Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[Br-].CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.[CH3:69][C:70]1[O:74][CH:73]=[C:72](/[CH:75]=[C:76](/[C@H:78]2[O:96][C:94](=[O:95])[CH2:93][C@H:92]([OH:97])[C:91]([CH3:99])([CH3:98])[C:89](=[O:90])[C@H:88]([CH3:100])[C@@H:87]([OH:101])[C@@H:86]([CH3:102])[CH2:85][CH2:84][CH2:83][C@H:81]3O[C@H:80]3[CH2:79]2)\[CH3:77])[N:71]=1.CC1SC=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)N=1>CO>[CH3:69][C:70]1[O:74][CH:73]=[C:72](/[CH:75]=[C:76](/[C@H:78]2[O:96][C:94](=[O:95])[CH2:93][C@H:92]([OH:97])[C:91]([CH3:99])([CH3:98])[C:89](=[O:90])[C@H:88]([CH3:100])[C@@H:87]([OH:101])[C@@H:86]([CH3:102])[CH2:85][CH2:84][CH2:83][CH:81]=[CH:80][CH2:79]2)\[CH3:77])[N:71]=1
Reactant: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1
Solvent: CO
Product: C/C(=C\c1coc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]D22−84.2 (c 0.2, MeOH); UV (MeOH) λmax nm (ε) 203 (19600), 237 (12000); IR (KBr) νmax 3436, 2933, 2880, 2860, 1734, 1688, 1585, 1251, 1007 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.47 (1H, s, H-19), 6.31 (1H, bs, H-17), 5.43 (1H, ddd, J=10.6, 10.2, 4.5 Hz, H-12), 5.36 (1H, dddd, J=10.6, 9.6, 5.0, 1.3 Hz, H-13), 5.30 (1H, dd, J=9.9, 2.0 Hz, H-15), 4.16 (1H, ddd, J=11.2, 5.3, 2.8 Hz, H-3), 3.73 (1H, ddd, J=3.9, 2.5, 2.3 Hz, H-7), 3.12 (1H, dq, J=2.3, 6.9 Hz, H-6), 2.92 (1H, d, J=2.5 Hz, 7-OH), 2.91 (1H, d, J=5.3 Hz, 7-OH), 2.66 (1H, ddd, J=15.1, 9.9, 9.6 Hz, H-14a), 2.50 (1H, dd, J=15.4, 11.2 Hz, H-2a), 2.43 (3H, s, H-21), 2.37 (1H, dd, J=15.4, 2.8 Hz, H-2b), 2.23 (1H, m, H-14b), 2.18 (1H, m, H-11a), 2.01 (1H, m, H-11b), 2.08 (3H, d, J=1.3 Hz, H-27), 1.74 (1H, m, H-8), 1.65 (1H, m, H-10a), 1.33 (1H, m, H-9a), 1.31 (3H, s, H-23), 1.19 (1H, m, H-10b), 1.18 (1H, m, H-9b), 1.17 (3H d, J=6.9 Hz, H-24), 1.08 (3H, s, H-22), 0.99 (3H, d, J=7.1 Hz, H-25); 13C NMR, see Table 1; EIMS m/z 461 [M]+ (6), 310 (5), 274 (10), 273 (7), 171 (63), 152 (100), 148 (18), 111 (15); HREIMS m/z 461.2743 (calcd. for C26H39NO6, 461.2777).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[O:27][C:26]([F:25])([F:37])[F:38])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1OC(F)(F)F
Yield: 69.7 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.247 g (1.1 mmol) of 2-(trifluoromethoxy)benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane at room temperature for 1.5 hours. The product is triturated with dichloromethane-hexane to give 0.35 g of crystals, m.p. 232°-235° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:6]=1.[OH-].[Na+]>CO>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[CH2:14][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:23])=[O:2])=[CH:6]1
Reactant: COC(=O)Cc1cn(Cc2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cn(Cc2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [1-(3,4-dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid methyl ester (23 mg, 0.066 mmol) in MeOH (0.5 mL), is added 4N NaOH (0.25 mL). The reaction mixture is stirred at 25° C. for 5 minutes. The reaction mixture is evaporated in vacuo, to remove MeOH then cooled in an ice bath and acidified with concentrated HCl. The resultant solid is collected by filtration and triturated in CHCl3 to afford [1-(3,4-dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid; MH+=335.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.O>[CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2[nH]c(=O)n(CC(=O)OC(C)(C)C)c2c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Step A (7.15 g, 44.1 mmol) in DMF (200 mL) was added sodium hydride (1.76 g of a 60% dispersion in mineral oil, 44.1 mmol) over 2 min. The mixture was stirred for 20 min, then tert-butyl bromoacetate (8.17 g, 41.9 mmol) in DMF (40 mL) was added and stirring was continued for 1 h. The reaction mixture was diluted with H2O (400 mL) carefully and a solid precipitated. The mixture was aged for 5 min, then filtered to give a crude solid, which was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 40:60, to provide the title compound. MS: m/z=277 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.BrN1C(=O)CCC1=O.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].[H-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.O>[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=2)=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: COc1cc(C)cc(C)c1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [H-]
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(C)cc(COc2ccc(S(C)(=O)=O)cc2)c1
Yield: 56.3 %

Procedure:
To a solution of 5.0 g (36.7 mmol) of 3,5-dimethylanisole in carbon tetrachloride (35 mL) was added 5.2 g (29.4 mmol) of N-bromosuccinimide and 0.2 g (0.74 mmol) of benzoyl peroxide at room temperature, followed by heating under reflux for 2 hours. The reaction mixture was left standing to cool and then filtered. The filtrate was concentrated under a reduced pressure. The obtained residue was dissolved in ethanol (7.5 mL), and treated with 4.5 g (26.1 mmol) of 4-methylsulfonylphenol and 7.5 mL (30.0 mmol) of a 4 N aqueous sodium hydride, and heated under reflux for 1 hour. After standing to cool, water and hexane was added to the reaction mixture, and the precipitates were collected by filtration and washed with ether. The residue was purified by column chromatography (silica gel 80 g, developing solvent: chloroform-ethyl acetate=4: 1) to obtain 4.5 g (yield 40.4%) of 1-(4-methanesulfonylphenoxymethy)-3-methoxy-5-methylbenzene (VI-7) as a colorless crystal. Its physical properties are shown below.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: OCc1cccc(CBr)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: BrCc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-(bromomethyl)phenyl)methanol (8.78 g) and 3,4-dihydro-2H-pyran (5.99 mL) in THF (60 mL) was added p-toluenesulfonic acid monohydrate (415 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate (367 mg), and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.9 g) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>C(O)C>[CH3:23][Si:8]([CH3:7])([CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: C1CNCCN1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCNCC1
Temperature: 70 °C

Procedure:
Piperazine (3.14 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities. Excess piperazine was removed by sublimation.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(OC(C)(C)C)=O)CC1.[CH:30]12[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH:31]1[CH2:40][O:41][C:42]1[C:54]([CH:55]3[CH2:57][CH2:56]3)=[CH:53][C:45]([C:46]([O:48]C(C)(C)C)=[O:47])=[C:44]([F:58])[CH:43]=1)[CH2:37]2>>[CH:30]12[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH:31]1[CH2:40][O:41][C:42]1[C:54]([CH:55]3[CH2:56][CH2:57]3)=[CH:53][C:45]([C:46]([OH:48])=[O:47])=[C:44]([F:58])[CH:43]=1)[CH2:37]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 4, and making variations as required to replace tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was obtained as a colorless solid (0.79 g, 46%): MS (ES−) m/z 343.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.C(N(CC)CC)C.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].Cl>ClCCl.O>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:31]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)cc2C)cc1
Reaction time: 1 h
Yield: 41.1 %

Procedure:
Methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2) (1.84 g, 7.6 mmol) and triethylamine (2.6 ml, 19 mmol) were stirred in dichloromethane (100 ml) as 4-chlorobutyryl chloride (0.94 ml, 8.4 mmol) was added dropwise. The mixture was stirred for 1 h, vigorously stirred with water for 15 min, acidified with 5M HCl, and separated. The organic portion was washed with water and K2CO3 /brine solution, dried (Na2SO4) and evaporated to give a light yellow solid. Chromatography on silica gel, eluting with 0-40% ether/dichloromethane, gave the title compound (1.08 g, 41%) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:23]2=[O:44])=[O:20])[CH2:15][CH2:14]1.Cl.[CH3:46][O:47]C1C=C(C2NC(=O)N(C3CCNCC3)C=2)C=CC=1>>[O:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:47][CH3:46])[CH:8]=2)=[CH:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:23]2=[O:44])=[O:20])[CH2:15][CH2:14]1
Reactant: COc1cccc(-c2cn(C3CCNCC3)c(=O)[nH]2)c1
Reactant: O=C(O[C@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Agent: Cl
Product: COc1cccc(-c2cn(C3CCN(C(=O)O[C@H]4N=C(c5ccccc5)c5ccccc5N(CC(F)(F)F)C4=O)CC3)c(=O)[nH]2)c1

Procedure:
The title compound was prepared in the same way as (3R)-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl 4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate, except using 4-(3-methoxyphenyl)-1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one hydrochloride in place of 4-phenyl-1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one hydrochloride. MS 634.2266 (M+1)
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([N:7]3C(OC(C)(C)C)=O)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2].C(OC(=O)C(F)(F)F)(=O)C>C(Cl)Cl>[CH:6]12[CH2:5][C:4]3([C:1]([NH2:2])=[O:3])[CH2:11][CH:10]([CH2:9][CH:8]([CH2:13]3)[NH:7]1)[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(N)=O)(C3)C2
Agent: CC(=O)OC(=O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-carbamoyl-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-11 (0.1 g, 0.0357 mmol) in DCM (5 mL). The reaction mixture was cooled to 0° C. and trifluoroacetic acetic anhydride (0.21 g, 0.17 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-12 (0.09 g, yield=90%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:54]([NH:56][C@H:57]([C:67]([O:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:55])[CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:45])[CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:35])[C@@H:27]([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])[CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]>CN(C=O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:54]([NH:56][C@H:57]([C:67]([O:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:55])[CH2:48][O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:45])[CH2:38][O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:35])[C@@H:27]([CH3:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:24])[CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C

Procedure:
A solution of Z-Ala-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 (20.16 g; 16.8 mmol) in DMF (400 mL) was hydrogenated with 5% Pd-BaSO4 (10 g) for 2 h in a Vibromixer apparatus. The reaction mixture was filtered through celite which was washed with additional DMF (228 mL). The combined filtrate was used directly in the next stage of synthesis. A portion of the material was precipitated by addition of H2O, filtered and dried in vacuo; mp >275°; [α]D25 -9.28° (c 1, TFE); Rf 0.77 (n-BuOH:AcOH:Pyr:H2O; 4-7-1-1); Rf 0.65 (n-BuOH:H2O:AcOH:EtOAc; 1-1-1-1). Anal. calc. for C53H89N7O15.H2O (1082.36): C, 58.82; H, 8.48; N, 9.06. Found: C, 59.11; H, 8.56; N, 9.23.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:23][N:24]([CH:34]([C:38]1[N:47]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](=[O:55])[C:45]2[C:40](=[CH:41][C:42]([Cl:56])=[CH:43][CH:44]=2)[N:39]=1)[CH:35]([CH3:37])[CH3:36])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=O)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:23][N:24]([C@@H:34]([C:38]2[N:47]([CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:46](=[O:55])[C:45]3[C:40](=[CH:41][C:42]([Cl:56])=[CH:43][CH:44]=3)[N:39]=2)[CH:35]([CH3:37])[CH3:36])[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)N(CC(CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2=N[C@@H](CCCNC(=O)OCc3ccccc3)CN2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 240 h
Yield: 32.4 %

Procedure:
A solution of (1-{[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(1-p-tolyl-methanoyl)-amino]-methyl}-4-benzyloxycarbonylamino-butyl)-carbamic acid tert-butyl ester (235 mg, 0.37 mmol) in CH2Cl2/TFA (4:1, 5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was diluted with THF (10 mL) and saturated aqueous NaHCO3 (1 mL). The mixture was stirred at room temperature for 10 days, diluted with ether (20 mL) and washed with brine. The aqueous layer was extracted with two 10 mL portions of EtOAc and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (19:1 CH2Cl2:MeOH) to provide 81 mg (40%) of the title compound as a pale white powder. MS(ES+) m/e 675.6 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[CH:15]=[C:9]2[NH:8][CH:7]=1)C.C(OC1C=CC(C2C=C(N)NN=2)=CC=1)C>>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:15]=[C:9]3[NH:8][CH:7]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[C:11](=[O:12])[N:10]3[N:13]=2)=[CH:21][CH:20]=1)[CH3:24]
Reactant: CCOC(=O)Cc1c[nH]c2cc(-c3ccc(OCC)cc3)nn2c1=O
Agent: CCOc1ccc(-c2cc(N)[nH]n2)cc1
Product: CCOc1ccc(-c2cc3[nH]cc(CC(=O)O)c(=O)n3n2)cc1

Procedure:
The expected compound was obtained according to general procedure G using [2-(4-ethoxy-phenyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl]acetic acid ethyl ester. The starting material was obtained according to general procedure E using 5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine. The expected compound was isolated as white powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:16]2[N:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[N:19]=[C:18]([NH:25][CH:26]3[CH2:28][CH2:27]3)[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl.ClCCl>[N:9]1([C:16]2[N:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[N:19]=[C:18]([NH:25][CH:26]3[CH2:28][CH2:27]3)[C:17]=2[Br:1])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Brc1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
N-Bromosuccinimide (0.39 g, 2.2 mmol) is added to a solution of 6-(1-azepanyl)-N,2-dicyclopropyl-4-pyrimidinamine 62 (0.5 g, 1.84 mmol) in chloroform (2 ml). The mixture is stirred at 60° C. overnight then cooled, diluted with dichloromethane and washed two times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography (dichloromethane/ethanol: 97/3) to give pure 6-azepan-1-yl-5-bromo-N,2-dicyclopropylpyrimidin-4-amine 61 (134 mg, 21%) as a brownish paste.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([OH:32])[CH:31]=1)[C:25]([NH:27][NH2:28])=[O:26]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:28][NH:27][C:25](=[O:26])[C:24]3[CH:23]=[C:22]([OH:21])[CH:31]=[C:30]([OH:32])[CH:29]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=O)c1cc(O)cc(O)c1
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1cc(O)cc(O)c1

Procedure:
From 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 3,5-dihydroxybenzoic hydrazide, 40.1 mg of the desired product was obtained in the same manner as in Synthetic Example 1 as a yellow solid (yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:14]=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1OC

Procedure:
A mixture of 3,4,5-trimethoxyaniline (365 mg; 2.0 mmol) in toluene (20 ml) and phosgene (6 ml 20% in toluene; 12 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trimethoxyphenylisocyanate. To the crude product was added 3(4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine) propanol (420 mg; 1.5 mmol) in DMF (10 ml). The mixture was stirred at 100° C. for 2 h and then at room temperature for 16 h, whereupon it was taken up in ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride and concentrated in vacuo. The resulting oil was taken up in acetone/ethanol (4:1, v/v) and oxalic acid (150 mg) in 2 ml acetone added to precipitate the desired product. The product was washed with ice cold ethanol giving 550 mg of the title compound. M.p. 77°-80° C. MS (70 eV): m/z 487 (9%, M+), 287 (31), 233 (40), 209 (56), 194 (45), 140 (67), 96 (100).