Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])C(F)(F)F)[N:5]([CH3:7])[CH:6]=1.Cl.[OH-].[NH4+:16]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:16])=[O:13])[N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)cc1C(=O)C(F)(F)F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: Cn1cc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trifluoroethanone (5.0 g, 19.5 mmol) was dissolved in ammonium hydroxide (72.5 ml, 29.4% aqueous solution) and stirred at room temperature for 45 min. The solution was brought to pH=7 with 2N HCl. The solid precipitate was collected by filtration. The solid was washed with water and dried overnight under reduced pressure at 50° C. The aqueous layer was extracted twice with dichloromethane. The organic phase was concentrated in vacuo to afford more solid. Solid from the filtration and extraction were combined to afford 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (3.2 g, 81%) as a white solid: LC/MS-ESI observed [M+H]+ 203 and 205.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[C:5]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2-c2ccc(CC(C)C)cc2)c1C
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)cc2-c2ccc(CC(C)C)cc2)c1C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of the compound of Example 43 (0.4 g, 1.0 mmol) and pyridine (0.082 mL, 1.0 mmol) in acetone (3 mL) was added benzoyl chloride (0.12 mL, 1.0 mmol). The mixture was stirred for 18 hours and concentrated. The residue was dissolved in methanol (50 mL) and a 5% solution of sodium hydrogen carbonate in water (10 mL) was added. The solution was stirred for 1 hour and the methanol was removed under vacuum. The aqueous residue was acidified to pH 3 with 6N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, and dried (magnesium sulfate). The residue was chromatographed on silica with (1:1) ethyl acetate:hexanes to afford 98 mg (19%) of the title compound as a tan solid, mp 207-211° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[C:11]1([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quenched with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36](=[O:57])[NH:37][C@H:38]([C:46]1[O:47][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][N:50]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])O.[Na+].[O:73]=[C:74]1[CH:78]=[CH:77][C:76](=[O:79])N1C(OC)=O.FC(F)(F)C(O)=O>O1CCOCC1.O>[O:73]=[C:74]1[CH:78]=[CH:77][C:76](=[O:79])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36](=[O:57])[NH:37][C@H:38]([C:46]1[O:47][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][N:50]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11 mg (12 μmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 235) were taken up in 500 μl of 1:1 dioxane/water and admixed with 253 μl of 1M aqueous sodium hydrogencarbonate solution and then with 2.8 mg (18 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 30 min and then acidified with trifluoroacetic acid. The reaction mixture was purified by means of preparative HPLC. After lyophilization, 0.8 mg (7% of theory) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:47][C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([O:40][CH3:39])[CH:42]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2ccc(Oc3ccc(OCc4ccccc4)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
A solution of the product from Example 43D and 3-Methoxy-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-(3-methoxy-phenyl)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (12 mg, 40%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J=6.99 Hz, 6 H) 3.11-3.29 (m, 1 H) 3.75 (s, 3 H) 6.68 (dd, J=8.09, 1.84 Hz, 1 H) 6.75 (d, J=8.82 Hz, 2 H) 6.89 (t, J=8.64 Hz, 3 H) 7.24 (t, J=8.09 Hz, 1 H) 7.37 (d, J=8.09 Hz, 1 H) 7.45 (t, J=2.21 Hz, 1 H) 7.60 (d, J=8.46 Hz, 1 H) 7.86 (dd, J=8.64, 1.65 Hz, 1 H) 8.17 (s, 1 H) 8.61 (s, 1 H) 8.82 (d, J=8.46 Hz, 1 H) 9.38 (s, 1 H) 10.01 (s, 1 H) 10.15 (s, 1 H); MS (ESI+) m/z 522 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[C:38]([N+:45]([O-:47])=[O:46])=[CH:37][C:33]=1[C:34](O)=[O:35].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>C(Cl)Cl.CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:34](=[O:35])[C:33]2[CH:37]=[C:38]([N+:45]([O-:47])=[O:46])[C:39]([NH:41][C:42](=[O:44])[CH3:43])=[CH:40][C:32]=2[O:31][CH3:30])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-Dicyclohexylcarbodiimide (4.12 g; 0.02 moles) and 1-benzyl-4-aminopiperidine (3.8 g; 0.02 moles) were added successively to a solution of 2-methoxy-4-acetamido-5-nitrobenzoic acid (5.1 g; 0.02 moles) in methylene chloride (125 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohexylurea was filtered off, the solution was washed with water, dried (Na2SO4) and the solvent removed in vacuo to give a solid. It was suspended in hot methanol and treated with the stoichiometric amount of fumaric acid to give a solution from which the N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-nitrobenzamide fumarate (6.2 g) crystallized. After recrystallization from methanol this compound melted at 204°-206° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:58])[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]3[N:35]=[CH:36][N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:38]=3)=[CH:29][N:28]=2)[CH:26]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:58])[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]3[N:35]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH:4]=4)[CH:36]=[N:37][CH:38]=3)=[CH:29][N:28]=2)[CH:26]=1
Reactant: N#Cc1ccc(CO)cc1OCCc1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-phenethyloxy-benzonitrile from step 2 (65 mg, 0.26 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23 Step 5 (136 mg, 0.26 mmol) in CH2Cl2 (2 ml) was added DIEA (100 μl, 0.56 mmol) followed immediately by the addition of Tf2O (65 μl, 0.39 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (2 ml) and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[C:21]3([OH:25])[CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1NCCN1c1ccnc(Cl)c1
Reactant: OC1(c2ccncc2Br)CCC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1(O)CCC1
Yield: 14.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(2-chloro-pyridin-4-yl)-imidazolidin-2-one (I-33b: 100 mg, 0.5076 mmol) was reacted with 1-(3-bromo-pyridin-4-yl)-cyclobutanol (I-33c: 127 mg, 0.5583 mmol) copper iodide (9.6 mg, 0.0507 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (21 mg, 0.1522 mmol), potassium phosphate (269 mg, 1.269 mmol) and 1,4-dioxane (3 mL) to afford crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 25 mg of pure product (14% yield)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(cyclopropylmethyl-methyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example C16) (5.66 g, 14.5 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as yellow solid (4.7 g).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][N:21]=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][NH:19]2)[CH:7]1[CH2:9][CH2:8]1)C.[OH-].[Na+]>CO>[NH:19]1[C:20]2[C:15](=[C:14]([CH2:13][CH2:12][CH2:11][C:10]([N:6]([CH:7]3[CH2:8][CH2:9]3)[CH2:5][C:4]([OH:25])=[O:3])=[O:24])[CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)CN(C(=O)CCCc1ccnc2c1CCCN2)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN(C(=O)CCCc1ccnc2c1CCCN2)C1CC1
Yield: 60 %

Procedure:
A solution of ester 23-5 (200 mg, 0.5774 mmole), 1N NaOH (600 μl, 0.600 mmole) and CH3OH was stirred at ambient temperature for 1.5 h. The solution was concentrated. The residue was dissolved in 1N HCl (600 μl) and then the solution was concentrated. The residue was dissolved in CHCl3, filtered and concentrated to give the carboxylic acid 23-6 (110 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[C:16]([CH3:23])([O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 52A], 3-nitro-5-trifluoromethyl-phenol [PCT Int. Appl. (1994), WO 94/20467A1] was reacted with ethyl bromoisobutyrate to yield the title compound as yellow oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[O:17][CH2:18][C:19](O)=O)[CH:10]([CH3:12])[CH3:11]>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:19]=1[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([O:13][CH2:9][CH:10]([CH3:11])[CH3:12])[CH:15]=1
Reactant: CC(C)COc1cccc(OCC(=O)O)c1
Reactant: Nc1ccccc1N
Agent: Cl
Product: CC(C)COc1cccc(OCc2nc3ccccc3[nH]2)c1
Yield: 58.7 %

Procedure:
A 250 mL flask fitted with a stir-bar and condenser was charged with 1,2-phenylenediamine (2.46 g, 22.7 mmol), acid 72 (5.10 g, 22.7 mmol), and 4M HCl (50 mL). The resultant suspension was heated in a 125° C. bath for 72 hr. The mixture was cooled, and concentrated in vacuo to a green solid. The solid was triturated with acetone (50 mL), filtered, and rinsed with acetone (2×20 mL). The solid was then triturated with H2O (50 mL) and filtered. The material was next taken up in MeOH:H2O 1:1 (75 mL), and the pH was adjusted to 11 with 2M NaOH (10 mL). The mixture was then extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL), filtered through phase separation paper, and concentrated in vacuo to a light pink glass. The material crystallized to give 3.95 g of 73 as a white solid (59%). 1H NMR (60 MHz, CDCl3): δ 7.8-7.6 (m, 2H), 7.5-7.0 (m, 3H), 6.6-6.4 (m, 3H), 5.4 (s, 2H), 3.5 (d, 2H), 1.9 (nonet, 1H), 0.9 (d, 6H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 8.5 min.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:64])/[CH:31]=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[CH:31]/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:64])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a solution of DMAP (647 mg, 5.30 mmol), EDC (1016 mg, 5.30 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (663 mg, 3.18 mmol) (11) in Dichloromethane (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylamide (685 mg, 1.060 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with Petrol ether/Ethyl acetate (5:1) to afford the product 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (480 mg, 0.542 mmol, 51.2%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25]C)=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:7]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[CH:7]=1
Reactant: COc1ccc(Br)cc1Cc1c(CNCCC(C)C)nc2ccccn12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)CCNCc1nc2ccccn2c1Cc1cc(Br)ccc1O
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of 416 mg (1.0 mmol) of ({3-[(5-bromo-2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl) (3-methylbutyl)amine in 20 mL dichloromethane at −78° C. is treated with boron tribromide 0.4 mL (4.0 mmol). The resulting solution is allowed to return to room temperature over 1 hr, quenched by addition of 10 mL sat. NaHCO3 and extracted with 2×10 mL dichloromethane. The combined extract is dried over anhydrous MgSO4 and the solvent removed in vacuo to yield 360 mg (89%) ({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(3-methylbutyl)amine.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:18](OS(C)(=O)=O)/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(OC(N[C@@H](CC1C=CC=CC=1)[C@@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C.CCCCCC>C(OCC)(=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)/[CH:18]=[CH:19]/[C@H:20]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:21]([O:23][CH3:24])=[O:22])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cl[Mg]C1CCCCC1
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: COC(=O)/C=C/[C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 82 %

Procedure:
Using the procedure of Example 8 but replacing benzylmagnesium chloride with cyclohexylmagnesium chloride (2.0M solution in ether) and replacing the resultant compound of Example 7 with the resultant compound of Example 14 provided, after chromatography on silica gel using 6:1 hexane:ethyl acetate, the desired compound (Rf 0.65, 2:1 hexane:ethyl acetate) in 82% yield. 1H NMR (CDCl3) δ 0.6-1.7 (br envelope, 11 H), 1.41 (s, 9 H), 2.69 (m, 1 H), 2.75 (dd, J=14, 7 Hz, 1 H), 2.89 (dd, J=14, 5 Hz, 1 H), 3.66 (s, 3 H), 4.41 (m, 2 H), 5.44 (AA', 2 H), 7.1-7.3 (m, 5 H). Mass spectrum: (M+H)+ =402.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4CCCCC4)n3)c2[C@@H]2CCN12
Yield: 96.5 %

Procedure:
3.76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 5 g (58 mmol) of piperidine and 25 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there were obtained 4.1 g (96%) of (S)-8-chloro-1-[5-(piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 177°-179°, which was converted into the hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CC(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)CC(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
14.4 g (0.05 mole) β-chloro-β,β-diphenyl-propionic acid ethyl ester (prepared from β-hydroxy-β,β-diphenyl-propionic acid ethyl ester, Ber. 40, 4538, by treatment with phosphorus pentachloride) are heated in 100 ml acetonitrile with 10 g imidazole at boiling temperature for 16 hours. The solvent is distilled off in a vacuum, the residue treated with 50 ml of water and extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum. The β-imidazolyl-β,β-diphenyl-propionic acid ethyl ester is thus obtained in the form of crystals of m.p. 75° C.