Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44]O)[CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44][Br:1])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a slurry of N-bromo succinimide (3.54 g, 19.9 mmol) in DCM (30 ml) was added a solution of triphenyl phosphine (4.87 g, 18.8 mmol) in DCM (15 ml). The solution was stirred for a further 5 minutes before addition of pyridine (644 μl, 7.96 mmol) and a solution of (S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid cyclopentyl ester (2.0 g, 6.64 mmol) in DCM (20 ml). The solution was stirred for 18 hrs, concentrated in vacuo and the residual solvent azeotroped with toluene (3×30 ml). The residue was triturated with diethyl ether (30 ml) and ethyl acetate:heptane (1:9, 2×30 ml). The combined ether and ethyl acetate/heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9-2:8) to provide 1.34 g (55% yield) of title compound as a clear oil. 1H NMR (300 MHz, CDCl3), δ 5.25 (1 H, m), 5.05 (1H, bd), 3.45 (2H, m), 2.00-1.55 (12H, bm), 1.45 (9H, s).
Reaction SMILES: [OH:1][C:2]1[C:17]([CH:18]([CH3:28])[CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:5]2[O:6][C:7]([CH3:15])([CH3:14])[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:4]=2[CH:3]=1>[Pd].C(O)C>[OH:1][C:2]1[C:17]([CH:18]([CH3:28])[CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][C:5]2[O:6][C:7]([CH3:14])([CH3:15])[C@@H:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]3[C:4]=2[CH:3]=1
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1)C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: CC(CCCc1ccccc1)c1cc2c(cc1O)[C@H]1CCCC[C@H]1C(C)(C)O2

Procedure:
To a solution of 1.0 g. of dl-7,8,9,10-tetrahydro-2-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran in 75 ml. of ethanol is added 200 mg. of 5% palladium-on-carbon catalyst and the resulting mixture is hydrogenated at room temperature and 60 psig. (4.3 kg./cm2) until the theoretical amount of hydrogen is consumed. After filtering to remove the catalyst, the solvent was evaporated to provide the desired 6a,10a-cis compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[N:13]1([C:5]2[N:4]=[C:3]([NH2:18])[C:2]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[C:7]([N:8]3[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Cs+]
Agent: [F-]
Product: Nc1nc(-n2cccn2)nc(-n2cccn2)c1-c1nccs1
Temperature: 80 °C
Reaction time: 24 h
Yield: 47.2 %

Procedure:
A mixture of 8.9 mg (13.1 μmol) of Pd-PEPPSI-IPr-catalyst, 0.1 g (0.33 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine (Example 1), 0.1 g (0.65 mmol) of cesium fluoride and activated, crushed 4 Å molecular sieves (33 mg) in a glass vial was purged with argon and 1 ml of dioxane was added. 0.15 (0.39 mmol) of 2-tributylstannylthiazole was then added and the reaction was stirred at 80° C. for 24 h. The mixture was filtered throw celite/CsF. The solvent was removed in vacuum. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as eluent to give 47.9 mg (47.2%) of the desired product.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:19][NH:20][C:21]([NH2:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (108 mg, 0.49 mmol), semicarbazide hydrochloride (57 mg, 0.51 mmol) and potassium carbonate (58 mg, 0.42 mmol) in ethanol (3.0 mL) was refluxed under a nitrogen atmosphere overnight (14 h). The reaction mixture was cooled to room temperature, water was added, and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4. After filtration and concentration, the crude material was purified by Biotage chromatography to afford phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone semicarbazone as two isomers, Example 62 (5.3 mg, 4%) and Example 63 (5.9 mg, 4%), as a yellow solid:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:49][C:50]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=1[C:57]1[C:58]([CH3:64])=[N:59][N:60]([CH3:63])[C:61]=1[NH2:62].Br[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:72][C:68]1[CH:67]=[C:66]([NH:62][C:61]2[N:60]([CH3:63])[N:59]=[C:58]([CH3:64])[C:57]=2[C:51]2[CH:52]=[CH:53][C:54]([F:56])=[CH:55][C:50]=2[F:49])[CH:71]=[CH:70][CH:69]=1
Reactant: Clc1cccc(Br)c1
Reactant: Cc1nn(C)c(N)c1-c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1nn(C)c(Nc2cccc(Cl)c2)c1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Palladium(II) acetate (90 mg, 0.40 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (460 mg, 0.80 mmol) and powdered potassium carbonate (5.5 g, 40 mmol) were combined in anhydrous 1,4-dioxane (20 mL), and the mixture was sparged with a subsurface stream of N2 gas for 10 min. 4-(2,4-Difluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine (i.e. the product of Step B) (0.89 g, 4.0 mmol) was added in one portion, and 1-bromo-3-chlorobenzene (0.47 mL, 4.0 mmol) was added via a syringe. The reaction mixture was heated at reflux under a nitrogen atmosphere for 3 h. Additional 1-bromo-3-chlorobenzene (0.09 mL, 0.8 mmol) was added, and heating was continued for 1 h. The reaction mixture was allowed to cool to room temperature, and then partitioned between water (40 mL) and ethyl acetate (40 mL). The organic phase was washed with additional water (40 mL), brine (40 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography through 10 g of silica gel eluted with hexanes/ethyl acetate (1:1) to give the title compound, a compound of the present invention, as a solid (0.41 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>CN(C=O)C.C(O)C>[CH2:15]([N:12]1[CH2:11][CH:10]=[C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(CCc2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C1=C(CCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a stirred solution of 120b (500 mg, 2.73 mmol) in DMF (5 ml) was added benzyl bromide (810 mg, 4.05 mmol) at 20-35° C. and the reaction mixture was stirred at 100° C. for 3 h. After 3 h, the reaction mixture was cooled to 20-35° C., diluted with ethanol (10 ml) and NaBH4 (110 mg, 2.97 mmol) was added slowly portion wise at 0° C., then heated at 100° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with NaOH solution at 20-35° C., excess ethanol was removed under vacuum and resultant residue was diluted with ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated. The crude compound was triturated with pet ether to get the desired compound as a yellow sticky solid (440 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.43 (m, 5H), 7.38-7.7.28 (m, 2H), 7.27-7.20 (m, 2H), 7.19-7.12 (m, 1H), 5.44 (s, 1H), 4.61 (d, J=12.7 Hz, 1H), 4.41 (d, J=12.7 Hz, 1H), 3.62-3.56 (m, 2H), 3.39 (t, J=6.1 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.62-2.52 (m, 2H), 2.41 (t, J=7.6 Hz, 2H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([CH2:21][O:22][C:23]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]3[C:24]=2[C:25]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=2)=[N:26][CH:27]=[N:28]3)[CH2:10]1)(C(C)(C)C)(C)C.C(#N)C>FC(F)(F)C(O)=O>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[F:42])[NH:35][C:25]1[C:24]2[C:29](=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:23]=2[O:22][CH2:21][C@@H:11]2[NH:12][CH2:13][C@H:9]([OH:8])[CH2:10]2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc(OC[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(OC[C@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
tert-Butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[({4-[3-chloro-4-fluoro-anilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (839 mg) was dissolved in trifluoroacetic acid (50 ml) and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo, and excess water was added, followed by the careful addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with 3% methanol in DCM and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a green solid. Trituration with cold acetonitrile gave (3R,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol as grey solid (540 mg, 98%); NMR spectrum (DMSO-d6) 10.54-10.02 (br s, 1H), 8.48 (s, 1H), 8.32 (dd, 1H), 7.93-7.88 (m, 1H), 7.38 (t, 1H), 6.79 (d, 1H), 6.69 (d, 1H), 5.05-4.74 (br s, 1H), 4.40-4.32 (m, 2H), 4.16 (t, 1H), 3.91 (s, 3H), 3.80-3.40 (br m, 21), 2.98 (dd, 1H), 2.86 (dd, 1H), 2.22-2.14 (m, 1H), 1.52-1.44 (m, 1H); Mass spectrum MH+ 419.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16].Cl[C:18]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][C:18]2[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=2)=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COCOc1c(C)cc(O)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(Oc2cc(C)c(OCOC)c(C)c2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a suspension of 50 g of sodium hydride (55% by weight, washed with n-hexane) in 1000 ml of anhydrous N,N-dimethylformamide, 300 ml of a solution of 193 g of 4-methoxymethoxy-2,3,5-trimethylphenol in anhydrous N,N-dimethylformamide were added dropwise over one hour under ice cooling; the mixture was then stirred at room temperature for 2 hours. To the reaction mixture, 800 ml of a solution of 197 g of 6-chloro-2-methylamino-3-nitropyridine in anhydrous N,N-dimethylformamide were added dropwise over one hour under ice cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was poured into iced water. To the resulting mixture, ethyl acetate and water were added. The insoluble product was collected by filtration and washed with water and ethanol, whereby 141 g of the title compound were obtained. Separately, the organic layer was separated from the filtrate and the water layer was extracted with ethyl acetate. The organic layer and extract were combined, followed by washing with saturated saline and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with ethanol, whereby 126 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(CN2CCC(NCCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.5 %

Procedure:
Tert-butyl (S)-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate prepared in Example 284 (0.196 g, 0.354 mmol) was dissolved in methylene chloride (2 ml). To the solution, trifluoroacetic acid (1 ml) was added followed by stirring at room temperature for 4 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and treated with isopropyl ether to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-2-(4-trifluoromethylphenyl)ethylamine (0.020 g, yield 12%) as a light yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:40]>ClC(Cl)C.ClCCl.C(OCC)C>[ClH:40].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)[CH2:12][CH2:13]1.[ClH:40]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1cccc(NC2CCNCC2)c1

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 2.51 mmol), 3-trifluoromethyl-phenylamine (404 mg; 2.51 mmol) and sodium triacetoxyborohydride (1.59 g; 7.53 mmol) are suspended in dichloroethane (25 mL). After 1 day reaction time at room temperature, the mixture is diluted with dichloromethane (100 mL) and the organic layer is washed with aq. sat ammonium chloride (2×50 mL) and water (3×50 mL), is then dried over magnesium sulfate and is concentrated under reduced pressure. The residue obtained is triturated with cold diethylether (10 mL) until precipitation is observed. The precipitate is filtered and dried under vacuum. The crude product is dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) is added dropwise under vigorous stirring. After 30 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated with dichloromethane (2×10 mL). The residue obtained is then dissolved in diethylether (5 mL) and a molar solution of hydrochloric acid in diethylether (5 mL) is added. The precipitate formed is filtered and dried under high vacuum to afford the desired product as hydrochloride (289 mg; 1.03 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]([C:14](=[O:19])N(OC)C)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]([CH:14]=[O:19])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CON(C)C(=O)[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)C[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-[1-(Methoxy-methyl-carbamoyl)-3-methyl-butyl]-methyl-carbamic acid tert-butyl ester (288 mg, 1.0 mmol) was dissolved in Et2O (10 mL), cooled to 0° C., treated with LAH (38 mg, 1.0 mmol), and stirred cold for 30 minutes. The reaction was quenched by dropwise addition of a solution of 150 mg Na2S2O3 in 5 mL H2O. The reaction was diluted with H2O (100 mL), washed with Et2O (3×100 mL), then the organic layers were combined, washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated to give the desired product which was carried on immediately without further purification.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH2:13][CH3:14])[CH2:5][CH2:6][CH2:7][O:8][S:9]([CH3:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.Cl>[CH2:13]([CH:4]([CH2:5][CH2:6][CH2:7][O:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:3]=[O:2])[CH3:14]
Reactant: CCC(CCCOS(C)(=O)=O)C(OC)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCC(C=O)CCCOS(C)(=O)=O

Procedure:
To a solution of 2.55 g (0.01 mol) of 4-dimethoxymethyl-1-methanesulfonyloxyhexane in 40 ml of diethyl ether, 20 ml of 1.2 N HCl was added and the mixture stirred at reflux for 12 h. Solid potassium carbonate (3 g) was slowly added, the organic layer separated and the aqueous layer extracted with 25 ml of ether. The combined ether solutions were washed with brine, dried over magnesium sulfate, filtered and concentrated to 1.66 g of the aldehyde IXe;
Reaction SMILES: C([NH:4][C@H:5]([C:17]([O:19]C)=[O:18])[CH2:6][S:7]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])(=[O:9])=[O:8])(=O)C.[ClH:21]>C(O)(=O)C>[ClH:21].[CH2:11]([CH:10]([S:7]([CH2:6][C@@H:5]([C:17]([OH:19])=[O:18])[NH2:4])(=[O:8])=[O:9])[CH2:14][CH2:15][CH3:16])[CH2:12][CH3:13]
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](NC(C)=O)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Product: CCCC(CCC)S(=O)(=O)C[C@H](N)C(=O)O

Procedure:
A 250 ml round bottom flask equipped with magnetic stir bar, reflux condenser, and N2 inlet was charged with 9.2 g methyl N-acetyl-3-[(1-propylbutyl)sulfonyl]alaninate in 50 ml acetic acid and 50 ml conc. HCl. The solution was refluxed for 4 hours then concentrated in vacuo. The residue was chased with toluene (2×) then vacuum dried overnight to yield 7.8 g of the desired 3-[(1-propylbutyl)sulfonyl]alanine HCl salt.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH2:14]2.BrC1OC(C(Cl)=O)=CC=1.Cl>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH:14]2[C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)c1ccc(Br)o1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)N1C(=O)C(C(=O)c2ccc(Br)o2)c2cc(Cl)ccc21

Procedure:
Using the procedure of Example 32, 1.91 g (10.0 mmoles) of commercially available 5-bromo-2-furan-carboxylic acid was dissolved in 10 ml of thionyl chloride and heated to reflux under nitrogen for 1 hour and the acid chloride product was recovered. A 40 ml N,N-dimethylformamide solution of 1.75 g (8.3 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25 mmoles) of 4-(N,N-dimethylamino)pyridine was reacted with 2.09 g (10 mmoles) of 5-bromo-2-furan carbonyl chloride in 10 ml of N,N-dimethylformamide. After a reaction time of about 45 minutes, the mixture was acidified by pouring into 250 ml of 1N HCl. The product was recrystallized from acetic acid, washed with acetic acid, then hexane and dried overnight in vacuo at room temperature. The resulting product then was dried over refluxing isopropanol under high vacuum to yield 1.37 g of the title compound.
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][OH:14].[H-].[Na+].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (5.0 g, 26.4 mmol) in THF (50 mL) was added sodium hydride (55% dispersion in mineral oil, 1.27 g, 29.1 mmol). The mixture was stirred at room temperature for 30 min. After addition of 3,6-dichloropyridazine (4.33 g, 29.1 mmol) the mixture was stirred at room temperature for another 5 h. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded the title compound (6.62 g, 83%) as a white solid. MS: m/e=302.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccccn1
Agent: NN
Solvent: CO
Product: NCCCc1ccccn1
Reaction time: 12 h
Yield: 129.6 %

Procedure:
Place 2-(3-pyridin-2-yl-propyl)isoindole-1,3-dione (7.0 g, 26.0 mmol) in a flask and add a solution of hydrazine (4.0 mL) in MeOH (200 mL). After 12 hours, filter the mixture and concentrate the filtrate, titrate with methylene chloride, and filter a second time. Perform flash chromatography on silica gel eluting with 80:18:2 CHCl3/MeOH/concentrated NH4OH to afford the title compound as a brown oil (4.59 g) MS: m/e=137 (MH+).
Reaction SMILES: C([O:5][C:6]([C@@H:8]([N:10]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([N:20]=[N+]=[N-])[C:11]1=[O:23])[CH3:9])=[O:7])(C)(C)C.[ClH:24]>[Pd].C(O)C>[ClH:24].[NH2:20][C@H:12]([C:11]([NH:10][C@H:8]([C:6]([OH:7])=[O:5])[CH3:9])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@H](N=[N+]=[N-])[C@H]1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reaction time: 15 h

Procedure:
After 1-(1(S)-t-butoxycarbonylethyl)-3(S)-azido-4(R)-phenylazetidin-2-one (200 mg., 0.63 mmol) was hydrogenated in 50 ml. of ethanol under ambient pressure at room temperature for 4 hours, using a 10% Pd-C (200 mg.) as a catalyst, 1 normal (1 N) hydrochloric acid (0.76 ml.) was added thereto. Then, the hydrogenation under ambient pressure was continued further for 15 hours at 50° C. to give quantitatively hydrochloride of t-butyl ester of L-phenylalanyl-L-alanine.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=[O:13])[CH3:12]>C(O)C>[C:11]([NH:14][C:15]1[S:16][C:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:3]([NH2:4])[N:17]=1)(=[O:13])[CH3:12]
Reactant: N#CC(Br)c1ccccc1
Reactant: CC(=O)NC(N)=S
Solvent: CCO
Product: CC(=O)Nc1nc(N)c(-c2ccccc2)s1
Yield: 23.1 %

Procedure:
α-Bromophenylacetonitrile (1.08 g, 5.48 mmol) in ethanol (10 ml) was treated with N-acetylthiourea (649 mg, 5.49 mmol) at ambient temperature for 4 hr, and then heated to reflux for 3.5 hr. The cooled mixture was concentrated in vacuo and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 2-(acetylamino)-4-amino-5-phenylthiazole (295 mg, 23%).