Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:19](=[O:20])[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 60 %

Procedure:
3-Quinuclidinol and 3-methoxyphenyl isocyanate were used. The reaction solution was evaporated under reduced pressure, and the residual solid was recrystallized from ethyl acetate to afford the title compound (60%) as a white solid: mp 130.5-132.0° C.; FAB LRMS m /z (relative intensity, %) 278 (18), 277 (MH+, 100).
Reaction SMILES: BrC1N=C(/C=C(\C#N)/C(NC(C2C=CC(OCCN(CC)CC)=CC=2)CCC)=O)C=CC=1.[F:33][C:34]1[N:39]=[C:38]([CH:40]=O)[CH:37]=[CH:36][CH:35]=1.[C:42]([CH2:44][C:45]([NH:47][CH:48]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)=[CH:54][CH:53]=1)[CH2:49][CH2:50][CH3:51])=[O:46])#[N:43]>>[C:42](/[C:44](=[CH:40]\[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[N:39]=1)/[C:45]([NH:47][CH:48]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]2[CH2:62][CH2:63][O:64][CH2:65][CH2:66]2)=[CH:54][CH:53]=1)[CH2:49][CH2:50][CH3:51])=[O:46])#[N:43]
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCOCC2)cc1
Reactant: O=Cc1cccc(F)n1
Agent: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccc(OCCN2CCOCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and 2-cyano-N-(1-(4-(2-morpholinoethoxy)phenyl)butyl)acetamide (32) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 37 (130 mg, 77%) as a light yellow oil: MS (ES+) m/z 453.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH:25]C(=O)OC(C)(C)C)[CH2:13]2)=[CH:8][CH:7]=1.O1C=CN=C1C1C=CC(N2CCCC2CN[C@@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH2:25])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NCC1CCCN1c1ccc(-c2ncco2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (1R,2R)-2-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-ylamino)cyclohexylcarbamate (32 mg, 0.073 mmol) and tert-butyl (1R,2R)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate (134.0 mg, 0.304 mmol) in CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL, 19.47 mmol). The reaction was stirred at rt for 1 h. After this time, LC/MS showed no starting material remained and the desired product formed. The reaction was concentrated, and the resulting residue was reconcentrated from CH2Cl2 (2×5 mL). The residue was dried under high vacuum for 1 h to afford the desired product (1R,2R)—N1-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine bis-trifluoroacetate (41 mg, 0.072 mmol, 99% yield) and (1R,2S)—N1-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methyl)cyclohexane-1,2-diamine bis-trifluoroacetate (35 mg, 0.073 mmol, 100% yield) as an oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:7]([F:6])([F:17])[F:18])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 429 %

Procedure:
To N-tert-butylamine (3.50 g, 0.0048 mol) in 75 mL of benzene was added 4-trifluoromethylbenzoyl chloride (5.00 g, 0.024 mol). The temperature was maintained below 15° C. during the addition and then the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The solvent was then stripped and the residue was dissolved in 75 mL of dichloromethane. This solution was washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent was removed in vacuo to provide 5.05 g (85-9% yield) of the title compound, m.p. 146-148° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][C:13]=3[CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:25][NH:26][O:27][CH3:28].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:18]1[C:12]2[O:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:14][C:13]=2[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=1)=[O:20]
Reactant: COc1cc(C(=O)O)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N(C)OC)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 63.5 %

Procedure:
A solution of 44 (0.400 g, 1.27 mmole), N,O dimethylhydroxylamine hydrochloride (0.247 g, 2.53 mmole), DMAP (0.309 g, 2.53 mmole), and EDCI (0.364 g, 1.90 mmole), in 40 mL dimethylformamide was stirred at rt for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.290 g (63%) of amide 45 as a tan solid: Mp=100-102° C.; 1H NMR (DMSO-d6) δ 7.74 (dd, 1H, J=2.0 Hz), 7.66 (d, 1 H, J=8.6 Hz), 7.37 (s, 1 H), 7.31 (t, 1 H, J=8.7 Hz), 7.24 (d, 1 H, J=2.6 Hz), 6.93 (d, 1 H, J=2.6 Hz), 3.90 (s, 3 H), 3.82 (s, 3 H), 3.59 (br s, 3 H), 3.30 (s, 3H); MS 360 (M+H)+
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(C)C=CC=CC=1>CCOCC>[N:20]1([CH2:2][CH2:3][O:4][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:13])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: O=C(c1ccccc1)C(OCCCl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCNCC1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
27 g (0.1 mole) of benzoin 2-chloroethyl ether and 34 g (0.4 mole) of piperazine are heated to 70° C. After 11/2 hours, 5 ml of toluene are added in order to prevent the piperazine from subliming and the mixture is heated to 140° C. and kept for 2 hours at reflux temperature. After cooling, the reaction mixture is diluted with ether and extracted with dilute hydrochlorid acid. The hydrochloric acid solution is freed from ether and neutralised with K2CO3. The alkaline solution is extracted with ether and then with toluene. The toluene solution is dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum at 60° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([NH:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH2:15]1)(=[O:13])=[O:12]>CC(O)=O>[C:1]([NH:8][CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([NH:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH2:15]1)(=[O:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(C)(C)ONC(=O)[C@H]1CN(S(=O)(=O)CCN)CCN1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NOC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Acetic anhydride (36 mg) was added to a solution of (2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide (130 mg) in AcOH (2 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 142 mg of (2R)-4-[2-(acetylamino)-ethanesulfonyl]-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:30])[C:26]([NH:28][NH2:29])=[O:27])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C[O:34][CH2:33]C1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:26]3[O:27][C:33](=[O:34])[NH:29][N:28]=3)=[O:30])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 26, (542 mg, 1.25 mmol) in THF (16 mL) is added CDl (244 mg, 1.50 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) and by Chiral-HPLC (OJ-H 21×250 mm, EtOH(0.1% TFA)/Heptane=30/70) to give (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (333 mg). HPLC retention time=1.74 minutes (condition A); MS 458.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=7.1 Hz, 3H) 1.12 (t, J=7.1 Hz, 3H) 1.58-1.74 (m, 1H) 1.76-1.91 (m, 1H) 2.45-2.50 (m, 1H) 2.77 (dd, J=13.7, 7.9 Hz, 1H) 2.86 (dd, J=13.7, 7.9 Hz, 1H) 4.00 (q, J=7.1 Hz, 2H) 4.06-4.22 (m, 1H) 7.28 (d, J=8.1 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.58-7.66 (m, 3H) 7.67-7.73 (m, 1H) 8.86 (d, J=8.8 Hz, 1H) 12.95 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Product: ClCCSc1cccc2nccn12

Procedure:
Using 3.0 g (20 mmol) of 5-mercaptoimidazo[1,2-a]pyridine, 2.79 ml (20 mmol) of triethylamine and 1.66 ml (20 mmol) of 1-bromo-2-chloroethane, the same procedure as in Reference Example 1 was followed, to yield 2.29 g (54.0%, light brown oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:37][CH:38]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 106 mg (0.56 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 201 mg (1.05 mmol) of EDC and 95 mg (0.7 mmol) of HOBT in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA are reacted with 0.35 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5 (S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane to form the title compound: m.p: 227°-229° C.; HPLC20-100 : tRet =14.5; FAB MS (M+H)+ =697.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCc2ccccc2C1
Solvent: CCOCC
Product: Fc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of p-fluorophenyl magnesium bromide, and 200 ml. of diethyl ether is stirred for four hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1N hydrohloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated. The residue, containing 2-p-fluorophenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5% palladium-on-charcoal catalyst; the resulting mixture is heated to 200° C for 6 hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2p-fluorophenylnaphthalene.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[C:8]([F:38])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:36][CH3:37])=[C:21]([CH2:24][N:25]([CH3:35])[C:26]4([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:1]([N:29]1[CH2:30][CH2:31][C:26]([N:25]([CH2:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:36][CH3:37])[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[F:38])[CH3:35])([C:32]([NH2:34])=[O:33])[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Acetyl chloride (7 μl, 0.094 mmol) was added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.05 g, 0.085 mmol, prepared as described in Example 64) and triethylamine (53 μl, 0.38 mmol) in dichloromethane (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, concentrated and purified by column chromatography on silica eluting with increasingly polar mixtures of dichloromethane/methanol (100/0-90/10) to give the title product (0.039 g, 91%) as a pale yellow solid; 1H NMR Spectrum: (DMSO-d6) 1.75-1.98 (m, 2H), 2.05 (m, 5H), 2.19 (s, 3H), 3.32-3.75 (m, 6H), 3.94 (s, 3H), 7.20 (s, 1H), 7.26 (m, 2H), 7.34 (t, 1H), 7.51-7.57 (m, 2H), 8.38 (s, 1H), 8.46 (s, 1H), 9.80 (s, 1H); Mass Spectrum: (M+H)+ 515.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.FC(F)(F)S(O)(=O)=O.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([F:34])[CH:26]=1.C(=O)([O-])O.[Na+].[C:40](#[N:42])[CH3:41]>>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:33][C:40]([CH3:41])=[N:42][CH:32]=2)=[C:27]([F:34])[CH:26]=1
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: CC#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Cc1ncc(-c2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of iodobenzene diacetate (6.7 g) in acetonitrile (100 mL) was added dropwise trifluoromethanesulfonic acid (3.7 mL), and the mixture was stirred at room temperature for 30 min. A mixture of 1-(4-bromo-2-fluorophenyl)ethanone (6.7 g) in acetonitrile (20 mL) was added to the reaction mixture, and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.6 g).
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[C:77]([O:81][C:82](=[O:93])[CH2:83][CH2:84][C:85]1[CH:90]=[CH:89][C:88]([NH2:91])=[C:87]([F:92])[CH:86]=1)([CH3:80])([CH3:79])[CH3:78]>CN(C)C1C=CN=CC=1>[C:77]([O:81][C:82](=[O:93])[CH2:83][CH2:84][C:85]1[CH:90]=[CH:89][C:88]([NH:91][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:87]([F:92])[CH:86]=1)([CH3:80])([CH3:78])[CH3:79]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), 3-(4-amino-3-fluoro-phenyl)-propionic acid tert-butyl ester and using 4-(dimethylamino)pyridine as base. Light brown foam (78%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[CH2:11].C(N(CC)C(C)C)(C)C>CC(C)=O>[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:14][CH:13]=1)=[CH2:11]
Reactant: C=Cc1ccc(N)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 18.4 g (0.1 mole) of cyanuric chloride in 150 ml of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g (0.1 mole) of 4-vinylaniline and 12.9 g (0.1 mole) of N,N-di-iso-propylethylamine. After the addition was complete, the solution was stirred at room temperature for 15 min., and then poured into 1 liter of ice water to isolate the product. The product was collected by filtration, washed with 200 ml of water, and dried in vacuo at room temperature to give 25 g. Recrystallization from 75 ml. of benzene gave 15.0 g (56%) (mp 152°-154°).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](=O)=O.C(Cl)(Cl)Cl>CI>[OH:8][C:7]1[C:2](=[O:1])[N:3]([CH3:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: Oc1cccnc1O
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cccc(O)c1=O
Temperature: 140 °C

Procedure:
2,3-Dihydroxypyridine (5.55 g) is suspended in methyl iodide (20 ml) in a sealed tube and heated for 24 hours at 140° C. The reaction is taken to be complete when a dark brown residue forms as a separate phase from the methyl iodide and the tube is then cooled in solid carbon dioxide and opened. The excess methyl iodide is poured off, distilled water (10 ml) is added to the brown residue, and sulphur dioxide gas is bubbled through the mixture until the aqueous phase becomes clear. The pH of the reaction mixture is adjusted to a value of 6 with 1M aqueous sodium carbonate and the resulting solution then saturated with ammonium sulphate and extracted with chloroform until the chloroform layer no longer gives a blue colouration when added to ferric chloride solution. The chloroform extracts are combined and dried over sodium sulphate. The solvent is then evaporated under vacuum and the resulting residue is crystallised from petroleum ether (b.p. 100°-120° C.) using activated charcoal to give 3-hydroxy-1-methylpyrid-2-one, m.p. 129°-131° C.; νmax (nujol) 1,660, 3,100 cm-1 ; δ(d6DMSO) 3.6(s,3H), 6.1(t,1H), 6.8(m,2H), 7.3(s,1H); M+ 125.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(Cl)c2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(Cl)c3)n2)CN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 43A is reacted analogously to the synthesis of the compound of Example 1 with 22 mg (0.18 mmol) of 4-imidazolinone-hydrochloride. 72 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:39]1[C:40]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[N:41][C:42]([NH2:46])=[C:43]([NH2:45])[CH:44]=1>CN(C=O)C>[NH2:46][C:42]1[N:41]=[C:40]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[C:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[F:32])=[CH:44][C:43]=1[NH:45][C:7]([C:5]1[CH:4]=[N:3][CH:2]=[N:1][CH:6]=1)=[O:9]
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: O=C(O)c1cncnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyrimidine-5-carboxylic acid (0.088 g, 0.709 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.136 g, 0.709 mmol) and 1H-1,2,3-benzotriazol-1-ol (0.072 g, 0.534 mmol) in DMF (4 mL) was heated at 40° C. for 15 minutes. Finally, 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.15 g, 0.534 mmol) in DMF (4 mL) was added and the mixture was stirred at room temperature overnight. The crude mixture was extracted between ethyl acetate and water. The organic layer was washed with 4% sodium bicarbonate aqueous solution and water, dried (MgSO4) and evaporated. The residue (0.2 g) was used in the next step without further purification.