Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH3:32])[C:14]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:30])[C:7]([O:9]CC)=[O:8].CO>C1COCC1>[CH3:32][C:13]1[CH:12]=[C:6]([CH:5]=[C:4]([CH3:3])[C:14]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][C:26](=[O:29])[CH2:27][CH2:28]2)[CH:20]=[CH:19][C:18]=1[CH3:30])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of ethyl 3,5-dimethyl-4-[[2-methyl-5-(4-oxo-1-piperidyl)benzoyl]amino]benzoate (0.11 g, 269.28 μmol) in THF:MeOH (2.4 ml:1.2 ml). After 16 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 7 with 1N HCl, and extracted twice with ethyl acetate. The organic layers are combined with aqueous layer and concentrated under reduced pressure. The resulting solids are triturated with 1:1 mixture of acetonitrile and ethanol to give white slurry that is filtered through Celite™ bed. The filtrate is concentrated under reduced pressure and the precipitate is triturated with acetone and filtered to afford the title compound as an off-white solid (99 mg, 99%). Mass spectrum (m/z): 381.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]2[CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2)no1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2CC2CCOCC2)no1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg, 0.338 mmol) in N,N-dimethylformamide (2 mL) is added tetrahydro-pyran-4-carbaldehyde (77 mg, 0.676 mmol) and acetic acid (0.073 mL, 1.28 mmol). The reaction is stirred at room temperature for 45 minutes before adding sodium cyanoborohydride (42.5 mg, 0.676 mmol). The reaction is stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound with low purity and further purification by pre-HPLC yields pure title compound, m/z 352 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:9][C:5]2=[N:6][C:7]=1[Cl:8].[C:23]([O:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].N#N>O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[N:6]=[C:5]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[C:4]2=[CH:3][C:2]=1[C:34]1[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:28]([O:27][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:29]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (5.0 g, 13 mmol), (3-(tert-butoxycarbonyl)phenyl)boronic acid (2.75 g, 12.4 mmol). Pd(Ph3P)4 (2.26 g, 1.96 mmol) and cesium carbonate (8.49 g, 26.1 mmol) was degassed/charged with N2 and diluted with water (22 ml)/DMF (220 ml). The resultant mixture was then degassed, charged with N2, heated to an internal temperature of 65° C. and allowed to stir under N2 atmosphere for 16 h. The reaction mixture was cooled to rt then diluted with EtOAc and sat. 1M HCl. The layers were separated and the aq layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4 filtered and concentrated. The resultant solid was then flashed on SiO2 eluting with a 0-100% EtOAc in hexanes gradient over 16 CV to give tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (5.2 g, 11 mmol, 83% yield) as a slightly yellow solid contaminated with the bis-coupled product di-tert-butyl 3,3′-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridine-5,6-diyl)dibenzoate. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.18 (s, 1H), 8.08-8.02 (m, 2H), 7.95-7.89 (m, 2H), 7.63 (dt, J=7.6, 1.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.24-7.18 (m, 2H), 6.03 (d, J=4.3 Hz, 1H), 2.99 (d, J=4.9 Hz, 3H), 1.62 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[N:12]=3)=[CH:7][N:31]=[C:29]([NH:28][CH2:27][CH2:26][OH:25])[N:30]=2)[CH2:3][CH2:2]1
Reactant: N=C(N)NCCO
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
To a solution (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (1288 μl), 1-(2-hydroxyethyl)guanidine (23.92 mg, 0.232 mmol) and potassium carbonate (107 mg, 0.773 mmol) were added dropwise, and the reaction mixture was stirred at 120° C. for 2 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (9.13 mg, 16.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)Cc1ccc(OC2CCN(C(C)=O)CC2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 2-methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetate (0.18 g, 0.56 mmol) was dissolved in THF (5 ml) and treated with lithium hydroxide (0.67 ml of a 1M aqueous solution, 0.67 mmol). The mixture was stirred at ambient temperature for 4 hours, then treated with an additional 0.2 ml of 1M lithium hydroxide. The mixture was heated at 60° for 6 hours, then cooled and concentrated in vacuo. The residue was acidified with 1M HCl, and extracted with ethyl acetate. The combined ethyl acetate layers were extracted with saturated aqueous sodium carbonate. The combined sodium carbonate layers were acidified with concentrated HCl and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 2-methoxy-4-(1-acetyl-4-piperidyloxy)phenyl-acetic acid.
Reaction SMILES: C([O:3][P:4]([CH2:9]/[CH:10]=[CH:11]/[CH2:12][NH:13][C:14]1[C:17](=[O:18])[C:16](=[O:19])[C:15]=1[NH2:20])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCCl>[NH2:20][C:15]1[C:16](=[O:19])[C:17](=[O:18])[C:14]=1[NH:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(C/C=C/CNc1c(N)c(=O)c1=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCCl
Product: Nc1c(NC/C=C/CP(=O)(O)O)c(=O)c1=O

Procedure:
A solution of [(E)-4-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester (1.0 g, 3.3 mmol) and bromotrimethylsilane (4.6 mL, 35 mmol) in anhydrous 1,2-dichloroethane (30 mL) under nitrogen was refluxed for 20 minutes, and then cooled and evaporated. The residue was dissolved in water (150 mL) and washed with diethyl ether (2×75 mL). The resulting material, upon concentrating the aqueous layer, was recrystallized from methanol in ethyl acetate (final volume=100 mL) to yield [(E)-4-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid one third hydrate as a yellow solid (0.59 g, 71%, mp 220°-230° C. (dec)); IR (KBr, cm-1): 3280, 3100, 1800, 1640; MS (-FAB): 245 (M-H); 1H NMR (DMSO, 400 MHz): δ 7.47 (br s, 3 NH), 5.63-5.58 (m, 2H), 4.10 (br s, 2H), 2.38 (d of d, J=21 and 6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(NCc3ccccc3)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 162 using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) and benzyl bromide (0.1 mL) as starting materials, N-[(4-benzylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.13 g) was obtained.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:20]#[N:21])[C:12](=[CH:15][C:16]=1[N+:17]([O-])=[O:18])[C:13]#[N:14])([C:3](OCC)=[O:4])=[O:2].[H][H]>CN(C)C=O.[Pd]>[C:20]([C:11]1[CH:10]=[C:9]2[C:16](=[CH:15][C:12]=1[C:13]#[N:14])[N:17]([OH:18])[C:3](=[O:4])[C:1](=[O:2])[NH:8]2)#[N:21]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)c(C#N)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: N#Cc1cc2[nH]c(=O)c(=O)n(O)c2cc1C#N
Yield: 57.9 %

Procedure:
A solution of 0.8 g (3.03 mmol) 4-ethoxalylamino-5-nitrophthalonitrile in 50 ml dimethylformamide was hydrogenated at atm. pressure by using 25 mg 5% Pd-C as a catalyst. When the hydrogen uptake had ceased, the reaction mixture was filtered and evaporated in vacuo. The residue was recrystallized (dimethylformamide-water) to give 0.4 g (66%) of 6,7-dicyano-1-hydroxy-quinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 7.97 (1H, s), 7.57 (1H, s). MS (m/e): 228 (M+, 80%).
Reaction SMILES: F[S:2]([C:5]1[N:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH3:12][O:11][C:8]1[N:7]=[N:6][C:5]([S:2]([N:13]2[C:22]3[CH:17]([CH2:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)(=[O:4])=[O:3])=[CH:10][CH:9]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1ccc(S(=O)(=O)F)nn1
Product: COc1ccc(S(=O)(=O)N2CCCC3CC=CC=C32)nn1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
A mixture of 3-fluorosulfonyl-6-methoxypyridazine (2 mmol, 384 mg) and tetrahydroquinoline (4 mmol, 532 mg) was heated at 140° C. for two hours. The reaction mixture was cooled, extracted with EtOAc (20 mL), and the EtOAc extract was dried, filtered and evaporated to obtain 3-methoxy-6-(tetrahydroquinoline-1-sulfonyl)-pyridazine (73%, 451 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH:31]1[CH2:34][S:33](=[O:36])(=[O:35])[CH2:32]1>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:31]4[CH2:34][S:33](=[O:36])(=[O:35])[CH2:32]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=S1(=O)CC(Br)C1
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CS(=O)(=O)C5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.072 mmol) in MeOH (1 mL) was added 3-bromothietane 1,1-dioxide (15 mg, 0.079 mmol) followed by TEA (15 mg). The resulting mixture was stirred at room temperature for 5 hr and then concentrated. The resulting residue was purified by preparative RP-HPLC to provide 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(1,1-dioxido-3-thietanyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ 8.02 (s, 1H), 7.37 (s, 1H), 7.02 (s, 1H), 6.23 (s, 1H), 4.28-4.22 (m, 2H), 4.12-4.07 (m, 2H), 3.22-3.18 (m, 1H), 2.95-2.92 (m, 2H), 2.68-2.62 (m, 1H), 2.22 (s, 3H), 2.13 (s, 3H), 2.07-2.01 (m, 2H), 1.71-1.55 (m, 4H). ESMS m/z 520.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11](O)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:14])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.O[N:29]1C2C=CC=CC=2N=[N:30]1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:29][NH2:30])=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2F)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)C1(c2ccc(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 41.4 %

Procedure:
A solution of the compound (26.55 g, 102.5 mmol) obtained in Example 14-3), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.6 g, 112.7 mmol), 1-hydroxybenzotriazole monohydrate (17.26 g, 112.7 mmol), triethylamine (42.9 mL, 307 mmol), and tert-butoxycarbonylhydrazide (16.3 g, 123 mmol) in N,N-dimethylformamide (400 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. A 4 M solution (60 mL) of hydrochloric acid in 1,4-dioxane and methanol (300 mL) were added to the obtained partially purified product, and the mixture was stirred at room temperature for 6.5 h. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, hexane was added to the obtained partially purified product, and the solid was collected by filtration to obtain the title compound (11.6 g, 42%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=2[CH3:26])=[O:19])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=2[CH3:27])=[O:19])[CH2:12][CH2:13]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of the above phenol (45 mg, 0.087 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 138 as a white solid (43 mg, 80%) following work-up and purification. 1H NMR (CDCl3) δ 0.82-1.12 (m, 5H), 1.54-1.58 (m, 1H), 1.76-1.79 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.25 (s, 3H), 2.51 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.74-2.86 (m, 3H), 3.30-3.36 (m, 1H), 3.56-3.62 (m, 1H), 3.82-3.87 (m, 1H), 3.89 (s, 2H), 6.53 (d, 2H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 7.41-7.46 (m, 1H), 7.52-7.55 (m, 3H), 8.60 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 12.37, 20.06, 20.93, 28.06, 29.26, 29.75, 38.92, 42.58, 47.57, 50.96, 55.43, 59.14, 111.59, 113.16, 117.91, 121.16, 128.32, 128.89, 129.64, 129.83, 129.94, 140.71, 141.26, 145.13, 156.53, 162.07, 165.32, 169.07. ES-MS m/z 555 (M+H). Anal. Calcd. for C32H38N6O3.0.8CH2Cl2: C, 63.27; H, 6.41; N, 13.50. Found. C; 63.46; H, 6.39; N, 13.29.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@H:8]([CH2:12][S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH:48]([C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59])[C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][CH2:52][CH2:53][NH2:54].Cl>ClCCl>[CH:64]1[C:63]2[CH:62]([CH2:61][O:60][C:58]([NH:48][C@@H:49]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:9](=[O:11])[C@@H:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:12][S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:55]([OH:57])=[O:56])=[O:59])[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[CH:67]=[CH:66][CH:65]=1
Reactant: C=CCOC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.8 %

Procedure:
A solution of (R)-2-(allyloxycarbonylamino)-3-(tert-butyldisulfanyl)propanoic acid (Alloc-Cys(StBu)-OH) (1.9 g, 6.48 mmol) and N-hydroxysuccinimide (0.745 g, 6.48 mmol) in dichloromethane (10 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 1.24 g, 6.48 mmol) was added and the reaction solution was stirred at room temperature for 20 hours. After 20 hours, the reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (2.49 ml, 14.25 mmol) and Fmoc-Lys-OH (2.39 g, 6.48 mmol) were added and the reaction solution was stirred at room temperature for 2 hours. Dichloromethane and 1 M hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 25 wt % brine, the resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-((R)-2-(allyloxycarbonylamino)-3-(tert-butyldisulfanyl)propanamido)hexanoic acid (Compound 150a, Fmoc-Lys(Alloc-Cys(StBu))-OH) (2.66 g, 64%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29](Cl)=[O:30]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[C:32]([Cl:37])=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[Cl:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(Cl)cc(Cl)cc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,4,6-trichlorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)=[O:6].Cl.NO>O1CCOCC1.O>[O:6]1[C:5]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1cccc(O)c1
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Solvent: O
Product: Oc1cccc(-c2ccno2)c1
Temperature: 0 °C
Yield: 75.5 %

Procedure:
A solution of 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (2.2 g, 11.5 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45 ml dioxane/water 1:1 is heated for 2 hours at 60° C. The reaction is poured into ice-water and the precipitate is collected by filtration, washed with water, and dried in vacuo to give 1.4 g of 3-(5-isoxazolyl)phenol (75.5%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 1.33 g of the title epoxide (70%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](/[N:8]=C/C2C=CC(OC)=CC=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1.O.C(O)(C(F)(F)F)=O>CO>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][C@H:2]1[OH:1]
Reactant: COC(=O)N1CC[C@@H](/N=C/c2ccc(OC)cc2)[C@H](O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](N)[C@H](O)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (3R,4R)-methyl 3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate (499 mg, 1.707 mmol) in MeOH (17 ml) was added water (1 ml, 55.5 mmol) and TFA (2 ml, 26.0 mmol). The reaction was stirred at 50° C. overnight. The reaction mixture was applied on a SCX column (Phenomenex, Strata XC) and eluted with 2N ammonia in methanol. The solvents removed to afford (3R,4R)-methyl 4-amino-3-hydroxypiperidine-1-carboxylate (290 mg).