t, 6 H), 1.6 (d, 3 H), 2.0 (s, 3 H), 2.9 (d, 2 H), 4.2 (q, 4 H), 5.15 (m, 1 H) 5.5 (m, 1 H), 6.7 s, 1 H).