Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>C(O)C>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C(O)Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccccc1COc1cccc(CC(=O)O)c1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
3-Hydroxyphenylacetic acid (760 mg, (5 mmol) was dissolved in ethanol (99.5%, 20 ml). Potassium hydroxide (560 mg, 10 mmol) was added. The mixture was stirred for 30 minutes. 2-Bromomethylbenzoic acid methyl ester (1.144 g, 5 mmol) was then dropped in. The resulting mixture was heated to reflux for 2 hours and then evaporated in vacuum to dry. Water and ethyl acetate were added into the residue and the phases were separated. The water phase was acidified with 10% hydrochloric acid, pH˜5, and then extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated in vacuum to dry. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using DCM, MeOH/DCM (1:99) as eluant gave 213 mg, the desired product, yield 14%.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:85])[C:81]([F:84])([F:83])[F:82])[C:69](OCC#N)=[O:70])=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(#N)C>[C:60]([O:64][C:65]([NH:67][C@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:85])[C:81]([F:83])([F:84])[F:82])[C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])=[O:66])([CH3:63])([CH3:61])[CH3:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)C(F)(F)F)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 4.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (81 mg, 0.127 mmol) and (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk53) (194 mg, 0.509 mmol) in acetonitrile (0.7 mL) was added to buffer A (20 mL), and the mixture was stirred at room temperature for 1.75 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk54) (5.3 mg, 4%).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][NH2:17])=[CH:12][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH:27]=O)[CH:22]=[CH:23][CH:24]=1>>[C:2]([O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][NH:17][CH2:27][CH2:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)=[CH:12][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN)s1
Reactant: O=CCCc1cccc(Br)c1
Agent: Cl
Product: CC(C)(C)OC(=O)c1ccc(CCCNCCCc2cccc(Br)c2)s1

Procedure:
The title compound was prepared from 5-(3-amino-propyl)-thiophene-2-carboxylic acid tert-butyl ester hydrochloride and 3-(3-bromo-phenyl)-propionaldehyde following the method described in Step A of Example 141. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.28–7.30 (m, 2H), 7.06–7.14 (m, 2H), 6.75 (d, 1H), 2.85 (t, 2H), 2.65–2.78 (m, 4H), 2.60 (t, 2H), 1.92–2.04 (m, 4H), 1.52–1.54 (m, 9H); MS 438 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]([C:57]2([C:60](O)=[O:61])[CH2:59][CH2:58]2)=[O:56])=[CH:50][CH:49]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:60]([C:57]2([C:55](=[O:56])[NH:54][C:51]3[CH:50]=[CH:49][C:48]([F:47])=[CH:53][CH:52]=3)[CH2:58][CH2:59]2)=[O:61])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To intermediate 13 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF (20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (16) [US 2007/0004675 A1] (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol). The mixture was stirred at r.t. for 18 h and partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, brine, dried (anhydrous MgSO4), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded intermediate 17 (0.60 g, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J=8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.65 (d, J=5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:27]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C(C)(C)C)nn1
Yield: 87 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using pivaloyl chloride instead of methoxyacetyl chloride, to the title compound (320 mg, 87%) which was obtained as a white solid. MS: m/e=367.1 [M+H].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:19]([C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)=O.[OH-].[K+]>CCO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])/[CH:17]=[CH:19]/[C:21]3[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-(4-acetyl-piperazin-1-yl)-phenyl]-ethanone (prepared following the procedure described in Example 16 STEP A, 533 mg, 2.16 mmol), 4-formylcinnamic acid (381 mg, 2.16 mmol) and 1.7 M KOH (2.54 ml) in EtOH (15 ml) and water (3 ml) was stirred overnight at room temperature. The resulting precipitate was filtered to get 260 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its potassium salt. The mother liquors were acidified with 10% HCl and the resulting green precipitate was filtered to give 240 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride. The mixture of both, the potassium salt and of the hydrochloric salt, was used in the next step without any further purification.
Reaction SMILES: O[CH2:2][C@H:3]([NH:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:20]3[CH:21]=[CH:22][S:23][C:19]=3[C:18](=[O:24])[N:17]([CH3:25])[CH2:16][C:15]=12)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:25][N:17]1[C:18](=[O:24])[C:19]2[S:23][CH:22]=[CH:21][C:20]=2[N:14]2[CH:13]=[N:12][C:11]([C:9]3[O:10][CH2:2][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[N:8]=3)=[C:15]2[CH2:16]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2sccc2-3)=N1
Yield: 22.5 %

Procedure:
A solution of 13.7 g (0.0377 mol) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-ylcarbonylamino)-propionate in 270 ml of tetrahydrofuran was treated while gassing with argon with 9.87 g (0.0414 mol) of methoxycarbonylsulphamoyl-triethylammonium hydroxide internal salt (Burgess reagent) according to the method described in Tetr. Letters 1992, 33, 907. The mixture was boiled at reflux for 2 hrs. and completely freed from the solvents. The residue was partitioned between water and dichloromethane, extracted, chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from acetonitrile. There were obtained 2.94 g (22%) of methyl (S)-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate as white crystals; m.p. 215-217°. [α]D20 =+41.2° (CHCl3, c=1%). A further 3.25 g (25%) of yellowish crystals were recovered from the mother liquor.
Reaction SMILES: CO.[C:3]([O:7]OC(C)(C)C)(C)(C)C.[C:13]([CH:17]=[CH:18][F:19])([F:16])([F:15])[F:14]>>[C:13]([CH2:17][CH:18]([CH2:3][OH:7])[F:19])([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: FC=CC(F)(F)F
Solvent: CO
Product: OCC(F)CC(F)(F)F
Yield: 616.1 %

Procedure:
Under nitrogen, into a quartz tube equipped with a dry-ice condenser was added anhydrous methanol (20 g, 0.62 mol) and di-tertiarybutylperoxide (.79 g, 0.003 mol). The quartz tube was placed in a Rayonet UV photochemical reactor and HFC 1234zc, CF3CH═CFH (5 g, 0.044 mol) was added drop-wise via a dry-ice condenser (−78° C.) over a period of ˜1 hour while being irradiated at (UV wavelength) 254 nm. After complete addition, the reaction mixture was irradiated for ˜1 hour. The reaction mixture was concentrated under reduced pressure. The residue was extracted in diethyl ether (˜50 mL), washed with 20 mL aq. Na2SO3 (20%) and brine (10 mL). The ether layer was then concentrated to afford 7 g of the crude material. Distillation of this material under reduced pressure (24-28 mm Hg) afforded CF3CH2CFHCH2OH (2.7g) as a colorless liquid; yield=42% based on HFC 1234 zc. Boiling point, 58° C./24 mm Hg. GC-MS: m/e at 146 (C4H6F4O) for M+; 19 F and 1H NMR spectra are consistent with the structure. 19 F NMR (CDCl3)δ=−64.6 (3F, m), −191.2 (1F, m) ppm; 1H NMR (CDCl3)δ=2.2 (1H, br), 2.4(1H, m), 2.6 (1H, m), 3.7-3.9 (2H, m), 4.9 (1H, dm) ppm.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2cccc(CNC(=O)Nc3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 66.1 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.44 g, 1.3 mmol) and triethylamine (0.25 mL, 1.8 mmol) in THF (8 mL) at 5˜10° C., was added 4-chlorophenyl isocyanate (0.21 mL, 1.7 mmol) and stirred for ten minutes. Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as a yellow solid (390 mg, 66% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.34 min (98.7%); mp, 255-257° C.; 1HNMR (DMSO-d6) 2.17-2.23 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.72 (d, J=6 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.65 (t, J=5 Hz, 1H, CH2NH), 7.21-7.78 (m, 7H, Ar), 8.92 (s, 1H, NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.70, 23.31, 30.62, 42.30, 56.51, 117.81, 119.02, 124.42, 125.77, 126.21, 128.42, 133.99, 139.47, 141.32, 148.50, 154.76, 154.88, 161.02, 169.49, 172.65. LCMS MH=454, 456; Anal Calcd For C22H20N5O4Cl: C, 58.22; H, 4.44; N, 15.43; Cl, 7.81. Found: C, 58.11; H, 4.24; N, 15.16; Cl, 7.80.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].C([NH:22][CH2:23][CH2:24]O)(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:24][CH2:23][NH2:22])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCN)c([N+](=O)[O-])c1
Yield: 38.6 %

Procedure:
To a stirred solution of methyl 3-nitro-4-hydroxybenzoate (1.98 g, 10.04 mmol), N-Boc ethanolamine (1.63 g, 10.11 mmol) and PPh3 (3.43 g, 13.08 mmol) in THF (40 mL) was added DIAD (2.57 mL, 13.05 mmol), and the reaction mixture was then heated under reflux overnight. The resulting mixture was evaporated to give a gum. The residual crude gum was dissolved in CH2Cl2 (30 mL) and TEA (30 mL), and the mixture was stirred for 1 hr at room temp. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2SO4. The solvent was evaporated in vacuo to give the oily residue, which was purified by column chromatography on silica-gel with CHCl3 then CHCl3—MeOH (20:1, v/v) as eluent to give 930 mg (27% for 2 steps ) methyl 3-nitro-4-(2-aminoethoxy)benzoate as gum. 1H-NMR (CDCl3) d 3.16-3.19 (m, 1 H), 3.53-3.57 (m, 1 H), 3.90 and 3.94 (s, 3 H), 3.95-3.98 (m, 1 H), 4.21-4.24 (m, 1 H), 6.89-6.91 and 7.11-7.13 (m, 1 H), 8.03-8.19 and 8.21 (m, 1 H), 8.52 and 8.86 (m, 1 H).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][NH:23][CH2:22]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][N:23]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:7])=[CH:4][CH:3]=1)[CH2:22]2
Reactant: C1CC2CNCC(C1)C2
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CC3CCCC(C3)C2)cc1

Procedure:
A solution of 4-fluoro-N-quinolin-3-yl-benzamide (0.080 g, 0.299 mmol), 3-aza-bicyclo[3.3.1]nonane (0.200 g, 1.60 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in dimethyl sulfoxide (2 mL) was heated to 100° C. for 11 days. The DMSO solution was applied to a preparative reverse phase C18 column, and the product was eluted with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, to give the product as a trifluoroacetate salt, a yellow solid, 0.065 g (36%). MS: m/z 372 (MH+). 1H NMR (DMSO-d6): 1.40-1.50 (m, 1 H), 1.58-1.93 (m, 7 H), 2.05 (br s, 2 H), 3.04-3.08 (m, 2 H), 3.85 (d, 2 H), 7.00 (d, 2 H), 7.62-7.76 (m, 2 H), 7.96 (d, 2 H), 8.02 (d, 2 H), 8.95 (d, 1 H), 9.28 (d, 1 H) and 10.45 (s, 1 H).
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([NH2:19])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35](O)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35]([NH:19][CH:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(CC1CCC1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 47 from α-cyclobutylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[N:7]1.Cl.[OH-].[Na+]>CCOCC>[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2([NH2:12])[CH2:2][CH2:1]2)=[N:7]1
Reactant: CC[Mg]Br
Reactant: Cn1ccc(C#N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cn1ccc(C2(N)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl magnesium bromide (2.5 mol, 1 M in ether) was added at −78° C. to a solution of a 1-methyl-1H-pyrazole-3-carbonitrile (0.5 g, 1 mmol) and Ti(Oi-Pr)4 (1.1 mmol) in Et2O (5 mL). The yellow solution was stirred for 10 min. After the solution was warmed to ambient temperature (1 h), BF3OEt2 (2 mmol) was added. After the mixture was stirred for 1 h, 1 N HCl and ether were added. NaOH (10%) was added to the resulting two clear phases and the mixture was extracted with ether. The combined ether layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Et2O). 1H NMR (400 MHz, CDCl3): δ 0.94-1.05 (m, 4H), 2.32 (s, 2H), 3.83 (s, 3H), 5.92 (d, 1H), 7.23-7.24 (d, 1H). LCMS: (ES+) m/z observed 137.7.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:9][C:8]=1[F:18].[C:19](=[O:21])=[O:20].Cl>C1CCCCC1.O1CCCC1.O>[F:18][C:8]1[C:7]([F:6])=[CH:12][CH:11]=[C:10]([O:13][CH2:14][C:15]([CH3:17])=[CH2:16])[C:9]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: C=C(C)COc1ccc(F)c(F)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C=C(C)COc1ccc(F)c(F)c1C(=O)O
Temperature: -75 °C
Reaction time: 2.5 h

Procedure:
To a 1.4 M solution of sec-butyllithium in cyclohexane (6.7 mL) and anhydrous tetrahydrofuran (15 mL) at −75° C. was added 1,2-difluoro-4-(2-methylallyloxy)benzene (731) (1.6 g, 8.68 mmol). The resulting mixture was stirred at −75° C. for 2.5 hours and was then transferred to a round bottom flask containing dry ice. The resulting mixture was shaken for 5 min, and water (10 mL) was added dropwise. The mixture was acidified to pH 1 with concentrated hydrochloric acid and extracted with EtOAc (80 mL×3). The organic phase was washed with brine (60 mL×2), water (60 mL), and dried over anhydrous sodium sulfate, and the solvent removed in vacuo to give an oil 2,3-difluoro-6-(2-methylallyloxy)benzoic acid (732) (1.9 g), The product was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+]>C(OCC)(=O)C.O.[Ru](=O)(=O)(=O)=O>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:11](=[O:21])[CH2:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CCN(C(=O)OC(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Step B (0.275 g, 1.01 mmol) was dissolved in ethyl acetate (5 mL). A solution of sodium periodate in water (0.5 g in 5 mL) and ruthenium tetroxide (13 mg, 0.10 mmol) was added, and the heterogeneous reaction stirred vigorously overnight at room temperature. An additional portion of sodium periodate in water was added (0.5 g in 5 mL) and the reaction stirred overnight. The reaction was quenched with 10% sodium thiosulfate, and filtered through celite. The phases were separated, and the organic phase dried over magnesium sulfate. Filtration and evaporation gave the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][OH:22])[CH:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][O:22][C:28]2=[O:30])[CH:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1Nc1ccccc1CO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)OCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-Boc-4-(2-hydroxymethylphenylamino)-3-piperidine carboxylate from Step 2 above (4.1 g, 11.3 mmol) was stirred in THF (40 mL) in an ice bath and treated with triphosgene (1.11 g, 3.74 mmol) followed by triethylamine (4.7 mL, 3.41 g, 33.7 mmol). The mixture was stirred at ambient temperature for 18 h, then treated with an additional 0.47 g of triphosgene and 1.9 mL of triethylamine, and stirred an additional 4.5 h. Water was added and the mixture was extracted with ethyl acetate. The combined ethyl acetate layers were washed with 2N HCl then with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with CHCl3 followed by 1:99 MeOH:CHCl3. The combined product fractions were evaporated to dryness in vacuo to give methyl 1-Boc-4-(3,1-benzoxazin-2-one-1-yl)-3-piperidine carboxylate.