Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1C.[N+](C1C=CC=CC=1)([O-])=O.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH2:24].Br>CCCCCC>[CH3:22][C:23]([NH:12][C:10]([NH:9][C:1]1[CH:2]=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1)=[O:11])([CH3:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(NC(N)=O)c(C)c1
Reactant: C=C(C)c1ccccc1
Agent: Br
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
12.4 parts of 2,4 -xylylurea was suspended in 50 parts of nitrobenzene, and 30 parts of α-methylstyrene was added. The mixture was stirred while introducing anhydrous hydrobromic acid portionwise. When the amount of the mixture increased by 10 parts, the introduction of the hydrobromic acid was stopped. The reaction was then performed at 40° C. for 5 hours. The resulting reaction mixture was allowed to stand overnight. Then, 30 parts of n-hexane was added, and the mixture was further allowed to stand overnight. The precipitated crystals were recrystallized from 60% methanol to afford 13.4 parts of N-(α,α-dimethylbenzyl)-N'-(p-tolyl)urea having a melting point of 203° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:35]3[CH:36]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:33]=[CH:34]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc(-c4ccccc4)c3)cc2)cc1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A mixture of 4-{2-[({[(4-Methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 4-phenylimidazole (40 mg, 0.28 mmol), Copper(II) acetate (50 mg, 0.28 mmol), triethylamine (115 μL, 0.83 mmol), molecular sieves 4A (100 mg), and dichloromethane (4 mL) was stirred at room temperature for 1 week. Insoluble materials were removed by Celite pad, the filtrate was diluted with dichloromethane, and washed with water. The combined organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 58 mg (46%) of the title compound as white solids: MS (ESI) m/z 462 [M+H]+, 460 [M−H]−, 1H-NMR (DMSO-d6) δ 2.35 (3H, s), 2.88 (2H, t, J=6.5 Hz), 4.23 (2H, t, J=6.5 Hz), 7.22-7.43 (7H, m), 7.62 (2H, d, J=8.3 Hz), 7.74 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=7.3 Hz), 8.26 (1H, s), 8.32 (1H, s).
Reaction SMILES: I[C:2]1[C:3]([CH3:19])=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1>>[CH3:19][C:3]1[C:2]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[C:6]([CH3:7])[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(I)c2C)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl trans-4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)cyclohexane-carboxylate (100.0 mg, 0.2658 mmol) in THF (5 mL, 60 mmol) was added 2 M isopropylmagnesium chloride in THF (0.5316 mL, 1.063 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2178 mL, 1.329 mmol) was added, and the mixture stirred at rt overnight. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1)/[C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5]/[N:6]=[C:7](\[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N+:18]=1[O-:32])/[C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O/N=C(/c1cc(F)c(Cl)cc1O)c1ncccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)O/N=C(/c1cc(F)c(Cl)cc1O)c1c(O)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of (Z)-2-(4-chloro-5-fluoro-2-hydroxybenzoyl)-3-hydroxypyridine O-t-butyloxime (0.82 g) in chloroform (30 ml) was added 70% m-chloroperbenzoic acid (1.01 g) at 0° C. The mixture was warmed up to room temperature and stirred for 5 hours. To the reaction mixture was added an aqueous solution of sodium hydrogensulfite to quench the reaction. The reaction mixture was subjected to extraction with chloroform. The organic layer was dried (anhydrous magnesium sulfate). The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give (Z)-2-(4-chloro-5-fluoro-2-hydroxybenzoyl)-3-hydroxypyridine N-oxide O-t-butyloxime (0.79 g) (Compound 56).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[O:34])=[CH:28][CH:27]=1)[NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:15])=[CH:10][C:9]=1[Cl:24])=[O:7].[OH-].[Li+]>CO.O1CCCC1>[Cl:24][C:9]1[CH:10]=[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:15])[CH:12]=[CH:13][C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:43])=[O:2])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]2[C:36]([Cl:42])=[CH:37][CH:38]=[CH:39][C:40]=2[Cl:41])=[O:34])=[CH:30][CH:31]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(C(=O)Nc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cccc(O)c1)c1ccc(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
A solution of N-[[2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]phenyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (35 mg; 0.053 mmol) in methanol (0.35 mL) and tetrahydrofuran (0.35 mL) was treated with an aqueous 1N lithium hydroxide solution (0.16 mL) and the mixture was stirred at room temperature under argon for 90 minutes. The solution was concentrated under reduced pressure, then was diluted with water (5 mL) and extracted with diethyl ether (2×5 mL). The separated aqueous layer was acidified with 1 N HCl (0.18 mL) and the resulting colorless solid was filtered off, washed with water, and dried to give 29 mg of N-[[2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]phenyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine. FAB HRMS: (C31H24Cl3N3O6) Obs. Mass 640.0821 Calcd. Mass 640.0809 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:34]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].CO.[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:34]=[C:8]2[N:9]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:25]=3)[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:12]([O:13][CH3:37])[N:7]2[N:6]=1)=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2nc(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(OC)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106 %

Procedure:
To an ice cold mixture of 22 mg (0.048 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester in 3 mL of tetrahydrofuran (THF) was added 0.008 mL (0.192 mmol) of methanol (MeOH), 50 mg (0.192 mmol) of triphenylphosphine (PPh3), followed by 0.038 mL (0.192 mmol) of diisopropyl azodicarboxylate (DIAD) and the mixture was allowed to warm up to rt and stirred at rt for 2 h when analysis by thin layer chromatography (TLC) revealed complete consumption of starting material. The reaction mixture was then concentrated and the residue was chromatographed on silica gel (Biotage; gradient elution dichloromethane (DCM) to 10% ethyl acetate in DCM) to give 24 mg of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-methoxy-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as indicated by 1H-NMR (containing traces of impurities).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:23])=[C:17]([CH2:20][CH2:21]Cl)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]2[C:44]3[CH:45]=[CH:46][C:47]([OH:49])=[CH:48][C:43]=3[O:42][N:41]=2)[CH2:36][CH2:35]1>CO>[Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:23])=[C:17]([CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][CH:37]([C:40]4[C:44]5[CH:45]=[CH:46][C:47]([OH:49])=[CH:48][C:43]=5[O:42][N:41]=4)[CH2:38][CH2:39]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Oc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-((tert-butyldimethylsilyl)oxy)-3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (0.5 g, 1.40 mmol) in methanol (25 mL) and diisopropylethylamine (732.83 μL, 4.20 mmol) was treated with 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol hydrochloride salt (374.62 mg, 1.47 mmol), and the reaction mixture was stirred for 17 h at 60° C. under argon. Diisopropylethylamine (732.83 μL, 4.20 mmol) was added and the mixture was stirred additionally for 4 h at 60° C. The reaction mixture was evaporated under vacuum and the residue was taken up in water (25 mL), extracted with chloroform (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by silica gel chromatography (elution with dichloromethane/methanol (98/2) to give the title compound (ESI-MS (M+1) 539).
Reaction SMILES: FC1C(F)=C(OCCCCCCCC)C=CC=1[B:18]([OH:20])[OH:19].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:30]([F:43])[CH:29]=2)=[CH:24][CH:23]=1.C([Li])CCC.C(OB(OC(C)C)OC(C)C)(C)C>>[F:43][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([B:18]([OH:20])[OH:19])=[CH:23][CH:24]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1F
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1F

Procedure:
This was prepared using a similar method to that described for compound 5. Quantities: 4'bromo-3-fluoro-4-octoxybiphenyl (4.95 g, 0.013 mol), n-butyllithium (5 ml, 2.5M/hexane, 0.013 mol), tri-isopropylborate (4.7 g, 0.026 mol).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1CCC=CC=1>>[C:1]1([CH:7]([N:9]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]3[CH2:12][CH2:11][CH:10]2[CH:20]=[CH:21]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCCC=C1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](C2)N1[C@@H](C)c1ccccc1
Product: CCOC(=O)C1C2C=CC(CC2)N1C(C)c1ccccc1

Procedure:
In the reaction (a) of Example 1, 1,3-cyclohexadiene is used in place of cyclopentadiene to give ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:54]([NH:56][C@H:57]([C:63]([OH:65])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61])=[O:55])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30].C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:54]([NH:56][C@H:57]([C:63]([OH:65])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61])=[O:55])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.69 Gram of Z-Leu-OSu, the above-obtained H-Ile-Leu-Leu-Ala-Gln-OH and 0.22 ml of triethylamine were dissolved in 50 ml of dimethylformamide, and the mixture was stirred at a room temperature for 20 hours. After removal of dimethylformamide by distillation, 1N-succinic acid was added to the residue, the precipitated material was collected by filtration and washed with water until the filtrate become neutral and then dried. The dried material was washed with hot methanol to obtain 1.10 g of Z-Leu-Ile-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>CCO>[OH:1][CH:2]([CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)=[N:6]1)[CH2:3][N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:30][CH2:31]1
Reactant: O=C1COc2ccccc2N1C1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1COc2ccccc2N1C1CCN(CC(O)Cn2cc(-c3cnccn3)c(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
To a solution of 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (61 mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031 mL, 0.220 mmol). The reaction mixture was heated to 80° C. overnight, concentrated, and purified by column chromatography (silica, 5-10% MeOH/CH2Cl2) to afford 4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.09. MS (electrospray): m/z 579.2 (579.2, calculated for C30H29F3N6O3, M++H). 1H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4 Hz, 1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H), 3.13 (d, J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m, 2H), 2.40-2.55 (m, 3H), 2.17 (t, J=11.9 Hz, 1H),1.77 (d, J=11.9 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH2:13][C:14]2[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])=[CH:8][C:7]=1[Cl:25].[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:25][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:6]=1[O:5][C:4]1[CH:26]=[CH:27][CH:28]=[C:2]([C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)[C:3]=1[C:29]#[N:30])[C:10]([NH:12][CH2:13][C:14]1[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])=[O:11]
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(Br)c3C#N)c(Cl)c2)c(O)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4ccncc4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
To a solution of 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (500 mg, 1.03 mmol), pyridin-4-ylboronic acid (150 mg, 1.2 mmol), sodium carbonate (425 mg, 3.07 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate, washed with water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the pure product 3-chloro-4-(2-cyano-3-(pyridin-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (348 mg, 70%). LRMS (M+H+) m/z: calcd 484.13. found 484. 1H NMR (300 MHz, d6-DMSO): δ 11.48 (s, 1H), 8.75 (d, J=6.0 Hz, 2H), 8.55 (t, J=4.5 Hz, 1H), 8.15 (s, 1H), 7.94-7.91 (m, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.67-7.65 (m, 2H), 7.44 (d, J=7.5 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.86 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([OH:26])[CH3:25].C1COCC1.[BH4-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:21][C:24](=[O:26])[CH3:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]1CC2
Temperature: 80 °C

Procedure:
A solution of 60 mg. of rac.-1,3-dimethoxy-8α-estra-1,3,5(10)-trien-17-one in 3 ml. of ethanol and 1.0 ml. of THF is gradually combined at room temperature with 60 mg. of NaBH4 and agitated for 30 minutes under N2 and at room temperature. The reaction mixture is neutralized with glacial acetic acid, concentrated, taken up in ether, washed neutral with saturated NaCl solution, dried, and evaporated. The residue is dissolved in 1 ml. of pyridine, the solution is mixed with 0.5 ml. of acetic anhydride and maintained for 1 hour at 80° C. under N2. After cooling, the mixture is introduced into ice water; the precipitate is filtered off and taken up in ether. The ether solution is washed neutral with saturated NaCl solution, dried, and evaporated. Recrystallization from methanol over carbon yields 42 mg. of product, m.p. 131°-134° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][C:10](=[O:27])[CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([O:15]C(C)(C)C)=[O:14]>ClCCl>[CH3:8][S:9][C:10](=[O:27])[CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([OH:15])=[O:14]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)O
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 83.1 %

Procedure:
Trifluoroacetic acid (0.684 ml, 9.20 mmol) was added to a solution of (S)-tert-butyl 4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1e-IA, 69.3 mg, 0.23 mmol) in dichloromethane (1.2 ml), and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→60/40) to afford (S)-4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IA) (46.9 mg, 83%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42](C(O)=O)([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[N:27]([CH2:52][CH2:53][CH2:54][O:55]C(=O)C2C=CC=CC=2)[N:26]=1)(=O)C.C(O[C:72]([N:74]1[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]1)=[O:73])C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:72]([N:74]4[CH2:75][CH2:76][NH:77][CH2:78][CH2:79]4)=[O:73])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[N:27]([CH2:52][CH2:53][CH2:54][OH:55])[N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCCOC(=O)c3ccccc3)c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1c(Cc2ccc(CCCC(=O)NC(C)(C)C(=O)N3CCNCC3)cc2)c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)nn1CCCO

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-1-(3-benzoyloxypropyl)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.