Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH2:7][CH:8]([CH:16]=[CH2:17])[O:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([O:3][CH2:4][CH3:5])=[O:2]>C(OCC)(=O)C>[C:1]([C:6]1[CH2:7][CH:8]([CH2:16][CH3:17])[O:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C=CC1CC(C(=O)OCC)=C(CCCCC)O1
Solvent: CCOC(C)=O
Product: CCCCCC1=C(C(=O)OCC)CC(CC)O1
Yield: 98 %

Procedure:
4-Carbethoxy-5-pentyl-2-vinyl-2,3-dihydrofuran prepared in accordance with the procedure of Example I was hydrogenated to obtain 4-carbethoxy-2-ethyl-5-pentyl-2,3-dihydrofuran. For the reaction, 13 grams of the 4-carbethoxy-5-pentyl-2-vinyl-2,3-dihydrofuran and 75 mls ethyl acetate were charged to the reactor of a Parr apparatus. The system was thoroughly purged with nitrogen and 0.65 gram of a hydrogenation catalyst (5 percent palladium on carbon) was added under a nitrogen atmosphere. After additional nitrogen purging, shaking was begun and the system was pressurized with hydrogen to 15 psig. The system was repressurized as necesary until no futher hydrogen uptake was noted. The reaction mixture was then filtered through Dicalite to remove the catalyst. Ethyl acetate was removed under reduced pressure. Gas chromatographic analysis indicated 98 percent yield crude 4-carbethoxy-2-ethyl-5-pentyl-2,3-dihydrofuran. The crude product was fractionated using a spinning-band distillation apparatus to obtain essentially pure 4-carbethoxy-2-ethyl-5-pentyl-2,3-dihydrofuran (B.P. 112°-114° C. @ 1 mm Hg. nD25° 1.4636). The structure ##STR11## was confirmed by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][C:4]=1[CH3:17]>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]2=[O:14])=[CH:5][C:4]=1[CH3:17]
Reactant: COc1ccc(C(C)(C)CCC(=O)O)cc1C
Agent: CS(=O)(=O)O
Product: COc1cc2c(cc1C)C(C)(C)CCC2=O
Yield: 54.1 %

Procedure:
A solution of 4-(4-methoxy-3-methylphenyl)-4-methyl-pentanoic acid (Compound 5, 7.8 g, 33 mmol) and 150 mL of methanesulfonic acid was stirred at room temperature under an argon atmosphere for 24 h, then poured into ice, extracted three times with ethyl acetate, washed with NaHCO3 1 N, brine, and dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by flash chromatography (Hexane:Ethyl Acetate=4:1) to afford 3.9 g (54%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:28](OCC)(=[O:34])[C:29](OCC)=[O:30]>C(OCCO)C>[CH:23]1([N:22]2[C:3]3[N:4]=[C:5]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]5)=[CH:11][CH:10]=4)[N:6]=[CH:7][C:2]=3[NH:1][C:29](=[O:30])[C:28]2=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CN1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)CC1
Solvent: CCOCCO
Product: CN1CCN(c2ccc(Nc3ncc4[nH]c(=O)c(=O)n(C5CCCC5)c4n3)cc2)CC1
Yield: 52.2 %

Procedure:
A mixture of 0.367 g (1 mmol) of 5-amino-4-(cyclopentylamino)-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidine and 5 mL (32 mmol) of diethyl oxalate in 20 mL of 2-ethoxyethanol is heated under reflux for 3 hours, and cooled, to give 0.22 g (52%) of the title compound (Compound 24): mp (EtOH) 266–270° C.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([NH:20][C:21]([C:23]4[N:27]5[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34][N:35]6[CH2:48][C:37]7([CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]7)[CH2:36]6)=[CH:31][C:26]5=[N:25][CH:24]=4)=[O:22])[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:49])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[ClH:50].O1CCOCC1>C(Cl)Cl.CO>[ClH:50].[ClH:50].[ClH:50].[CH2:48]1[C:37]2([CH2:38][NH:39][CH2:40]2)[CH2:36][N:35]1[CH2:34][CH2:33][O:32][C:30]1[CH:29]=[CH:28][N:27]2[C:23]([C:21]([NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[C:13]([CH3:49])=[N:12][N:11]4[CH2:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:9]=3)=[O:22])=[CH:24][N:25]=[C:26]2[CH:31]=1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CC6(C5)CN(C(=O)OC(C)(C)C)C6)ccn34)c12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CC6(CNC6)C5)ccn34)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
tert-Butyl 6-(2-(3-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.075 g, 0.113 mmol) was dissolved in 2 mL of 1:1 DCM/MeOH and 4M HCl/dioxane (0.282 mL, 1.13 mmol) was added. The mixture was stirred at ambient temperature for 4 hours, then concentrated under reduced pressure. The resulting residue was triturated with DCM and the solids were collected by filtration to give 57 mgs (75%) of the title compound. MS (APCI), positive scan, m/z=567.1 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([NH2:24])[CH3:23])=[N:20][CH:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([NH:24][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH3:23])=[N:20][CH:21]=1
Reactant: C[C@@H](N)c1ccc(Br)cn1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-isopropylphenylacetic acid (0.356 g, 2.000 mmol), (1R)-1-(5-bromopyridin-2-yl)ethanamine hydrochloride (0.475 g, 2.000 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.383 g, 2.000 mmol), and 1-hydroxy-7-azabenzotriazole (0.272 g, 2.000 mmol) in 15.0 ml of CH2Cl2 was added slowly triethylamine (0.836 ml, 6.000 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (0-80% EtOAc/Hex) gave N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.503 (d, J=2.20 Hz, 1H); 7.740 (dd, J=2.20 Hz, J=8.30 Hz, 1H); 7.207 (d, J=8.30 Hz, 2H); 7.182 (d, J=8.30 Hz, 2H); 7.102 (d, J=8.30 Hz, 1H); 6.591 (br d, J=7.08 Hz, 1H); 5.094 (dq, J=7.08 Hz, 1H); 3.571 (d, J=15.87 Hz, 1H); 3.536 (d, J=16.11 Hz, 1H); 2.907 (sept, J=6.83 Hz, 1H); 1.391 (d, J=6.59 Hz, 3H); 1.254 (d, J=6.83 Hz, 6H); MS (Electrospray): m/z 361.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[F:30])=[C:18]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:17]=1>>[CH3:34][C:31]([C:18]1[CH:17]=[C:16]([CH2:15][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:21]=[CH:20][C:19]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[F:30])([CH3:32])[CH3:33]
Reactant: COc1ccc(F)c(-c2ccc(CCl)cc2C(C)(C)C)c1
Reactant: COC(=O)CCc1cccc(O)c1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(C(C)(C)C)c2)c1
Yield: 83 %

Procedure:
Methyl 3-(3-hydroxyphenyl)propanoate (commercially available from Aagile Labs Division of Tyger Scientific) (0.025 g, 0.14 mmol) was alkylated by reaction with compound 8.10 (0.043 g, 0.14 mmol) according to the method given in Example 1 to give compound 34.1 as a clear oil (0.052 g, 83% yield). MS ESI (pos.) m/e: 473.2 (M+Na)+, 468.2 (M+H2O)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1)#[N:2].[ClH:15]>CO.CCOCC.[Pd]>[ClH:15].[F:14][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:1][NH2:2]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CN)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
4-cyano-2-fluoro-1-methanesulfonylaminobenzene (1.03 g) prepared in step 2 was dissolved in methanol (20 mL) and added a catalytic amount of 10 wt. % Pd/C and concentrated HCl (3 mL) to hydrogenate. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with ether, filtered through celite, concentrated under reduced pressure and washed with ethylacetate to yield the title compound (1.13 g, 92%).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25](Br)[CH:26]=O)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([NH2:46])(=[S:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CS(Cl)(=O)=O.Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:45][C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:46][CH:26]=1)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: NC(=S)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccccc4)s3)CSC12
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (a mixture of the bromoaldehyde epimers) (5.87 g) and thiobenzamide (1.5 g) in dry tetrahydrofuran (60 cc) is stirred at 20° C. for 1 hour 20 minutes, and thereafter there are added to the reaction mixture, cooled to 2° C., methanesulphonyl chloride (0.85 cc) followed, in 5 minutes, by triethylamine (5.6 cc). After having been stirred for 2 hours at 2° C., the reaction mixture is poured into a mixture of ethyl acetate (100 cc) and 1N hydrochloric acid (50 cc). The organic phase is washed with a saturated sodium bicarbonate solution (100 cc) and then with a saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is chromatographed on a column (height: 25 cm; diameter: 5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with an 80:20 (by volume) mixture of cyclohexane and ethyl acetate, and 125 cc fractions being collected. Fractions 17 to 22, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-phenyl-thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) is obtained in the form of a yellow froth.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9](=[O:25])[C:10]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[C:12]([C:13]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:11]=1)[CH3:7]>C1COCC1>[CH2:6]([O:8][C:9](=[O:25])[C:10]1[CH:22]=[C:21]([CH:23]([CH:1]2[CH2:3][CH2:2]2)[OH:24])[CH:20]=[C:12]([C:13]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:11]=1)[CH3:7]
Reactant: Br[Mg]C1CC1
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(O)C2CC2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
Add cyclopropyl magnesium bromide (0.8 M in THF, 1.3 mL, 1.02 mmol) dropwise to a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (283 mg, 1.02 mmol) in THF (5 mL) at −10° C. After stirring at 0° C. for 1.5 h, quench the mixture with 5% aqueous ammonium chloride solution while maintaining the temperature below 5° C. Extract with ethyl acetate (3×30 mL), dry (sodium sulfate) concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (122 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([OH:39])[CH2:31][N:30]([C:32](OC(C)(C)C)=O)[CH2:29]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:40]([OH:46])([C:42](F)(F)F)=[O:41].C(OC(C)(C)C)(=O)C=C.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([OH:39])[CH2:29][N:30]([CH2:32][CH2:42][C:40]([OH:46])=[O:41])[CH2:31]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(-c3noc(CCC4(c5cc(Cl)cc(Cl)c5)CCCCC4)n3)cc2)C1
Agent: C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCN1CC(O)(c2ccc(-c3noc(CCC4(c5cc(Cl)cc(Cl)c5)CCCCC4)n3)cc2)C1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 56 %

Procedure:
tert-Butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate (56 mg, 0.098 mmol, HPLC purity: 80%) was treated with TFA in dichloromethane for 1 h and concentrated. The residue was dissolved in 2-propanol (3 mL). tert-Butyl acrylate (0.143 mL, 0.978 mmol) and diisopropylethyl amine (0.034 mL, 0.196 mmol) were added and the mixture was heated to 80° C. overnight. The reaction mixture was concentrated and then treated with TFA in dichloromethane for 3 h. The mixture was concentrated and a DMF solution of the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain 3-(3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxy-1-azetidinyl)propanoic acid (30 mg, 56% yield). HPLC retention time=3.75 minutes (Waters XBridge C18 4.6×50 mm) eluting with 5-95% aqueous AcCN with 0.05% TFA over a 5.3 minute gradient. LC/MS: m/e 544.07, 545.97 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2nccc3ccccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2nccc3ccccc23)c2ccccc12
Yield: 104.8 %

Procedure:
0.333 g (7.94 mmol) of lithium hydroxide monohydrate and 60 cm3 of water are added at 25° C. to 1.2 g (3.97 mmol) of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-indole dissolved in 60 cm3 of tetrahydrofuran. After stirring at reflux for 22 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water and then triturated with 8 cm3 of 5N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1.2 g of 3-carboxy-1-(isoquinol-1-yl)-1H-indole are obtained in the form of a white solid. Mass spectrum (EI): m/e 288 (M+·), m/e 243.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[H+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([N+:7]#[N:12])[CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1c(F)c(N)cc(Br)c1F
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)c(Br)cc([N+]#N)c1F

Procedure:
To a suspension of 5-bromo-2,4-difluoro-3-methylaniline (24.60 g) in 42% fluoroboric acid (150 ml) with stirring vigorously at -3° to 0° C. was added sodium nitrite (11.47 g) in water (20 ml) dropwise during 40 minutes. After stirring for 1.5 hours at 0° to 5° C., the reacting mixture was cooled with ice bath sufficiently and the resulting precipitate was collected by filtration. This precipitate was washed with small portion of water and ether and dried under reduced pressure to give the title compound (28.83 g) as pale brown prisms, mp 147°-150° C. (decompd.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C@@H:5]([CH3:8])[O:4][C@H:3]1[CH2:9][OH:10].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[O:10]([CH2:9][C@H:3]1[C@H:2]([OH:1])[CH2:7][O:6][C@@H:5]([CH3:8])[O:4]1)[Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1OC[C@@H](O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
A mixture of (2R,4S,5R)-5-hydroxy-4-hydroxymethyl-2-methyl-1,3-dioxane (13.0 g), t-butyldimethylchlorosilane (14.5 g) and imidazol (13.1 g) in N,N-dimethylformamide (130 ml) was stirred at room temperature for 2 hours and the mixture was diluted with ethyl acetate (500 ml). The solution was washed successively with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2R,4S,5R)-4-t-butyldimethylsiloxymethyl-5-hydroxy-2-methyl-1,3-dioxane (24.2 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[C:16]([O:18][CH3:19])=[O:17])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH:13]([N:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)([CH3:14])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O

Procedure:
(3R,4S)-Methyl 4-((3S)-3-amino-2-oxopyrrolidin-1-yl)-1-isopropylpiperidine-3-carboxylate (50 mg, 0.176 mmol, 1 eq.), 4-chloro-6-(trifluoromethyl)-quinazoline (45 mg, 0.194 mmol, 1.1 eq.) and triethylamine (98 uL, 0.706 mmol, 4 eq.) were dissolved in ethanol (3 mL) at room temperature then microwaved at 100° C. for 1 hour. Purified by HPLC. Obtained (3R,4S)-methyl 1-isopropyl-4-(2-oxo-(3S)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)piperidine-3-carboxylate, bis TFA salt (88 mg) as a white solid. LCMS detects (M+H)+=480.39. 1H NMR (400 MHz) (CD3OD) δ 8.82 (s, 1H, J=7 Hz); 8.20 (s, 1H, J=7 Hz); 8.78 (s, 1H, J=7 Hz); 7.91 (d, 1H, J=7 Hz); 7.30-7.10 (m, 1H); 5.37 (m, 1H); 4.3-4.05 (m, 1H); 3.80-3.00 (m, 9H); 2.60-2.45 (m, 1H); 2.45-2.10 (m, 2H); 2.10-1.80 (m, 2H); 1.27 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[NH:4][C:3]1=[O:13].[Cl:14][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[ClH:14].[CH2:22]([N:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][N:4]2[C:5]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=3[N:2]([CH3:1])[C:3]2=[O:13])[CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc2c(c1)[nH]c(=O)n2C
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: COc1ccc2c(c1)n(CC1CN(Cc3ccccc3)CCO1)c(=O)n2C
Product: Cl
Yield: 44.6 %

Procedure:
The condensation of 0.1 mol of 1-methyl-5-methoxy-2,3-dihydro-benzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine is carried out in accordance with the procedure of Example 1. 18 g of 4-benzyl-2 -(1-methyl-5-methoxy-2,3-dihydrobenzimidazol-2-on-3-yl-methyl)-morpholine hydrochloride are obtained, m.p. 175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.B.[B](C1C(C)C2C(C)(C)C(C2)C1)C1C(C)C2C(C)(C)C(C2)C1.C1C2C(=CC=CC=2)CCN1>O1CCCC1>[C:7]12[CH2:6][CH:5]([C:8]1([CH3:10])[CH3:9])[CH2:4][CH2:3][C:2]=2[CH3:1]
Reactant: CC1=CCC2CC1C2(C)C
Agent: B
Agent: CC1C([B]C2CC3CC(C2C)C3(C)C)CC2CC1C2(C)C
Agent: c1ccc2c(c1)CCNC2
Solvent: C1CCOC1
Product: CC1=C2CC(CC1)C2(C)C

Procedure:
Another way to accomplish this assymetric reduction of compound 4' to optically active tetrahydroisoquinolines is to reduce the compound in tetrahydrofuran with the reagent which is obtained by reacting 2 moles of optically active alpha pinene with borane in tetrahydrofuran. The solution of the diisopinocampheylborane functions as the reducing agent in the reduction of the intermediate 4' to chiral tetrahydroisoquinoline. Basically, the compound 4' is treated with a slight excess of this reagent produced from optically active pinene and BH3 in tetrahydrofuran followed by evaporation and treatment with HCl which decomposes a complex and gives the hydrochloride of the tetrahydroisoquinoline in the aqueous phase. The base can then be recovered from the aqueous phase by treatment with ammonia and methanol as above.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:7]([Cl:21])[CH:6]=1)C.[H-]>ClCCl>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[C:7]([Cl:21])[C:8]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
To a solution of 3,5-dichloro-4-(4-methoxy-phenoxy)-benzoic acid ethyl ester (1.36 g, 4.01 mmol) in dichloromethane (35 ml) at 0° C. was added diisobutylaluminun hydride (1M in toluene, 12 ml, 12 mmol) and the mixture was stirred for 2.5 hours at 0° C. The reaction mixture was quenched with potassium sodium tartrate tetrahydrate (0.5 M aqueous solution, 50 ml), stirred for 20 minutes at room temperature and then was filtered through diatomaceous earth. The filtrate was concentrated and then taken up in water (60 ml). The aqueous solution was extracted with ethyl acetate (4×60 ml). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (2% ethyl acetate in dichloromethane) to afford the title compound (871 mg). NMR (400 MHz, CDCl3) δ7.39 (s, 2H), 6.74-6.82 (m, 4H), 4.69 (d, 2H), 3.76 (s, 3H), 1.83 (t, 1 H).