Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O.CC(C(OC(=O)C[N:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])[CH3:39])C)(C)C>O1CCCC1>[CH3:7][C:6]([CH3:9])([O:5][C:3](=[O:4])[CH2:2][N:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])[CH3:39])[CH3:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(OC(=O)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)(C)C
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (32.16 g., 72 mmole), tert-butyl bromoacetate (14.2 g., 72 mmole), triethylamine (20.1 ml., 144 mmole), and tetrahydrofuran (290 ml.) are stirred at room temperature for 72 hours. Benzyl chloroformate (12.4 ml., 87.8 mmole) and triethylamine (12.5 ml., 87.8 mmole) are added and the mixture stirred overnight. The reaction product is evaporated, and partitioned between water and ethyl acetate. The ethyl acetate solubles are washed with dilute hydrochloric acid and then water. The ethyl acetate solution is then evaporated and chromatographed over silica gel (mesh 230-400) using the solvent system ethyl acetate/hexane (1:1) (10 psi pressure) to give 19.5 g. of 1-[N-[2-(1,1-dimethylethylethoxy)-2-oxoethyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[CH:7]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=1)([O-:3])=[O:2].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>O1CCOCC1>[CH2:20]([NH:22][C:23]([NH:13][C:10]1[S:11][C:12]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][C:8]=2[N:9]=1)=[O:24])[CH3:21]
Reactant: Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Temperature: 100 °C
Yield: 23.8 %

Procedure:
A stirred mixture of 7-Nitro-5-pyridin-3-yl-benzothiazol-2-ylamine (100 mg, 0.3676 mmol), ethyl isocyanate (0.18 ml, 1.831 mmol) and dibutyltindiacetate (10 drops) in anhydrous 1,4-dioxane (10 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the precipitated solid was collected by filtration, washed with 1,4-doxane and dried in vacuo to give 1-Ethyl-3-(7-nitro-5-pyridin-3-yl-benzothiazol-2-yl)-urea as a yellow solid (30 mg, 24%).
Reaction SMILES: [N:1]1([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[N:1]1([C:13]2[CH:19]=[CH:18][C:16]([NH:17][C:21]3[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)aniline (55 mg) and 2-chloro-3-nitropyridine (35 mg) in NMP (3 mL) was stirred at 140° C. overnight. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) to afford N-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-3-nitropyridin-2-amine (34 mg) as a dark brown solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C:11](=[O:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](Cl)(Cl)Cl.[CH3:22][OH:23]>Cl>[CH3:22][O:23][C:11]1([O:17][CH3:18])[CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]2[CH2:15][O:16][C@@H:12]1[O:13]2
Reactant: ClC(Cl)Cl
Reactant: O=C1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reactant: CO
Agent: Cl
Product: COC1(OC)C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 0.5 h

Procedure:
1,6-Anhydro-4-O-benzyl-3-deoxy-β-D-erythro-hexopyranos-2-ulose (Example 6) (0.30 g) was dissolved in 3% HCl in dry methanol (10 ml) and the solution allowed to stand at room temperature for 0.5 h. Chloroform was added and the solution was washed with saturated aqueous sodium hydrogen carbonate, water, dried (MgSO4), and concentrated to a syrup. Purification by flash chromatography on silica gel gave the title compound (0.29 g) [α]D -52.1°; 13C-nmr data: 99.6 (C-1), 96.8 (C-2), 29.0 (C-3), 72.6 (C-4), 74.6 (C-5), 65.9 (C-6), 70.6 (PhCH2O), 138.1, 128.5, 127.7 and 127.6 (aromatic), 49.1 and 47.9 (OCH3).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[C:11]2[O:12][CH:13]([CH3:17])[C:14](=[O:16])[NH:15][C:10]=2[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][CH:2]([F:4])[O:5][C:6]1[C:11]2[O:12][CH:13]([CH3:17])[C:14](=[O:16])[NH:15][C:10]=2[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=1
Reactant: CC1Oc2c(O)cc(C=O)cc2NC1=O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 65.1 %

Procedure:
A 40 mL vial cooled in a dry ice/acetone bath was charged with chlorodifluoromethane (0.209 g, 2.413 mmol) followed by the addition of 8-hydroxy-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 398A (0.5 g, 2.413 mmol), Cs2CO3 (0.786 g, 2.413 mmol) and DMF (4.83 mL). The dry ice/acetone bath was removed; and with continued stirring, the reaction was slowly warmed to 23° C. After 2.5 hr, the reaction was transferred to a sand bath and stirred at 70° C. for 72 hr. The crude material was purified by prep HPLC-MS (30-55% MeCN in water, basic mode). The fractions were collected and concentrated in vacuo to give the title compound as a white solid (0.404 g, 57% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.51 (m, 3H) 4.93 (q, J=6.82 Hz, 1H) 7.08-7.28 (m, 1H) 7.32 (d, J=1.77 Hz, 1H) 7.46 (d, J=1.01 Hz, 1H) 9.83-9.88 (m, 1H) 11.14 (s, 1H). ESI-MS: m/z 258.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:22][CH3:23])[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH:18]=O)=[O:15])=[CH:7][CH:6]=2.N1C=CC=CC=1.Cl.[CH2:31]([O:35][NH2:36])[CH2:32][CH2:33][CH3:34].C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:22][CH3:23])[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH:18]=[N:36][O:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:15])=[CH:7][CH:6]=2
Reactant: CCCCON
Reactant: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCCON=CC(C)(C)NC(=O)C(Oc1ccc2ncc(Br)cc2c1)SC
Yield: 97.5 %

Procedure:
2-(3-Bromo-quinolin-6-yloxy)-N-(1,1-dimethyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (0.1 g) from Stage 2, Step 2 above, pyridine (0.022 ml) and O-n-butyl-hydroxylamine hydrochloride (0.035 g) in methanol (5 ml) were stirred at rt for 3 hours. The reaction mixture was diluted with ethyl acetate and poured onto sat. NaHCO3 (30 ml). The two phases were separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 3:1) to give 2-(3-bromo-quinolin-6-yloxy)-N-(2-butoxyimino-1,1-dimethyl-ethyl)-2-methylsulfanyl-acetamide as white solid (0.115 g). 1H NMR (CDCl3) δ ppm: 8.81 (1H, d); 8.24 (1H, d); 8.04 (1H, d); 7.71 (1H, s); 7.45 (1H, dd); 7.39 (1H, s); 7.17 (1H, d); 5.64 (1H, s); 4.08 (2H, t); 2.19 (3H, s); 1.68-1.58 (8H, m); 1.45-1.36 (2H, m), 0.94 (3H, t).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1[C:41](NC1C=CC(C(O)=O)=CC=1)=[O:42]>>[O:42]1[CH2:1][CH2:7][C@@H:8]([CH2:9][NH:10][C:29]([C:26]2[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:31])[CH2:41]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Reactant: NCCCc1ccccc1
Product: O=C(NC[C@@H]1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (S)-(tetrahydrofuran-3-yl)methamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.12 (t, J=6.1 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 4.89 (s, 4H), 3.80-3.55 (m, 3H), 3.50 (dd, J=8.5, 5.2 Hz, 1H), 3.37-3.31 (m, 2H), 2.63-2.51 (m, 1H), 2.01-1.85 (m, 1H), 1.71-1.55 (m, 1H); MS (ESI(+)) m/e 368 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18](OCC)=[O:19])=[N:16][N:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1.CO>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([CH2:18][OH:19])=[N:16][N:15]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c2cc(Cl)ccc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Temperature: 0 °C
Yield: 91.5 %

Procedure:
2.5 g (66.1 mmol) of sodium borohydride are added to a solution of 4.04 g (10.6 mmol) of ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-carboxylate in 150 ml of tetrahydrofuran. 2.25 ml of methanol are gradually added, with stirring, and then the mixture is heated at reflux for 5 hours. The mixture is poured onto an ice-cold 1 M hydrochloric acid solution and an insoluble product is separated by filtration on sintered glass, which product is washed with water and with diethyl ether and then dried. 3.3 g (9.7 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([OH:32])[CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:9]=2)[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=2[N:4]=1)[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)[OH:32])[N:14]3[CH3:17])=[C:10]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:9]=2)[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(hydroxy)methyl)piperidine-1-carboxylate (0.320 g, 0.555 mmol) in Methylene chloride (10 mL, 200 mmol;) was added Trifluoroacetic Acid (0.50 mL, 6.5 mmol;). The reaction was stirred at room temperature for 1 hr. and the reaction mixture was evaporated to dryness. To the residue was added 2M NH3 in MeOH to neutralize any residual acid. The mixture was then evaporated to dryness. The crude was then purified by flash chromatography (0-15% MeOH in DCM) to give the desired product as pinkish paste (0.24 g, 91%). LCMS m/z 477.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C

Procedure:
A solution of 4-fluoro-2-methylphenol (10 g, 79.28 mmol), ethyl 2-bromoisobutyrate (23.2 mL, 158.6 mmol), potassium carbonate (21.9 g, 158.6 mmol), and DMSO (80 mL) was stirred at room temperature for 72 hours. Water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to afford ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate. To a solution of ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate (13.3 g, 55.44 mmol) in tetrahydrofuran (40 mL) and methanol (10 mL) was added NaOH (6.66 g, 166.32 mmol) in water (14 mL) and stirred overnight. The volatiles were removed in vacuo and acidified with concentrated HCl. The milky white solution was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoic acid (658) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]#[N:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[Li+].[OH-:26]>O1CCOCC1>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:19])=[O:26])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: N#Cc1cccc2c(NCc3cccc(C(F)(F)F)c3)ccnc12
Reactant: [OH-]
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 90 °C
Yield: 34 %

Procedure:
To a solution of 4-{[3-(trifluoromethyl)benzyl]amino}quinoline-8-carbonitrile (20 mg, 0.05 mmol) in 2 mL of dioxane, 2N LiOH solution (250 μL, 0.5 mmol, 10 equiv.) was added. The resulting mixture was heated at 90° C. by microwave for 20 min. After work-up, the crude was purified by preparative HPLC to yield the title compound as a white solid in 34% yield. 1HNMR (in DMSO): 4.92 (d, J=5.8 Hz, 2H), 6.93 (d, J=7.4 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.85 9s, 1H), 7.87 (d, J=8.1 Hz, 1H), 8.22 (s, 1H), 8.48-8.54 (m, 2H), 8.75 (s, 1H), 8.80 (d, J=8.4 Hz, 1H), 10.06 (s, 1H). Mass: M+H+: 346.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=O)=[O:5].[CH2:29]([O:33][NH2:34])[CH2:30][CH2:31][CH3:32]>>[CH2:29]([O:33][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:6]([C:4](=[O:5])[C:3]2[CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[CH:19][C:2]=2[Cl:1])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCON
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: CCCCONC(=O)c1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1

Procedure:
Compound 424 (100 mg, 0.25 mmol) and O-butyl-hydroxylamine (63 mg, 0.50 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 20/80 to 60/40) provided the title compound. 13C NMR (CDCl3) δ 195.4, 165.9, 159.3 (dd), 155.7 (dd), 148.3, 142.0, 139.8, 135.4, 133.8, 131.7, 129.5, 129.1, 128.6, 127.7, 124.6 (dd), 124.1 (dd), 116.2, 112.8, 111.7 (dd), 105.0 (dd), 76.9, 30.1, 20.4, 19.1, 13.8
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:32][C:33]([O:35]C)=[O:34].[Cl-].[NH4+]>O1CCCC1>[C:13]1([CH2:19][C:20]([CH2:32][C:33]([OH:35])=[O:34])([CH3:1])[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CBr
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(=O)CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(CC(=O)O)(Cc1ccccc1)C(=O)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dissolve diisopropylamine (0.88 mL, 6.28 mmol) in tetrahydrofuran (7.5 mL). Cool in an ice bath and add, by dropwise addition, n-butyllithium (3.6 mL of a 1.6M solution in hexanes, 5.75 mmol). Stir for 15 minutes, then cool to -78° C. Add a solution of 3-phenylpropionic acid, t-butyldimethylsilyl ester (1.33 g, 5.04 mmol) in tetrahydrofuran (5 mL). Stir for 45 minutes then add methyl bromoacetate (949 mg, 6.2 mmol). Stir for 3 hours, add saturated ammonium chloride (6 mL) and warm to room temperature. Partition between ethyl ether (75 mL) and water (10 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography to give 3-phenyl-2-methylcarboxymethylpropionic acid, t-butyldimethylsilyl ester.
Reaction SMILES: [NH:1]([C:26]([CH3:28])=[O:27])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23](O)=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.[NH2:36][C@H:37]([C:49]([NH:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:50])[CH2:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.CN(C=O)C>[NH:1]([C:26]([CH3:28])=[O:27])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([NH:36][C@H:37]([C:49]([NH:51][CH2:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:50])[CH2:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1)C(C)C
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
The ketoamide (8) (227 mg, 0.5 mmol) was dissolved in ethyl acetate (10 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure to give 22. To a solution of Ac—Tyr—Val—Ala—OH (197 mg, 0.5 mmol) in dry THF (10 mL) and DMF (2 mL) cooled to −15° C. was added N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) followed by iso-butyl chlorofornate (68 mg, 65 μL, 0.5 mmol) and the solution stirred at −15° C. for 5 min. A previously prepared solution of 22 and N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) in dry THF (5 mL) was added, the solution stirred at −15° C. for 15-30 min and then at r.t. for 16 h. The solution was filtered and the solvent removed under reduced pressure to yield the product which was recrystallized from methanol/ether to give 340 mg (93%) of Ac—Tyr—Val—Ala—Asp(Bzl)—CONH—CH2CH2Ph: mp 192-194° C.; 1H NMR (DMSO) δ0.77 (m, 6H, Val CH3's), 1.19 (m, 3H, Ala CH3), 1.74 (s, 3H, Ac CH3), 1.93 (m, 1H, Val β-CH), 2.62 (obs, 2H, CH2Ph), 2.77 & 3.18 (m, 4H, Tyr & Asp β-CH2's), 3.37 (m, 2H, NH-CH2), 3.75, 4.09, 4.19 & 4.53 (m, 4H, α-CH's), 5.06 (s, 2H, benzyl CH2), 6.62 & 7.01 (2xd, 4H, Tyr aromatic CH's), 7.20 (m, 5H, phenethyl aromatic CH's), 7.35 (s, 5H, benzyl aromatic CH's), 7.83 (m, 1H, NH), 8.04 (m, 4H, NH's), 9.15 (s, 1H, Tyr OH); FABMS m/e 730 (M++1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@@H]2CCCC[C@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)cc2C)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Yield: 52.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (144 mg, 0.230 mmol) prepared in Example 170a, triethylsilane (0.184 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (15 mL) and 6 M hydrochloric acid (5.0 mL), to yield the title compound (51.7 mg, 52%) as a colorless solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]2)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)=O.[Pd].CO>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(C2CCC(=O)C2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CCCCCCCCc1ccc(C2CCC(=O)C2)cc1
Reaction time: 48 h

Procedure:
Several drops of formic acid and catalytic amount 5% Pd/C was added to a 25 mL flask charged with 10 mL methanol and 1.34 g (5 mmol) of 2. The reaction vessel was flushed with H2, 3 times, and then mounted with a H2 balloon. After two days of hydrogenolysis, the solute was filtered through a pad of silica, and concentrated to provide a yellow oil. 1.32 g (98%) product was collected. 1H NMR (CDCl3) δ 7.18 (s, 4H, ArH), 3.38 (m, 1H, ArCHCC), 2.60 (t, 2H, CCCH2CH2), 2.45-1.91 (m, 6H, cyclo-pentyl), 1.64-1.15 (m, 12H, CH2), 0.90 (t, 3H, CH3); 13C NMR (CDCl3) δ 220, 142, 140, 129, 127, 46, 42, 39, 36, 32, 32, 32, 30, 30, 29, 23, 14.
Reaction SMILES: F[C:2]1[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:20]1[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].BrC1C=[C:43]([NH:56]S(CC)(=O)=O)[CH:44]=[CH:45][C:46]=1OC1C=CC(F)=CC=1F>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[O:26][C:25]1[CH:24]=[CH:23][C:22]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:21][C:20]=1[C:6]1[CH:7]=[C:2]([N:56]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cc(N2CCCC2)c1=O

Procedure:
The title compound was prepared in a manner similar to Example 122, substituting 1-methyl-3-pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one and N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. LCMS (M+H)+=476.