Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C=O>[O:21]=[C:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:22])[F:23])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]1[CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: CCOC(=O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(CN2C(=O)CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)c1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a mixture of 95% dry sodium hydride (18 mg, 0.75 mmol) in anhydrous N,N-dimethylformamide (4 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (90 mg, 0.31 mmol) (PT-010 made as in Example 1B, above) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of ethyl 3-(chloromethyl)benzoate (100 mg, 1.00 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature until most of the starting material was converted (checked by LCMS), then it was quenched by addition of methanol (5 mL). The reaction mixture was concentrated under a reduced pressure, diluted with ethyl acetate (50 mL), and the organic phase washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL) and subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford ethyl 3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate (compound no. 91) (108 mg, 0.24 mmol, 77%) (PT-094). LCMS mz 455.0 (M+H), 476.0 (M+Na), anal HPLC >95% in purity. 1H NMR (400 MHz; CDCl3) δ 7.94 (m, 2H); 7.64 (m, 4H); 7.41 (m, 3H); 7.30-7.37 (m, 1H); 6.92 (d, J=8.6 Hz, 1H); 5.27 (s, 2H); 4.37 (q, J=7.0 Hz, 2H); 3.08 (m, 2H), 2.86 (m, 2H); 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OCC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:16])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: N
Reactant: CCOC(=O)c1cc2cc(C)ccc2o1
Solvent: CO
Product: Cc1ccc2oc(C(N)=O)cc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 5-methylbenzofuran-2-carboxylate, (1.19 g, 5.83 mmol) was suspended in 20 ml of 7M NH3 in MeOH. The mixture was stirred at 50° C. in a sealed tube overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure to give pure 5-methylbenzofuran-2-carboxamide, as a white solid (1.02 g). LCMS retention time=1.00 minutes (LC method 3); MS (m+1)=175.8. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.45 (d, J=0.9 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.53 (t, J=0.7 Hz, 1H), 7.63 (br. s., 1H), 8.05 (br. s., 1H).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[NH:23]>>[CH3:20][C:21]([C:22]1[N:23]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[N:24]=1)([CH3:26])[CH3:25]
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Product: CC(C)(C)c1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 54 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and 2,2-dimethylpropionamidine hydrochloride. Yield: 54%.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C@@H:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:18][CH:17]=1>CO>[ClH:1].[ClH:1].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(O)cc2)[C@@H](COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1ccc(O)cc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 88 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of (R)-tert-butyl 4-(4-hydroxyphenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (182 mg, 0.335 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 118 mg (88%) of the title compound as a white solid. LC-MS: RT=2.11 min, [M+H]+=329.1.
Reaction SMILES: Cl.[CH:2]1([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[C:14]([C:13]1[CH:12]=[N+:11]([O-:25])[CH:10]=[CH:9][C:8]=1[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)([OH:16])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1cnccc1C1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)c1c[n+]([O-])ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyclohexylnicotinic acid hydrochloride (4.5 g, 0.018 mol) is dissolved in methylene chloride (40 ml). This solution is mixed with a cold solution of metachloroperbenzoic acid (10.82 g, 0.063 mol) in CH2Cl2 (80 ml), and the resulting mixture is stirred at room temperature overnight. The precipitate obtained is filtered and the filtrate evaporated to dryness. The residue is suspended in ether. The precipitate is filtered, washed with ether and dried to yield 3-carboxy-4-cyclohexyl-pyridine N-oxide, m.p. 168°-169°. (c) To a solution of 3-carboxy-4-cyclohexyl-pyridine N-oxide (3.09 g, 0.014 mol), sodium cyanide (2.47 g, 0.05 mol) and triethylamine (7.08 g, 0.07 mol) in absolute dimethylformamide (50 ml), chlorotrimethylsilane (7.6 g, 0.07 mol) is added. The reaction mixture is then heated for 28 h at 85°. After cooling, the inorganic salts are filtered, washed with diethyl ether, and the filtrate is evaporated at 50° in vacuo. The dark residue is purified by chromatography on Florisil® (ethyl acetate/methanol 4:1) to yield 5-carboxy-2-cyano-4-cyclohexyl-pyridine; m.p. 225°-230°, Rf =0.55.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(O)(O)=[O:38].C(#N)C.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[C:32]=1[F:33])[C:11]([C@@H:12]([NH:14][C:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([OH:23])=[O:38])=[O:24])[CH3:13])=[CH:10]2
Reactant: O=C(O)O
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: OB(O)c1cccc(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@H](NC(=O)c1ccccc1C(=O)O)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1F
Temperature: 85 °C
Reaction time: 19 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.5388 mmol), 2,3-difluorobenzeneboronic acid (0.09358 g, 0.5926 mmol), tetrakis(triphenylphosphine)palladium (0.03113 g, 0.02694 mmol), and sodium carbonate anhydrous (0.2855 g, 2.694 mmol) in acetonitrile-water (3:1) (5.200 mL, 0.5387 mmol) was stirred at 85° C. After 19 h, the mixture was cooled to room temperature and partitioned between CH2Cl2 (30 mL) and 2 N HCl (30 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(((S)-1-(8-chloro-2-(2,3-difluorophenyl)quinolin-3-yl)ethyl)carbamoyl)benzoic acid as a yellow foam type solid: LC-MS (ESI) m/z 467.0 [M+H]+.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: CN1C[C@H](O)C[C@H]1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C
Yield: 100 %

Procedure:
Concentrated hydrochloric acid (3 mL) was added to a suspension of (2S, 4R)-4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid (3 g) in methanol (15 mL), and the mixture was refluxed for 4 hours. The solvent of the reaction mixture was removed by distillation under reduced pressure to give the title compound (4.0 g, yield 100%).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[N:24]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[N:24]=[C:25]([NH:29][C:7]2[N:8]=[CH:9][C:4]3[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:5]=3[N:6]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(N)n1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3cccc(N)n3)ncc12
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccccn3)ncc12
Temperature: 120 °C
Yield: 18.8 %

Procedure:
A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (370 mg, 1.0 mmol) and 2,6-diaminopyridine (163 mg, 1.5 mmol) in toluene (5 mL) was heated at 120° C. overnight. The solid formed upon cooling was collected by filtration, washed with toluene and sonicated in hot MeOH. After filtration the solid was dried further to give the desired product 2-(6-amino-pyridin-2-ylamino)-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (39 mg, 9.3%). mp: >274.6˜276° C. Calc'd for C18H19BrN6O.0.2H2O: C, 51.61; H, 4.67; N,20.06. Found: C, 51.42; H, 4.44; N, 19.87.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])O[CH2:12][CH3:13]>>[CH2:12]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH3:13]
Reactant: O=C1CCCCCCC1
Reactant: CCOC([O-])[O-]
Product: CCOC1=CCCCCCC1
Yield: 44.2 %

Procedure:
In the presence of 0.3 g of paratoluenesulfonic acid, 20 g (0.16 mol) of cyclooctanone and 27 g (0.18 mol) of ethyl orthoformate were stirred at room temperature overnight. The resultant mixture was heated at 100° C. for 15 hours and distilled under reduced pressure to give 10.9 g (45% yield) of 1-ethoxycyclooctene having a boiling point of 97.5° to 98.5° C./25 mmHg.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH:7]=[CH:6][N:5]=[N:4]2)=[CH:12][CH:11]=1
Reactant: c1c[nH]nn1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a suspension of 3.5 g (0.139 mol) of sodium hydride in 120 mL of DMF at 0° C. was added 8 g (0.115 mol) of 1,2,3-triazole in 50 mL of DMF dropwise, and the mixture was allowed to warm to room temperature and stirred for 1 h. The above mixture was cooled to 0° C., and 21.8 g (0.139 mol) of p-methoxybenzyl chloride was added, and the mixture was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica (hexane/ethyl acetate) to afford 14 g (64.5%) of 1-(p-methoxybenzyl)-1,2,3-triazole.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13](O)[CH:14]=[CH2:15].Cl.C(N=C=NCCCNC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:12][CH2:15][CH:14]=[CH2:13])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: C=CCO
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CCN=C=NCCCNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)CP(=O)(OCC)OCC
Yield: 82.2 %

Procedure:
29.2 g of the diethylphosphonoacetic acid thus obtained was dissolved in 350 ml of methylene chloride, and 17.8 g of allyl alcohol, 1.92 g of 4-dimethylaminopyridine and 29.0 g of 1-ethyl-3-(3-methylaminopropyl)carbodiimide hydrochloride were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, then sequentially washed with 1N hydrochloric acid, water, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure to obtain 28.9 g of allyl diethylphosphonoacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:18][CH3:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].II.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][NH:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)Cc1ccccc1OCc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCc1ccccc1OCc1ccccc1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
At 0° C., a solution of 2-(2-benzyloxyphenyl)-N-methylacetamide (9.39 g, 36.8 mmol) in tetrahydroufran (150 ml) was added dropwise to a suspension of sodium borohydride (1.67 g, 44.12 mmol) in tetrahydrofuran (100 ml). After the addition was finished, a solution of iodine (4.67 g, 18.39 mmol) in tetrahydrofuran (200 ml) was added dropwise. The solution was warmed to reflux for 16 h. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in an aqueous 20% sodium hydroxide solution (200 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×75 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using dichloromethane/methanol/25% aqueous ammonia as eluent (100:10:1), to give 4.38 g of N-(2-(2-benzyloxyphenyl)ethyl)-N-methylamine.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:10]
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccccc1O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccccc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 1.4 g (0.01 mole) of salicylic acid and 1.03 g (0.01 mole) of 5-aminotetrazole monohydrate in 40 ml. of pyridine was added dropwise 1.0 g (0.008 mole) of thionyl chloride. The mixture was stirred for one hour at 50° C. The stirred mixture was poured into water, acidified, and cooled. The resulting precipitate was collected by filtration and recrystallized from ethanol to provide 1.2 g 2-hydroxy-N-(tetrazol-5-yl)benzamide, in the form of a white solid, m.p. 264°-266° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:10][CH:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl.[NH2:25][OH:26]>CO>[N:1]1([CH2:6][CH:7]2[CH2:10][CH:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:25][OH:26])=[NH:16])=[CH:17][CH:18]=3)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2CC(CN3CCCC3)C2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc(C2CC(CN3CCCC3)C2)cc1
Temperature: 70 °C
Yield: 29.5 %

Procedure:
To a stirring solution of Example 222 (4-(3-Pyrrolidin-1-ylmethyl-cyclobutyl)-benzonitrile) (150 mg, 0.62 mmol) in MeOH (1.5 mL) was added NaHCO3 (58 mg, 0.62 mmol), followed by hydroxylamine hydrochloride (43.4 mg, 0.62 mmol). The reaction was then heated to 70° C. over night. Both TLC and MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and concentrated under reduced pressure. Water was added and a gummy solid formed. The water was removed and the residual was taken up in MeOH and concentrated under reduced pressure to yield the title compound (50 mg, 29% yield). This material was used without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][C:38]([NH2:40])=[O:39]>>[NH2:40][C:38](=[O:39])[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(N)=O
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(N)=O)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]4-carboxylic acid, and 2-aminoacetamide, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=423.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:18][CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:20]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCC1(c2cccs2)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(c2cccs2)OC(=O)N(C)c2ccc(Nc3ccc(Br)cc3)cc21

Procedure:
Prepared 6-amino-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in Example 1. MS (ESI) m/z 443/445 ([M+H]+); MS (ESI) m/z 441/443 ([M−H]−); Anal. calcd for C21H19BrN2O2S: C, 56.89; H, 4.32; N, 6.32. Found: C, 56.65; H, 4.09; N, 6.18.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17]CC)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CC1(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a 0° C. solution of ethyl 2-(benzyloxycarbonylamino)-1-hydroxycyclopropanecarboxylate (6b, 12.5 g, 44.7 mmol) in THF (100 mL) was added K2CO3 (24.7 g, 179.0 mmol) as a solution in H2O (300 mL). The reaction was allowed to warm to room temperature and stirred for 4 h and then additional H2O (200 mL) was added. After stifling an additional 18 h at room temperature the reaction was concentrated to remove most of the THF. The remaining aqueous solution was washed with Et2O (2×500 mL), acidified with 2 N HCl to pH 2, and then extracted with EtOAc (5×200 mL). The combined EtOAc layers were washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compounds (7.75 g, 69%) as a mixture of diastereomers. The mixture was triturated with Et2O to afford a white solid as mostly the major diastereomers. The supernatant was concentrated and then triturated with Et2O to afford a clean mixture of both diastereomers. Major Diastereomer: 1H NMR (300 MHz, MeOD) δ 7.50-7.14 (m, 5H), 5.22-4.96 (m, 2H), 3.23-3.10 (m, 1H), 1.60 (dd, J=8.9, 6.3 Hz, 1H), 1.10 (t, J=6.2 Hz, 1H); Multimode (APCI+ESI) MS m/z 250 [M−H]−. Mixture of Diastereomers: 1H NMR (300 MHz, MeOD) δ 7.45-7.14 (m, 5H), 5.24-5.01 (m, 2H), 3.25-3.15 (m, 0.46H), 3.14-3.01 (m, 0.54H), 1.71-1.53 (m, 1H), 1.42 (dd, J=9.1, 6.4 Hz, 0.54H), 1.12 (t, J=6.2 Hz, 0.46H); Multimode (APCI+ESI) MS m/z 250 [M−H]−.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Reactant: CNC
Solvent: CCO
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(N(C)C)cc1

Procedure:
A mixture of 11.0 g (0.05 mole) of 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one, 100 ml of 30% aqueous solution of dimethylamine and 200 ml of ethanol is heated in a pressure bomb at 130°-135° C. for 22 hours. The mixture is cooled, the solid is collected and recrystallized from isopropanol-water to give the title compound. M.P. >310° C. λ(max)(methanol) 364 nm (ε=23,300).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:43])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:43])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (322 mg, 79%).