Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].Cl.Cl.C([O:39][CH2:40][C:41]1[CH:46]=[N:45][C:44]([CH2:47][O:48][NH2:49])=[CH:43][N:42]=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(OCC)(=O)C.C(N(CC)CC)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:49][O:48][CH2:47][C:44]2[CH:43]=[N:42][C:41]([CH2:40][OH:39])=[CH:46][N:45]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(=O)OCc1cnc(CON)cn1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cnc(CO)cn2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 300 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 6 ml of DMF were added {5-[(aminooxy)methyl]pyrazin-2-yl}methyl acetate dihydrochloride, 0.16 ml of triethylamine, 119 mg of HOBt, and 200 mg of WSC, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue were added 4.5 ml of methanol and 2.4 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 0° C. for 2 hours, and then 1 M hydrochloric acid was added thereto for neutralization. Chloroform was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent:chloroform-methanol) and then recrystallized from ethyl acetate to obtain 73 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)pyrazin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Reaction SMILES: O[C:2]1([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(O)(c2cccs2)CC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(c2cccs2)CC1
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 80 mg (0.23 mmol) of the material prepared in Example 1 in 2 ml of dichloromethane and 32 mg (0.28 mmol) of triethylsilane at −78° C., was added 49 mg (0.35 mmol) of boron trifluoride diethyl etherate. The mixture was stirred for 1 h., the bath was removed and stirred at ambient temperature for 30 min. A saturated solution of sodium bicarbonate (2 ml) was added and extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (75 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded 38 mg (50%) of the title compound. Analysis calculated for C16H27NO2S2: %C, 58.32; %H, 8.26; %N, 4.25. Found: %C, 59.06; %H, 8.48; %N, 4.31. Field Desorption Mass Spectrum: M=329.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([N+:1]([O-:4])=[O:2])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)cc2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C

Procedure:
3.6 g (57 mmol) of concentrated nitric acid were added dropwise to a mixture of 11.1 g (38.0 mmol) of 3-chloro-2-(4-chloro-phenyl)-5-trifluoromethylpyridine in 50 ml of concentrated sulfuric acid while stirring and cooling in ice at 0°-5° C. The mixture was stirred at this temperature for two hours and then poured into 500 ml of ice-water. The product was extracted three times with 150 ml of ethyl acetate each time. The combined organic phases were washed twice with a little water, dried over sodium sulfate and finally concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 95:5). Yield: 11.8 g (90%) of colorless crystals of melting point 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[Cl:41][C:26]1[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[N:28][C:23]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:18])([CH3:19])[CH2:7][CH:8]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(N2CCOCC2)C(=O)Nc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(N2CCOCC2)CC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-3-morpholin-4-yl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 8-Amino-5,5-dimethyl-3-morpholin-4-yl-1,3,4,5-tetrahydro-1-benzazepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a yellow (5 mg, 10%), HPLC purity=99%, LCMS 570 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.32 (s, 1H), 9.06 (bs, 1H), 8.53 (bs, 1H), 8.13 (s, 1H), 7.58-7.52 (m, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.38-7.36 (m, 1H), 6.90 (d, 1H), 6.80 (bs, 1H) 6.73-6.71 (m, 1H), 4.33-4.30 (m, 1H), 3.63-3.50 (m, 8H), 2.72 (d, J=4.0 Hz, 3H), 1.77-1.73 (m, 1H), 1.49-1.46 (m, 1H), 1.24 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C@@H:14]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:15]([F:25])([F:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10](O)=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:34][C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:38]([C:35]1([NH:34][C:10](=[O:11])[C@@H:9]([NH:13][C@@H:14]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:15]([F:25])([F:24])[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:8][S:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:7])[CH2:37][CH2:36]1)#[N:39]
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a stirred mixture of 3-cyclopropylmethanesulfonyl-2(R)-[2,2-difluoro-2-(4-fluoro-phenoxy)-1(S)-(4-fluorophenyl)ethylamino]propionic acid (0.2 g, 0.42 mmol) and 1-aminocyclopropanecarbonitrile hydrochloride (0.060 g, 0.5 mmol) in DMF (3 ml), HATU (0.16 g, 0.42 mmol) and diisopropylethylamine (0.183 ml, 1 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and washed with water, sat. NaHCO3 and brine. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by flash chromatography, using ethyl acetate/hexanes (1/1) as eluent to give the title compound as a white solid (0.09 g, 39%). 1HNMR (DMSO-d6): δ 9.01 (1H, s), 7.47 (2H, m), 7.21 (2H, m), 7.13 (2H, m), 4.29 (1H, q), 3.74 (1H, m), 3.4 (2H, m), 3.19 (3H, m), 1.36 (2H, m), 1.10 (1H, m), 1.00 (1H, m), 0.72 (1H, m), 0.57 (2H, m), 0.30 (2H, m). LC/MS, M+1: 540.3; M−1: 538.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:26][C:25]3[CH:24]=[C:23]([CH:30]=[CH:29][CH:28]=3)[C:21]#[N:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloroquinaldine (17.7 g) in THF (80 mL) at -78° was added a solution of 100 mL lithium diisopropylamide (LDA) (1M) dropwise. After addition the solution was warmed to -20° and added dropwise to 3-cyanobenzyl bromide (20 g) in THF (80 mL) at 0°. The reaction mixture was stirred 1 hr at 0° and warmed to room temperature (30 min). The mixture was partitioned between pH 7 buffer (25% NH4OAc) and ethyl acetate. The organic layer was dried and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([OH:10])([CH3:9])[C:5]([F:8])([F:7])[F:6].[Br:12][C:13]1[CH:14]=[C:15]([C:19](=[O:23])[CH:20]=[N+]=[N-])[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:11])[C:4]([O:10][CH2:20][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:23])([CH3:9])[C:5]([F:7])([F:6])[F:8]
Reactant: [N-]=[N+]=CC(=O)c1cccc(Br)c1
Reactant: COC(=O)C(C)(O)C(F)(F)F
Agent: [Rh]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(OCC(=O)c1cccc(Br)c1)C(F)(F)F

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid methyl ester (22.94 g, 133 mmol) in CH2Cl2 (400 ml) was added rhodium(II) trifluoroacetate dimer (0.439 g, 0.667 mmol). After cooling to 0° C. a solution of 1-(3-bromo-phenyl)-2-diazo-ethanone (15.0 g, 66.7 mmol) dissolved in CH2Cl2 (100 ml) was added over a period of 2 h. The reaction mixture was concentrated and the title compound was obtained after flash-chromatography on silica gel (toluene) as a yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.45; HPLC RtH5=1.352 min; 1H NMR (360 MHz, CDCl3): δ 8.15 (s, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 7.40 (t, 1H), 4.87 (s, 2H), 3.89 (s, 3H), 1.72 (s, 3H); ESIMS: 386, 388 [(M+NH4)+].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[H-].[Na+].[CH3:14][N:15]([CH:17]=O)C>>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:17]3[N:15]=[CH:14][CH:5]=[CH:4][C:3]=3[C:2]#[N:1])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CN(C)C=O
Reactant: Nc1cccc2cnccc12
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cccnc1Nc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-amino-isoquinoline (526 mg) in DMF (20 ml) at 0-5° C. was added sodium hydride (400 mg of a 55 to 65% dispersion in mineral oil). The cooling bath was removed and the dark green reaction mixture was stirred at room temperature for 30 minutes. 2-Chloro-nicotinonitrile (506 mg) was added and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by addition of water and the products were extracted several times with EtOAc. The combined organic layers were washed with water and 3M CaCl2, dried (MgSO4) and evaporated under reduced pressure. The remaining red-brown solid material was re-crystallised from ethanol and gave 2-(isoquinolin-5-ylamino)-nicotinonitrile (306 mg): 13C-NMR (DMSO-d6) δ 157.6, 152.4, 152.4, 143.1, 142.5, 135.0, 132.1, 129.0, 127.2, 126.9, 125.1, 116.5, 116.3, 114.3, 92.5.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=O)C)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:19]3[CH2:20][CH2:21][CH:22]([C:25]4[CH:26]=[C:27]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C1CCCN1c1cccc(C2CCNCC2)c1
Reactant: CCn1c2ccccc2c2cc(C(C)=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(N5CCCC5=O)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Prepared by Scheme R and Procedure F. A solution of 1-(9-ethyl-9H-carbazol-3-yl)ethanone (22.3 mg, 0.100 mmol) and 1-[3-(4-piperidinyl)phenyl]-2-pyrrolidinone (27.2 mg, 0.100 mmol) in 1,2-dichloroethane (1.00 mL) was treated with sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and HOAc (5.70 uL, 0.100 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was treated with a saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 1-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-pyrrolidinone (4.60 mg, 9.43%) 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 1H, J=7.4 Hz), 7.99 (s, 1H), 7.43-7.28 (m, 5H), 6.96 (d, 1H, J=7.4 Hz), 4.31 (q, 2H, J=6.8 Hz), 3.77 (t, 2H, J=7.3 Hz), 3.70 (s, 2H), 3.06 (d, 2H, J=10.6 Hz), 2.56-2.42 (m, 3H), 2.07 (m, 4H), 1.77 (m, 4H), 1.36 (m, 3H); ESMS m/e: 452.5 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][N:2]([C:8]([O:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[NH:33][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CN(CCC(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)CNC(=O)CCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)aminocarbonyloxy]-3-phenylpropionate (460 mg) and isobutylamine (143 ml) in anhydrous methylene chloride (10 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (274 mg) portionwise at 0°-5° C. After being stirred at the same temperature for 3 hours, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 0.5N hydrochloric acid (30 ml), water (30 ml), aqueous sodium bicarbonate (30 ml), water (30 ml) and brine (30 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave benzyl 2(S)-[N-methyl-N-(2-isobutylcarbamoylethyl)aminocarbonyloxy]-3-phenylpropionate (440 mg) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-:12].[NH2:13][NH+:14]1[CH:18]=[CH:17][N:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:15]1(CC)[CH2:30][CH3:31]>C(O)(=O)C>[Br-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:21])[C:15]=2[CH2:30][CH3:31])=[CH:5][CH:4]=1
Reactant: CCC1(CC)N(CC(=O)c2ccc(OC)cc2)C=C[NH+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CC(=O)O
Product: CCc1n(CC(=O)c2ccc(OC)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.18 g (7.9 mmol) of p-dimethylaminobenzaldehyde are added to a solution of 2.7 g (7.9 mmol) of 1-amino-2-ethyl-3-(p-methoxyphenacyl)-2-ethylimidazolium bromide in 40 ml of glacial acetic acid. The mixture is stirred at room temperature for 4 days, the product is crystallized out by the addition of ether and filtered off. It is washed with water, dried at room temperature and recrystallized from ethanol. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethyl-3-(p-methoxyphenacyl)-imidazolium bromide of melting point 244°-246°.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CCO1
Reactant: C1CNCCN1
Product: CC1CN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CCO1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(2-methylmorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 40°-60° C.) and piperazine.
Reaction SMILES: CC1C=C(C=C(C)C=1)C([O:7][CH2:8][CH2:9][CH:10]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17](=[O:26])[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=O.[OH-].[Na+]>CO>[Cl:34][C:29]1[CH:28]=[C:27]([CH:10]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17](=[O:26])[C:18]2[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=2)[CH2:9][CH2:8][OH:7])[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(C)cc(C(=O)OCCC(Cn2ccnc2C(=O)c2cc(C)cc(C)c2)c2ccc(Cl)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)cc(C(=O)c2nccn2CC(CCO)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
3-(3,4-Dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]butyl 3,5-dimethylbenzoate (0.93 g) (see Preparation 31) was dissolved in methanol (10 ml) and 2N aqueous sodium hydroxide solution (2 ml) added. A thick gum formed, additional methanol was added (50 ml) and the resulting suspension stirred at room temperature overnight. The methanol was then removed under reduced pressure and the residue partitioned between dichloromethane (50 ml) and water (10 ml). The organic phase was separated, washed with brine and the solvent removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 99:1 changing to 95:5, by volume, dichloromethane:methanol, to give 3-(3,4-dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]butan-1-ol (0.67 g) as a white foam.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[C:18]([O:22][C:23]([NH:25][C@H:26]([C:37](O)=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:37](=[O:38])[C@H:26]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:24]
Reactant: NCCCCCCCO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCCCCO

Procedure:
N-Methylmorpholine (2.2 mL, 19.7 mmol) was added dropwise at room temperature to 7-amino-1-heptanol hydrochloride salt (3.3 g, 19.7 mmol), in 50 mL of dry DMF under argon with stirring. After stirring for 5 minutes the following were added: N-t-butoxycarbonyl-L-tryptophan, (5 g, 16.45 mmol), 1-hydroxybenzotriazole, (2.52 g, 16.45 mmol) and EDCI hydrochloride (4.73 g, 24.7 mmol). The mixture was stirred for 2 hours and then the DMF removed under reduced pressure. The residue was taken up in cold 2.5% HCl (100 mL) and ethyl acetate (3×100 mL) and transferred to a separatory funnel. The organic phase was isolated and washed consecutively with cold 2.5% HCl (100 mL) and then brine (100 mL). The ethyl acetate phase was dried (MgSO4), filtered and concentrated to obtain N-t-butoxycarbonyl-L-tryptophan-(7-hydroxyheptyl)amide; IR (neat): 3300, 2921, 1685, 1645, 1490, 1356, 1157 cm-1 ; 1H NMR (80 MHz, CDCl3): δ0.98-1.62 (m, 10H, --(CH2)5 --), 1.45 (s, 9H, t-butyl), 2.86-3.32 (m, 4H,CH--CH2, HN--CH2), 3.68 (t, 2H, J=5.6 Hz, --CH2OH), 4.22-4.55 (m, 1H, CH), 5.12-5.32 (broad d, 1H, NH--CH), 5.65-5.9 (broad t, 1H, NH--CH2), 6.98-7.92 (m, 5H, ArH), 8.63 (broad s, indole NH).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[S:39][C:40]([CH3:43])=[N:41][N:42]=1.C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[S:39][C:40]([CH3:43])=[N:41][N:42]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Cc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3nnc(C)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (223 mg, 0.536 mmol), potassium carbonate (222 mg, 1.607 mmol), tetrakis(triphenylphosphine)palladium(0) (61.9 mg, 0.054 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (125 mg, 0.696 mmol) then filled with ethanol (3 mL) and toluene (3 mL). The resulting mixture was degassed for 15 min under house vacuum (with several quenches with nitrogen) then stirred at 100° C. for 2 h before being cooled to room temperature and left stand still for 16 h. The insoluble material was filtered off and rinsed with AcOEt. Most of the solvent was removed in vacuo and the residue was dissolved in AcOEt. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 25 to 100% AcOEt in hexanes) gave a material which was then further purified by MDAP (modifier: ammonium bicarbonate) to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (60 mg, 0.154 mmol, 28.8% yield) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](C(F)(F)F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C(I)=CC([O:29][C:30]([F:33])([F:32])[F:31])=CC=1C(OC)=O>>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(OC(F)(F)F)cc(I)c1N
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C)c1N
Product: COC(=O)c1cc(OC(F)(F)F)cc(C)c1N

Procedure:
The title compound was prepared as in the method of compound 3 from methyl 2-amino-3-iodo-5-(trifluoromethoxy)benzoate to give an orange oil (0.413 g, 89%).