Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH3:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.CO>C(#N)C>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=2)[C@H:24]([CH3:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CO
Product: C[C@@H]1CN(Cc2ccccc2)CCN1c1nccc(C(=O)OC(C)(C)C)n1
Yield: 94.4 %

Procedure:
Tert-butyl 2-chloropyrimidine-4-carboxylate (4.12 g, 19.2 mmol) and (R)-1-benzyl-3-methylpiperazine (1.83 g, 9.6 mmol) were suspended in acetonitrile (50 ml), followed by addition of N,N-diisopropylethylamine (3.34 ml, 19.2 mmol), and then the resulting liquid was heated at reflux under nitrogen stream for 15 hours. The resulting reaction liquid was concentrated, followed by addition of distilled water (50 ml), and then extracted with MC (100 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (1% MeOH/MC), to obtain 3.34 g of yellow solid (94%).
Reaction SMILES: [CH3:1]NC(=[O:17])NC1(C2C=CC=CC=2)CCNCC1.C(O)(=O)C.O.O.[ClH:24].[C:25]([N:33]1[CH2:38][CH2:37][O:36][C:35]([C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=2)([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([NH:47][C:48]([NH2:50])=[O:49])[CH2:43][CH2:42]2)[CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO>[OH2:17].[ClH:24].[C:25]([N:33]1[CH2:38][CH2:37][O:36][C:35]([C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=2)([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C:44]([NH:47][C:48]([NH:50][CH3:1])=[O:49])([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:43][CH2:42]2)[CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Reactant: CNC(=O)NC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Yield: 73.2 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 68 from 1.85 g of 4-(N'-methylureido)-4-phenylpiperidine (free base), 0.44 ml of acetic acid and 26 ml of MeOH, and then 2.75 g of the compound obtained in step A of EXAMPLE 68 in 26 ml of MeOH and 0.55 g of sodium cyanoborohydride in 26 ml of MeOH. This gives 2 g of the expected product. M.p.=170-173° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:38](Cl)(=[O:40])=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C>[CH2:30]([S:38]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:40])=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 341.8 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-octanesulfonyl chloride (Aldrich) (0.095 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0805 g, 34%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](O)=[CH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(=Cc1ccncn1)c1cccc(Cl)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1ccncn1)c1cccc(Cl)c1
Yield: 67.8 %

Procedure:
To a suspension of 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (9.0 g, 38.7 mmol) in methanol (100 mL) was added hydroxylamine hydrochloride (11.5 g, 165 mmol) and sodium hydroxide (60 mL, 2.8 M in water, 166 mmol). The reaction mixture was refluxed 4 hours. After cooling, the excess methanol was removed in vacuo. Ice water (˜300 mL) was added to the resultant mixture and the ice was allowed to melt. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (3:1 to 2:1 hexanes:ethyl acetate) provided 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (6.5 g, 68%) as a white solid. Rf 0.14 (3:1 hexanes:ethyl acetate): 1H NMR (CDCl3) δ 9.50 (br, 1H), 9.18 (s, 1H), 8.61 (d, 1H), 7.78 (s, 1H), 7.58 (d, 1H), 7.38–7.25 (m, 3H), 4.38 (s, 2H); MS m/z 248 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Yield: 51.3 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 119) (215 mg, 0.77 mmol) and isopropyl isocyanate (72 mg, 0.84 mmol) according to the procedure described for Example 16. Obtained the title compound as a white solid (144 mg, 51%), MS (ISP) m/e=363.5 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6]2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17](=[N:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:13])([CH3:15])[CH3:14])=[N:6]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N
Product: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N=Cc1ccccc1

Procedure:
3-Amino-2-methyl-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (2.2 g) prepared as in Example 1 was heated under reflux in benzaldehyde (6.6 ml) for 11/2 hours. The solution was cooled to precipitate the product (2.4 g), m.p. 250°-253° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:29])[CH2:15][C@@H:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)[CH2:17][N+:18]([O-])=O)C1C=CC=CC=1>CCOC(C)=O.CCO.[Ni]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:16]2[CH2:17][NH:18][C:14](=[O:29])[CH2:15]2)=[CH:22][C:23]=1[F:28]
Reactant: O=C(C[C@H](C[N+](=O)[O-])c1ccc(Cl)c(F)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1C[C@@H](c2ccc(Cl)c(F)c2)CN1
Reaction time: 20 h
Yield: 50.9 %

Procedure:
To a solution of 88 (1.55 g, 3.68 mmol) in EtOAc/EtOH (1:1, 50 mL) was added a Raney Nickel suspension (0.316 g, 3.68 mmol) and the reaction mixture was purged with nitrogen then placed under 40 psi hydrogen for 20 h. A second aliquot of Raney Ni suspension (1 mL) was added and the reaction was placed under hydrogen pressure for another 24 h. A third aliquot of Raney Ni was added (1 mL) and the reaction was placed under hydrogen pressure of 45 psi for 24 h. The reaction was filtered through a plug of CELITE® and the filtrate was concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 30% EtOAc) to afford 400 mg (50.8%) of (S)-4-(4-chloro-3-fluorophenyl)pyrrolidin-2-one (90).
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=O.C(O)(=O)C>C(O)C>[NH:30]1[C:31]2[C:27](=[C:26]([CH:24]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc2[nH]ccc12
Solvent: CC(=O)O
Solvent: CCO
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (15 mg, 0.048 mM) in absolute ethanol (2.0 mL), there were added 4-formyl-indole (11 mg, 0.076 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off and then washed with ethanol to thus give the title compound (12 mg, yield: 58%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[CH2:8][C:9](=[O:30])[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:29])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+].N>C(OC(=O)C)(=O)C.CC(C)=O>[ClH:1].[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[C:8](=[O:36])[C:9](=[O:30])[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:29])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Agent: Cl
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
1.98 gm (4.0 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane hydrochloride were suspended in 50 ml of acetic anhydride; the suspension was mixed with 2.5 gm of potassium permanganate, and the mixture was stirred for 20 minutes at 20° C. The reaction mixture was poured into ice water and made alkaline with concentrated ammonia. The precipitated manganese dioxide was suction-filtered off, and the filtrate was extracted several times with methylene chloride. The extract was dried over magnesium sulfate, evaporated in vacuo, and the residue was purified on a silica gel column with methylene chloride +1% of ethanol as the eluant. The product thus obtained was dissolved in acetone, and the hydrochloride was precipitated with ethereal hydrochloric acid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC1C=CC=CC=1C.ClCCl.CO>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:23][N:24]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)c1ccccc1
Reactant: N#Cc1cnc(-c2ccccc2)nc1
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2ncc(-c3nnc(-c4ccccc4)[nH]3)cn2)cc1
Temperature: 200 °C
Reaction time: 24 h
Yield: 6.1 %

Procedure:
2-Phenyl-pyrimidine-5-carbonitrile (Biofine International, 0.10 g, 0.55 mmol) and benzoic hydrazide (Aldrich, 0.075 g, 0.55 mmol) were dissolved in o-xylene (5 mL) and heated to 200° C. in a sealed pressure tube while stirring for 24 hours. After cooling to room temperature, the reaction mixture was heated to 200° C. in an open vessel under a stream of nitrogen for six hours. The remaining crude solid was dissolved in a minimal amount of 98:2 v/v dichloromethane-methanol and purified by flash silica column chromatography. Elution through a 40-g Analogix® flash silica cartridge with 100% dichloromethane to 2% methanol in dichloromethane afforded the title compound as a pale yellow solid (10 mg, 6% yield); Rf 0.1 with 98:2 v/v dichloromethane-methanol; melting point 280-282° C.; 1H-NMR (400 MHz; CDCl3) δ 8.48-8.42 (m, 2H), 8.12-8.06 (m, 2H), 7.60-7.48 (m, 6H); MS (ESI+) m/z 300.1 (M+1); H-PGDS FPBA IC50: 1.0 μM; H-PGDS inhibitor EIA IC50: 0.084 μM.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=2[F:33])[O:15][CH2:14]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C@@H:22]2[C:21]3[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=3[F:33])[O:15][CH2:14][C@H:13]2[CH2:12][O:11][CH2:10][CH2:9][OH:8])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1COCCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)[C@@H]1c2c(F)ccc(F)c2OC[C@H]1COCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-Benzyloxy-ethoxymethyl)-4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman (0.4 g, 0.79 mmole) was dissolved in 10 ml EtOAc and Pd(OH)2 was added. Hydrogen was introduced via a balloon. The reaction was stirred at room temperature for 30 minutes. The catalyst was filtered and residue was used in next step without purification. Yield: 0.32 g, 97%. 1H NMR (CDCl3 400 MHz δ 7.73 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.03 (m, 1H), 6.41 (m, 1H), 4.90 (dd, J=8.8 and 2.9 Hz, 1H), 4.57 (s, 1H), 4.39 (td, J=11.7 and 1.5 Hz, 1H), 3.68 (br, 2H), 3.41-3.54 (m, 3H), 2.30 (t, J=9.5 Hz, 1H), 3.15 (m, 1H).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:71](OC)[O:72]C)[CH2:67][C:68]#[C:69][CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@@H:66]([CH2:67][C:68]#[C:69][CH3:70])[CH:71]=[O:72])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:54])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: CC#CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC#CC[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
49 mg (0.046 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentynyl]-L-leucinamide were dissolved in 4 ml of trifluoroacetic acid/dichloromethane (1:1) containing 3 drops of water and the solution was stirred for 1 hour under a nitrogen atmosphere. The solution was evaporated to dryness under a vacuum and the residue was re-evaporated twice with toluene. The solid was triturated with 10 ml of diethyl ether to give 30 mg of 2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexynal as a white solid; MS: m/e 843.6 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CON(C)[C:10](=[O:22])[CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH3:21][CH:11]([CH:10]=[O:22])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CON(C)C(=O)C(C)CNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of LAH (10 mL, 10 mmol, 1M in THF) was slowly added over ˜15 min to a stirred solution of tert-butyl {3-[methoxy(methyl)amino]-2-methyl-3-oxopropyl}carbamate (2.2 g, 8.9 mmol) in THF (40 mL) at −40° C. under nitrogen. After stirring at −40° for 30 min, the reaction mixture was quenched carefully by dropwise addition of saturated aqueous sodium bisulfate solution and stirred at room temperature for 1 hr. The mixture was filtered through Celite, and the filtrate was washed sequentially with ice-cold 1N hydrochloric acid (2×), saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to yield tert-butyl (2-methyl-3-oxopropyl)carbamate as colorless viscous oil. MS (M+1−Boc): 88.0
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].Cl.[NH2:18][OH:19].C[O-].[Na+].Cl>CO.C(OCC)(=O)C.O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:19][N:18]=[C:3]([OH:4])[CH:2]=2)=[CH:10][CH:11]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(O)no2)cc1
Reaction time: 12 h
Yield: 68.5 %

Procedure:
0.35 g of ethyl 2,3-dibromo-3-(4-methylphenyl)propanoate and 0.083 g of hydroxylamine hydrochloride was suspended in 7 mL of methanol, to which 0.19 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this solution was stirred for 12 hours at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 1 with 6M hydrochloric acid followed by addition of ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out therefrom under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:1] to yield 0.12 g of 5-(4-methylphenyl)-3-isoxazolol as yellow oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[NH:8]([C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[C@H:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 5 g (0.023 mol) of Boc-Valine dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred 15 minutes and filtered. The filtrate is added slowly to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and stirred 1 hour at ice-bath temperature then 1 hour at room temperature. The reaction mixture is cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][NH:6]C(OC(C)(C)C)=O.[OH-].[Na+].Cl.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>CO.C(Cl)Cl>[OH:26][C:20]([C:22]([F:25])([F:24])[F:23])=[O:21].[NH2:6][CH2:5][C:4]([CH3:15])([CH3:14])[C:3]([OH:16])=[O:2]
Reactant: COC(=O)C(C)(C)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-tert-butoxycarbonylamino-2,2-dimethyl-propionic acid methyl ester (2.5 g, 10.8 mmol) in MeOH (30 mL) was added 1 M NaOH (27 mL, 27 mmol), and the resulting mixture was stirred at r.t. for 16 h. 1 M HCl was added until pH was ˜3, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue obtained was dissolved CH2Cl2 (10 mL), and TFA (7 mL) was added. The resulting mixture was stirred at r.t. for 3 days, then concentrated to dryness to give 2.1 g of the title compound as a gray solid. 1H NMR (DMSO-d6, 200 MHz): δ ppm=7.8 (br s, 3H), 2.80-3.00 (m, 2H), 1.18 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9](OC)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([NH:24][C:9]1[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:11](=[O:12])[CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: CO
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)cc1NCc1ccccc1

Procedure:
To a stirred solution of 8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.5 g) in methanol (15 mL) was added benzylamine (0.3 mL). The mixture was heated to reflux for 24 hours. The solvent was evaporated to give a solid. The solid was recrystallized from dimethylformamide (5 mL) and water, washed (water) and vacuum dried (100° C., 15 Pa) to give the title compound (0.181 g); mp 309.1°-313.9° C.; NMR: 5.73 (s,1); MS: m/z=313(M+1). Analysis for C17H13ClN2O2 : Calculated: C, 65.29; H, 4.19; N, 8.96; Found: C, 65.02; H, 3.96; N, 8.61.