Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.CC1[N:6]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([C:28]4[N:33]=[CH:32][C:31]([C:34]5[N:39]=[N:38][C:37]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)([CH3:27])[CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=3)=[CH:13][N:12]=2)C(C)=CC=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CCO.O>[NH2:6][C:11]1[N:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[N:39]=[N:38][C:37]([C:40]([OH:43])([CH3:41])[CH3:42])=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)([CH3:27])[CH:24]([CH3:25])[CH3:26])=[CH:21][CH:22]=2)=[CH:15][N:16]=1
Reactant: Cc1ccc(C)n1-c1ncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(C)(C)O)nn4)cn3)C(C)C)cc2)cn1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(C)(c1ccc(-c2cnc(N)nc2)cc1)c1ccc(-c2ccc(C(C)(C)O)nn2)cn1
Temperature: 80 °C

Procedure:
Hydroxylamine hydrochloride (94.0 mg, 1.350 mmol) was added to a stirred solution of 4e (72.0 mg, 0.135 mmol) and triethylamine (10.0 μL, 0.0730 mmol) in EtOH/water (900 μL of a 2:1 mixture, respectively) at rt, and the resulting mixture was heated at 80° C. for approximately 14 h. After cooling to rt, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 4f. m/z (ES) 455 (MH)+.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=O>Cl.C(O)CC>[N:19]1([C:9]2[N:8]=[CH:7][C:6]([NH2:5])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:10]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CCCO
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N
Temperature: 92.5 °C

Procedure:
A suspension of 2.93 g (8.28 mmol) 2,2-dimethyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-propionamide in 80 ml 3 N hydrochloric acid solution and 5 ml 1-propanol was heated to 90-95° C. overnight. The reaction mixture was cooled to room temperature, washed with three 20 ml portions diethyl ether and filtered over celite. The filtrate was diluted with 20 ml water and was adjusted to pH 7-8 by addition of 28% sodium hydroxide solution under ice cooling. The product was extracted with four 100 ml portions of dichloromethane. The combined organic layers were washed with 50 ml brine, dried (magnesium sulfate) and evaporated to give 2.31 g (quantitative) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:33]([O:35][P:36]([CH2:41][CH2:42][NH2:43])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:38]([O:37][P:36]([CH2:41][CH2:42][NH:43][CH2:26][C:23]([CH3:24])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[CH2:1][CH3:2])[CH2:9][O:8][C:7]2=[O:13])(=[O:40])[O:35][CH2:33][CH3:34])[CH3:39]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCNCC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reaction time: 4 h
Yield: 98.7 %

Procedure:
4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalate salt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid (15.7 mg, 0.263 mmol) was added, followed by sodium triacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hrs, the crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide 27.7 mg (97%) of the desired product after lyophilization. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.14 (t, J=7.5 Hz, 3H), 1.26 (m, 2H), 1.30 (t, J=7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q, J=7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H), 5.15 (s, 2H), 5.51 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.39 ppm; MS=540 [M++1].
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[N:13]=2)=[CH:8][CH:7]=1)=[O:4]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:45][N:2]([CH3:1])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:33])[CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])[N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(CCN(C)C(=O)OC(C)(C)C)cc2-c2ccnc3[nH]c(-c4cccc(CO)c4)cc23)cc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Nc1ccc(-c2nn(CCN(C)C(=O)OC(C)(C)C)cc2-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)cc1
Temperature: 70 °C
Yield: 77.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl [2-(3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-4-{2-[3-(hydroxymethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (1.24 g, 2.0 mMol) in CHCl3 (100 mL) was added activated MnO2 (2.5 g, 28.7 mMol). The reaction was stirred and refluxed (70° C. oil bath) for 8 h, cooled to RT, filtered through a pad of Celite®, rinsed with CHCl3, and evaporated to dryness under vacuum. Purification by flash chromatography on silica gel (5 to 10% MeOH in (1:1) EtOAc/CHCl3) provided the title compound (0.94 g, 77%) as a pale yellow solid. ESMS [M+H]+: 608.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:21][C:22]1([CH3:31])[CH2:27]C(O)[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1.[NH2-].[Li+].CO>CCCCCCCC>[CH3:21][C:22]1([CH3:31])[CH2:27][CH:1]([O:2][C:3](=[O:20])[CH2:4][N:5]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1
Reactant: CCCCN(CC(=O)OC)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCCC
Solvent: CO
Product: CCCCN(CC(=O)OC1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 80.8 %

Procedure:
To the same flask as used in Example 1 were added 28.4 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-n-butylglycine methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 0.23 g (0.01 mole) of lithium amide and 100 g of n-octane. The temperature was raised with stirring, and reaction was carried out at 128° to 130° C. for 5 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the n-octane. The n-octane layer was separated, and n-octane in the layer was removed by distillation to obtain 33.1 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-n-butylglycine(2,2,6,6-tetramethyl-4-piperidinyl)ester as a brown oily product. Yield, 81% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-n-butylglycine methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([C@H:46]([NH:48][C:49]([NH2:51])=[O:50])[CH3:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCOCC1.C(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[OH:9][CH2:8][C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=[C:2]([NH:51][C:49]([NH:48][C@@H:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:47])=[O:50])[N:7]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(CO)c12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(ii) (67.5 mg, 0.084 mmol), (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 385 mg, 0.844 mmol), cesium carbonate (825 mg, 2.53 mmol) and (R)-1-(1-phenylethyl)urea (277 mg, 1.689 mmol) were taken up in dioxane (5 ml) in a 1.5 mL microwave vial and the vial was evacuated and back-filled with N2 (×3). The reaction mixture was stirred at 90° C. for 2 hours. The crude reaction mixture was diluted with DCM and filtered through syringe filter. The filtrate was concentrated, and purified on 80 g Redsep gold silica gel 5-25% DCM/EtOAc to provide (R)-1-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS: [M+H]+ m/z 584.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (304 mg) in DMF (5 mL) was added sodium hydride (68 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-4′ nitroacetophenone (348 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an orange colored solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.O.NN>CO.[Ni]>[CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2
Reactant: CNc1ccc2nccnc2c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CNc1ccc2nccnc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a solution of N-methyl-5-nitroquinoxalin-6-amine (1.3 g, 6.4 mmol) in MeOH (100 mL) was added hydrazine hydrate (1.27 g, 25.5 mmol) and Raney Ni (0.2 g). The mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filtrate was concentrated under reduce pressure to give N6-methylquinoxaline-5,6-diamine as a black solid (1.14 g, yield 100%). ESI MS: m/z 175.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH2:22][N:23]3C(=O)C4=CC=CC=C4C3=O)=[N:20][N:19]=[C:18]2[Br:34])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.NN>>[Br:34][C:18]1[N:17]2[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:35])([F:1])[F:36])=[CH:16][C:7]=3[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:23][CH2:22][C:21]2=[N:20][N:19]=1
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Br)n1-2

Procedure:
The 5-trifluoromethyl-2-(3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone is reacted with hydrazine to form the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[NH2:26][C:27]1[C:28]([C:34]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:9]=2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2N)nc(C(F)(F)F)n1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)nc(C(F)(F)F)n1
Temperature: 50 °C
Yield: 81 %

Procedure:
A solution of tert-butyl 6-(3-aminopyridin-4-yl)-2-(trifluoro-methyl)pyrimidin-4-ylcarbamate (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv.), HOAt (1.0 equiv.), and EDC (1.0 equiv.) in DMF at a concentration of (0.2 M) was stirred for 3 hrs then heated to 50° C. overnight (homogeneous solution). Water was added to the reaction and the precipitate was filtered. The solid was further purified via SiO2 column chromatography eluting with DCM/MeOH (10%) to yield a brown solid as the desired product (81%). LCMS (m/z): 554.1/556.1 (MH+); LC Rt=3.77 min.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:20][C:19]([CH3:31])=[N:18][C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.Cl.[OH-].[Na+]>O1CCOCC1>[CH3:31][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH2:23][CH2:24][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=3)[CH2:16][C:17]=2[N:18]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(nc(C)nc3-c3ccccc3)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(c(-c3ccccc3)n1)CCN(c1ccnc([C@@H](C)O)n1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (R)-1-[4-(2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 86, Step E, 11.0 g, 26.4 mmol) in dioxane (13 mL) was added concentrated hydrochloric acid (22 mL, 264 mmol). This mixture was stirred at room temperature overnight, cooled to 0° C., neutralized via slow addition of 6 N aqueous sodium hydroxide, and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2→5% methanol/ethyl acetate) to give an oil which after titration with hexanes provided 8.0 g (88%) of the title compound as a white solid. mp: 114-116° C.; 1H NMR (CD3OD, 250 MHz) δ 8.26 (d, 1H), 7.62-7.47 (c, 5H), 6.52 (d, 1H), 4.79 (s, 2H), 4.66 (q, 1H), 4.24 (br s, 1H), 3.90-3.80 (c, 2H), 2.95 (t, 2H), 2.70 (s, 3H), 1.49 (d, 3H); MS (APCI) 348 (MH+), [α]D+15.6 (c 1.0, MeOH).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:29])[CH:7]([C:14]([NH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>C(O)C.O>[CH3:28][O:27][C:18]1[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[NH:16][C:14]([CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([OH:29])=[O:5])=[O:15]
Reactant: CCOC(=O)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Reaction time: 41 h

Procedure:
To a stirred solution of KOH (10.70 g, 0.191 mol) in absolute ethanol (1.1 L) was added α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl]benzene acetic acid ethyl ester (55.28 g, 0.1480 mol), and the mixture was stirred for 41 hours. The resulting suspension was diluted with H2O (~900 mL) and rotoevaporated to remove ethanol. The solution was washed (ethyl acetate) and acidified with dropwise addition of 1M HCl (265 mL). The resulting precipitate was filtered off, washed (H2O), and dried in vacuo to give an off-white solid; yield 48.4 g (100%); 111°-113° C. (gas evolution).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+:17].[NH2:18][CH:19]1[C:37](=[O:38])[N:21]2[C:22]([C:34]([OH:36])=[O:35])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12.Cl.CN(C)CCCN=C=NCC.Cl>O>[Na+:17].[Na+:17].[C:10]([CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]([NH:18][CH:19]1[C:37](=[O:38])[N:21]2[C:22]([C:34]([O-:36])=[O:35])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12)=[O:9])([OH:12])=[O:11].[C:7]([CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:10]([NH:18][CH:19]1[C:37](=[O:38])[N:21]2[C:22]([C:34]([O-:36])=[O:35])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12)=[O:11])([OH:9])=[O:8]
Reactant: O=C(O)C(C(=O)O)c1cccs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(C(=O)O)c3cccs3)[C@H]2SC1

Procedure:
A suspension of thien-2-ylmalonic acid (0.93 g., 0.005 M) in water (25 ml.) was adjusted to pH 6.0 with saturated sodium bicarbonate solution, 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylic acid was added, the solution again adjusted to 6.0, cooled to 0° and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.01 g., 0.005 M) added. The mixture was maintained at pH 5.8-6.0 with 6 N hydrochloric acid for two hours at room temperature then saturated sodium bicarbonate was added to pH 7.7 and the solution washed with ethyl acetate (50 ml.). The solution was acidified to pH 4.0, washed with ethyl acetate (2×25 ml.), acidified to pH 2.0 and extracted with ethyl acetate (2×50 ml.), The extracts were washed with water (25 ml.) and brine (25 ml.), dried over anhydrous magnesium sulphate, treated with 2 N sodium 2-ethylhexoate in methylisobutylketone (2 ml.), diluted with ether (200 ml.) and the precipitated disodium salt collected and dried in vacuo. Yield 1.16 g., 43.0%; U.V. spectrum (95% ethanol), λmax (ε=8.250). Paper chromatography (butanol/ethanol/water) showed a zone at Rf =0.05.
Reaction SMILES: [C:1]1([CH:7]([OH:15])[CH2:8][CH2:9]CS([O-])(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:17]>O1CCCC1>[NH2:17][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:15]
Reactant: O=S(=O)([O-])CCCC(O)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCC(O)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 3-phenyl-3-hydroxypropylmethanesulfonate (1.71 g, Gao, et al., J. Org. Chem., 1988, 53, 4081), tetrahydrofuran (10 mL) and 28% ammonium hydroxide (30 mL) was heated in a bomb at 65° C. for 16 hours. After cooling, the volatiles were eliminated to leave the aqueous solution which was extracted with ether. The aqueous layer was concentrated under reduced pressure, azeotroped twice with anhydrous acetonitrile and dried under vacuum to give 3-amino-1-phenyl-1-propanol (1.04 g) as a white solid: mp 92-94° C., Rf=0.1 (silica, methanol/ethyl acetate 1/1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCNCC1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: N#Cc1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and piperidine. Yellow solid. MS (ESI): 348.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[O:13][C:14]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][O:20][C:21]=2[CH3:22])=[N:15][N:16]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[O:13][C:14]([C:17]2[C:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:19][O:20][C:21]=2[CH3:22])=[N:15][N:16]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
To a suspension of 2-(2-methoxy-4-nitro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.53 mmol) in ethanol (2 mL) was added iron powder (148 mg, 2.64 mmol) and aqueous HCl (1 M, 0.53 mL, 0.53 mmol). The reaction mixture was stirred for 2 h at 90° C., cooled to ambient temperature and poured onto an aqueous solution of sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL) and then stirred for 1 h. Filtration over Hyflo® was followed by washing of the Hyflo® with ethyl acetate. The aqueous phase was extracted with ethyl acetate (20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (80 mg, 43%) as a white solid. MS: m/e=349.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1.[Si](OC[C@@H]1[C@@H](C2C=CC=CC=2)CNC1)(C(C)(C)C)(C)C>>[CH:2]([C@@H:3]1[C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:5]([C@H:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:4]1)=[O:1]
Reactant: O=C(OCc1ccccc1)[C@@H](c1ccccc1)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Product: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)c2ccccc2)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from of 2-(R)-(3-(R)-hydroxymethyl-4-(S)-phenylpyrrolidin-1-yl)-2-(phenyl)acetic acid, benzyl ester (from Step B) using a procedure analogous to that described in the preparation given above of Aldehyde 1: RF: 0.69 (3:2 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ2.70-3.32 (m, 5H), 3.61 (q, J=7.4, 1H), 4.15 (s, 1H), 5.12 (s, 2H), 7.13-7.48 (m, 15H), 9.68 (d, J=1.9, 1H).