Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]([NH2:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[CH3:34][CH:35]([CH3:39])[C:36](Cl)=[O:37]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:19]([NH:21][C:36](=[O:37])[CH:35]([CH3:39])[CH3:34])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: NC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(=O)NC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetamide (137b, 20 mg, 60 μmol) in THF (2 ml) was cooled to 0° C., and potassium 2-methylpropan-2-olate (18.6 mg, 170 μmol) was added. The mixture was stirred at 0° C. for 10 min, and a solution of 2-methylpropanoyl chloride (30 mg, 280 μmol) in THF (0.5 ml) was added. Stirring was continued for 30 min at 0° C. Then the sample was concentrated in vacuo and purified by semi-prep. HPLC go give white solid material, 14 mg (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13](N)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I:26]CI.N(OCCC(C)C)=O.Cl>[Cu]I.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([I:26])[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: ICI
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1C1=NCc2cnc(I)nc2-c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 49.6 %

Procedure:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluoro-phenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:37][S:38]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Product: CS(=O)(=O)N[C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A arid methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C>C1C=CC=CC=1>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21
Temperature: 25 °C
Yield: 12.7 %

Procedure:
A stirred mixture of 8.86 g of 2-[(1-ethyl-2-methyl-3-indoly)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared as described in part A above, 4.0 g of N,N,N',N'-tetramethyl-m-phenylenediamine, and 10.0 ml of acetic anhydride was heated at reflux for a period of three hours. The reaction was then allowed to cool to room temperature, and the tan precipitate which formed was filtered and washed with isopropanol. The material thus obtained was dissolved in 500 ml of benzene and the resulting solution extracted with 70 ml of 10 percent aqueous sodium hydroxide. The benzene solution was filtered and evaporated to dryness at ambient temperature yielding 1.5 g of 3-[2,4-bis(dimethylamino)-phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R°=R1 =R2 =R3 =Cl; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3 ; Y1 =H), a white solid which melted with decomposition at 227°-229° C. A significant infrared maximum occurred at 1770 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was in complete agreement with the assigned structure. A benzene solution of this product spotted on silica gel developed an intense purple color.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reaction time: 0.33 h

Procedure:
The product from step (vi) (0.6 g) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The reaction mixture was stirred for 20 min, the solvents were evaporated and the product purified via SCX resin, eluting with ammonia in MeOH solution (3.5%). Yield 380 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14](C3CCN(C)CC3)=C[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([C:28]1[CH:29]=[C:30]2[C:35](=[C:36](F)[CH:37]=1)[C:34](=[O:39])[N:33]([C:40]1[N:47]=[CH:46][CH:45]=[C:44](I)[C:41]=1[CH:42]=[O:43])[N:32]=[CH:31]2)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:39])[N:33]([C:40]1[C:41]([CH2:42][OH:43])=[C:44]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[C:15]5[CH2:14][N:6]([CH3:8])[CH2:5][CH2:4][N:10]5[N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[CH:45]=[CH:46][N:47]=1)[N:32]=[CH:31]2)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ncc2c1
Reactant: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)ccc6c5=O)c4CO)nn(C)c3=O)cc2C1

Procedure:
Preparation by a similar procedure to example 1 (Step 5-6), except substituting 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one for 6-chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one and substituting 2-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-4-iodo-pyridine-3-carbaldehyde for 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-iodonicotinaldehyde in step 5 afforded 72 mg of the title compound as a white solid. (M+H)+=568 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 2.54 (s, 3 H) 2.97 (br. s., 2 H) 3.68 (s, 2 H) 3.90 (s, 3 H) 4.08 (t, J=6.99 Hz, 1 H) 4.17 (t, J=5.48 Hz, 2 H) 4.47-4.56 (m, 2 H) 5.86 (s, 1 H) 7.62 (d, J=4.91 Hz, 1 H) 7.77 (d, J=1.89 Hz, 1 H) 7.86-8.01 (m, 3 H) 8.38 (s, 1 H) 8.44 (d, J=8.31 Hz, 1 H) 8.72 (d, J=4.91 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16]C(N)=O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:11])[NH:16][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)C(=O)NC2=O
Temperature: 250 °C
Yield: 91.8 %

Procedure:
Equimolar quantities of 4-t-butylphthalic anhydride (150.33 grams, 0.7361 mol) and urea (44.21 grams) were mixed with a thermometer in a 1 liter round bottom flask. The solids were heated slowly with a Meker burner. At 175° C., the reaction became exothermic and had to be cooled with an air gun. When the exotherm subsided, the temperature was increased to 250° C. and maintained at that temperature for 30 minutes. The flask was then cooled and 300 milliters of dimethylformamide was added, after which the solution was filtered by gravity to remove any solids which should not dissolve. Water (1 liter) was added, resulting in precipitation of 137.34 grams (0.6757 mole) of 4-t-butyl-phthalimide, which exhibited a melting point of 136.5° to 140° C. The identity of the 4-t-butyl-phthalimide product was confirmed by IR spectrum.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[CH2:21](N(CC)CC)C>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([O:15][CH3:21])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: O=S(=O)(O)O
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (426 g) in methanol (3 l) was added 36N sulfuric acid (45 ml) at 10° C., and the mixture was allowed to heat to reflux for 2 hours. After cooling to ambient temperature, to this mixture was added triethylamine (430 ml) and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (3 l) and the solution was washed with brine, dried over magnesium sulfate and evaporated to give (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (385.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([CH3:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([CH2:13][Br:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.00 g (21.0 mmol) of acetoacetic acid benzyl ester was dissolved in 40 ml of ether. 1.1 ml (21.0 mmol) of bromine was dropped at 0° C. After stirring at 0° C. for 30 minutes and then at room temperature for 5 hours, about 4 g of ice and sodium carbonate were added so that pH showed 7 or more. The organic layer extracted with ether was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated and dried in vacuo to obtain 4-bromoacetoacetic acid benzyl ester. 1.68 g (24.0 mmol) of sodium hydride (60% oily substance) was suspended in 20 ml of THF and 11.7 g (21.0 mmol) of 2-chloroethanol was added at −40° C. 4-bromoacetoacetic acid benzyl ester was dropped at −40° C., gradually heated and stirred at room temperature for 16 hours. After adding 1 N hydrochloric acid and extracting with ethyl acetate, the obtained mixture was washed with water and saturated aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=7/3) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][N:4]=1.[CH3:22]I.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:22])=[CH:5][N:4]=1
Reactant: Cc1nc(Nc2ccc(N(C)C)nc2)c2ccccc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccc(N(C)C)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-dimethylamino-pyridine-5-yl)-(2-methyl-quinazolin-4-yl)-amine (45 mg, 0.16 mmol), methyl iodide (0.016 ml, 0.24 mmol), sodium hydride (9.6 mg, 0.24 mmol, 60% oil dispersion) in DMF similar to example 21 to give 22 mg (47%) of paint yellow solids. 1H NMR (CDCl3): 8.07 (d, J=2.4 Hz, 1H), 7.63 (dd, J=0.9 Hz, J=8.4 Hz, 1H), 7.56-7.51 (m, 1H), 7.27-7.18 (m, 2H), 7.05-7.00 (m, 1H), 6.50 (d, J=9.3 Hz, 1H), 3.55 (s, 3H), 3.12 (s, 6H), 2.72 (s, 3H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:16]1([CH2:22][C:23]([NH2:25])=[NH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:22]([C:23]1[N:25]=[C:11]([OH:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc(Cc2ccccc2)nc1O
Yield: 40 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (11 g, 52 mmol) with phenylacetamidine (8 g, 60 mmol) to afford 40% of ethyl 2-benzyl-4-hydroxypyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of 2-benzyl-4-hydroxypyrimidine-5-carboxylate (3 g, 12 mmol) with POCl3 (18 g, 116 mmol) to afford 45% of 2-benzyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of 2-benzyl-4-chloropyrimidine-5-carboxylate (1.5 g, 5.5 mmol) with hydrazine (0.5 g, 16 mmol) to afford 75% of 2-benzyl-4-hydrazinopyrinmidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 2-benzyl-4-hydrazinopyrimidine-5-carboxylate (1 g, 3.5 mmol) with citraconic anhydride (1 g, 11 mmol), in analogy to Example 21, to afford 70% (0.9 g) of the title compound; m.p. 117-118° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39]([C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:28])[CH:3]=2)[CH:34]=[CH:35][C:30]=1[Cl:29])=[O:40])[CH3:43]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=582.3 [M+H+].
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1>ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C@H:21]([O:30][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:31][CH:32]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
tert-Butyldimethylsilylchloride (3.75 g) and imidazole (1.69 g) were added to a solution of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (4 g, Example 21a)) in dichloromethane. The mixture was stirred for 16 hours at room temperature. The white precipitate was collected by filtration and the filtrate concentrated under reduced pressure to give the sub-title compound as an oil (5.4 g)
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])O.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH2:27].Cl>ClCCl>[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH:27][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C)O
Reactant: Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Under ice-cooling, methyl D-lactate (8.5 g) and 2,6-lutidine (11.4 g) were dissolved in dichloromethane (100 ml). After dropping anhydrous trifluoromethanesulfonic acid (25.4 g), the mixture was heated to room temperature and stirred for 30 minutes. Then it was cooled to 0° C. again and a solution (30 ml) of 2,3,4-trifluoroaniline (12.0 g) in dichloromethane was dropped thereinto. The mixture was stirred at the same temperature for 17 hours. To the resultant solution, hydrochloric acid (0.5 mol/l) was added and the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporating the solvent, the residue thus obtained was subjected to silica gel column chromatography. Thus, 17.1 g (90%) of the title compound was obtained as an oily substance. The optical purity determined by HPLC was 97% ee.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([C@H:7]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[O:6])[CH3:3].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.OC1C2N=NNC=2C=CC=1>CN(C=O)C>[CH3:3][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:18][C@H:19]([C:24]([NH:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12])([CH3:1])[CH3:27]
Reactant: CC(C)C[C@H](N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccccc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
11.4 g of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-L-leucine, prepared as in Example I, 3.64 g benzylamine, and 4.59 g hydroxybenzotriazole in 150 mL DMF was sparged with nitrogen for 10 min. 7.02 g of d icyclohexylcarbodiimide in 50 mL DMF was added dropwise at 0° C. The mixture was stirred for 15 h at 23° C., filtered, and the solvents were removed by evaporation. The residue was purified by silica chromatography using 80% hexane-ethyl acetate as eluent to give the title compound as a brown oil; 8.8 g.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].[BH4-].[Na+].C(O)(=O)C>O>[OH:8][CH:7]([C:4]1[CH:5]=[CH:6][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2][CH:3]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A 25.4 g. portion of 3-(4-biphenylylcarbonyl)propionic acid is dissolved in 2 liters of water made alkaline with sodium hydroxide. A 37.8 g. portion of sodium borohydride is added and the mixture is stirred for 2 hours. The suspension is then slowly poured into 100 ml. of glacial acetic acid. The mixture is cooled and the resulting solid is filtered, washed with water and dried giving the desired product, m.p. 139°-140° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN(C)C=O.O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:23])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Br)c2C1=O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
24.9 g (74.1 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide, treated at room temperature with 14.3 g (89 mmol) of 1,1'-carbonyldiimidazole and stirred at 70° for 30 minutes. 50 ml of 25% ammonia were added dropwise at 25°-30°. The reaction mixture was diluted with 200 ml of water and cooled to 0°, and the crystallizate was filtered off under suction and dried. There were obtained 21.6 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of m.p. 278°-279°.