Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:31]([Br:32])=[CH:30][C:5]([CH2:6][C@H:7]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[Br:33].[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[NH2:1][C:2]1[C:31]([Br:32])=[CH:30][C:5]([CH2:6][C@@H:7]([NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:16][N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:22][CH2:23]2)=[CH:4][C:3]=1[Br:33]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)C(=O)N1CCC(N2CCCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)CN1CCC(N2CCCCC2)CC1
Temperature: 5 °C

Procedure:
To a solution of 10 g (0.017 mol) of 1-[4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine in 350 ml of dioxane were added 3.1 g (0.082 mol) of sodium borohydride and the reaction mixture was cooled to 5° C. Then a solution of 4.92 g (0.082 mol) of acetic acid in 100 ml of dioxane was added dropwise with stirring. The reaction mixture was stirred for a further hour at room temperature and for 3 hours at 85° C. Then ice water was added, the organic solvent was removed in vacuo and the aqueous residue was repeatedly extracted with methylene chloride. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/cyclohexane/conc. aqueous ammonia=3600/150/150/20 (v/v/v/v). 4.1 g (42% of theory) of a colourless foam were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:36][CH2:35][CH2:34][N:25]1[C:26](=[O:33])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]1=[O:23])[CH:19]([CH3:20])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)nc(C(N)C(C)C)n2Cc1ccccc1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(C(NCCCN1C(=O)c3ccccc3C1=O)C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (0.56 mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114 mg, 0.56 mmol) in dry DCM (3 mL) at room temperature, was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). After 10 min., acetic acid (34 μl, 0.56 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give crude material that was used in step 7.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:24][C:22]1[N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[N:21]=1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
38 mg (0.17 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 50 mg (0.17 mmol) 6-(6-chloro-2-methyl-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.57 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at 80° C. Then another 15 mg (0.069 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one were added and the mixture was further stirred overnight at RT. The reaction mixture was diluted with water, the precipitate formed was suction filtered and dried i. vac.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[F:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:35][CH2:34]2)[CH:28]=[CH:29][C:30]=1[O:31]C>>[F:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:37][CH2:38]2)[CH:28]=[CH:29][C:30]=1[OH:31]
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1ccc(N2CCN(CCc3ccccc3)CC2)cc1F
Yield: 38 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(3-fluoro-4-methoxyphenyl)-4-phenethylpiperazine (482 mg), and the resulting crude product was purified on TLC (developer, chloroform: methanol=17:1) to provide 2-fluoro-4-(4-phenethylpiperazin-1-yl)phenol (175 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:11])=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:10][C:7]1[N:6]=[C:5]([F:11])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C)nc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOc1ccc(CBr)nc1F
Reaction time: 8 h
Yield: 65.1 %

Procedure:
3-Ethoxy-2-fluoro-6-methylpyridine (400 mg) was initially introduced in carbon tetrachloride (30 ml) and, after addition of N-bromosuccinimide (505 mg) and 2,2′-azobis(2-methylpropionitrile) (85 mg), the reaction mixture was heated at reflux for 7 h. After standing overnight at RT, it was treated with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (n-heptane-ethyl acetate gradient). After the combination of the product-containing fractions, it was brought to dryness. 393 mg of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]([CH3:12])=[C:4]([CH:13]2[CH2:15][O:14]2)[CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH:13]([C:4]2[CH:3]=[C:2]([F:1])[C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[C:5]=2[CH3:12])[OH:14])[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([C:4]2[CH:3]=[C:2]([F:1])[C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[C:5]=2[CH3:12])[OH:14])[CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: Cc1c(C2CO2)cc(F)c2c1COC2=O
Product: Cc1c(C(O)CN2CCN(CC(O)c3cc(F)c4c(c3C)COC4=O)CC2)cc(F)c2c1COC2=O

Procedure:
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(7-fluoro-4-methyl-2-benzofuran-1(3H)-one) was prepared in a similar fashion to that described for the synthesis of EXAMPLE 2 starting from 7-Fluoro-4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one and piperazine.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([S:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[C:15]([SiH2:14][O:13][C:12]([CH3:20])([CH3:19])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([S:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([OH:31])=[O:2])=[CH:11][CH:10]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1

Procedure:
3-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester (4.93 g, 10.66 mmol) was dissolved in THF (100 mL) and water (50 mL) and cooled down to 0° C. NaOH (6.39 g, 159.88 mmol) was added and the resulting suspension was stirred stirring for 1 h without removing the cooling bath and another 28 h at ambient temperature. 2N HCl was added until pH 2 was reached and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure to afford the crude product which was directly proceeded to the next step (4.79 g, 95.3%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, 2H), 7.06 (d, 2H), 6.99 (m, 2H), 6.85 (t, 2H), 4.62 (s, 2H), 3.38 (t, 1H), 3.09 (dd, 1H), 2.71-2.82 (m, 5H), 0.844 (s, 9H), 0.00 (s, 6H). Mass Spectrum: M−H+ 447.10.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6](O)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>FC(F)(F)C(O)=O.O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:26]3[C:24](=[O:25])[NH:23][C:21](=[O:22])[N:20]([CH3:19])[CH:27]=3)[C:5]3[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2O
Reactant: Cn1ccc(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step (i) (0.094 g) in trifluoroacetic acid (4 ml) under a nitrogen atmosphere was added 1-methyluracil (0.01 g), and the mixture stirred at room temperature for 1 hour. Evaporation of solvent afforded an orange oil which was azeotroped once with acetonitrile (5 ml). The crude product was redissolved in acetonitrile (2 ml), and stirred at room temperature for 0.5 h, giving a white precipitate. The reaction mixture was diluted with water (10 ml) and the white precipitate isolated by filtration. Yield: 0.085 g
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.I[CH3:26]>CCO>[CH3:26][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1
Reactant: CI
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Solvent: CCO
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (20.9 mg, 0.065 mmol) in EtOH (0.6 mL) was added iodomethane (40 μL, 0.65 mmol). The mixture was placed in an oil bath at 60° C. and heated for 4 h, then stirred at room temperature overnight. The solvent was removed under reduced pressure, and the crude product was purified by preparative thin layer chromatography (1:9 2M NH3 in MeOH:CH2Cl2) to obtain 4.1 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.35 (br s, 1H); 8.16 (d, J=7.5 Hz, 1H); 7.84 (d, J=7.1 Hz, 1H); 7.37 (m, 2H); 6.75 (d, J=5.5 Hz, 1H); 4.12 (m, 1H); 2.92 (d, J=9 Hz, 1H); 2.8 (d, J=11 Hz, 1H); 2.27 (s, 3H); 1.26 (d, J=6.7 Hz, 3H). Mass spectrum 337.3 (ESI, M+1).
Reaction SMILES: [O:1]=[S@@:2]1[C@@H:7]2[C@H:8]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:10])[N:6]2[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:22])=[C:4]([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])[CH2:3]1.ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[O:1]=[S:2]1(=[O:49])[C@@H:7]2[C@H:8]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:10])[N:6]2[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:22])=[C:4]([O:33][S:34]([C:37]([F:39])([F:40])[F:38])(=[O:36])=[O:35])[CH2:3]1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)C[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS(=O)(=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Yield: 71.3 %

Procedure:
A mixture of p-methoxybenzyl(1S,6R,7R)-1-oxo-7-phenylacetamido-3-(trifluoro-methanesulphonyloxy)ceph-3-em-4-carboxylate (767 mg, 1.27 mmol) and m-chloroperbenzoic acid (939 mg, 3.81 mmol) in chloroform (60 ml) was heated to reflux. After refluxing for 7 hours the mixture was chromatographed to give the title compound (560 mg, 71%); νmax (KBr) 1819, 1740, 1697 cm-1 ; δH (CDCl3) 3.60 (2H, m), 3.81 (3H, s), 3.87 (1H, d, J 18.1 Hz), 4.17 (1H, d, J 18.1 Hz), 4.53 (1H, d, J 4.9), 5.20 (1H, d, J 11.8 Hz), 5.37 (1H, d, J 11.8 Hz), 6.08 (1H, dd, J 4.9, 9.9 Hz), 6.55 (1H, d, J 9.8 Hz), 6.89 (2H, d, J 8.7 Hz), 7.18-7.37 (7H, m).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7].[C-:12]#[N:13].[K+]>C(O)C>[C:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7])#[N:13]
Reactant: Cc1cc(C#N)cc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C#N)cc(CC#N)c1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a stirred ethanol (150 mL), was added 3-(bromomethyl)-5-methylbenzonitrile (48 g, 0.228 M), potassium cyanide (27 g, 0.42 M), and distilled water (77 mL). The mixture was then refluxed for 3 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue was partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 18.3 g (51%) of 3-(cyanomethyl)-5-methylbenzonitrile as a pale yellow solid. m.p. 63-64° C. 1H NMR (300 MHz, CDCl3) δ 2.42 (3H, s), 3.77 (2H, s), 7.42 (2H, s), 7.45 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:43]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([C:21]([N:47]3[CH2:46][CH2:43][NH:45][CH2:49][C:48]3=[O:50])=[O:22])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: COc1cc(Br)cc(-c2cc(C(=O)N3CCNCC3=O)nn2-c2cccnc2)c1

Procedure:
50 mg (0.13 mmol) of the compound of Example 50A is reacted analogously to the synthesis of the compound of Example 1 with 15 mg (0.15 mmol) of 2-oxopiperazine. 54 mg (88% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:53])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with hexylamine (MCB) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].CC(=O)OCC>C(Cl)Cl.Cl>[OH:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: COCCOc1cc(C#N)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCOc1cc(C#N)c([N+](=O)[O-])cc1O
Yield: 56.5 %

Procedure:
To a solution of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzonitrile (1.5 g) in anhydrous DCM (30 mL) was added anhydrous AlCl3 (6 g) at 0° C. The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was diluted with 1N aqueous HCl (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.8 g of 4-hydroxy-5-(2-methoxyethoxy)-2-nitrobenzonitrile.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28]C>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Reactant: COc1ccc(B(O)O)cc1F
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)c(F)c1
Yield: 60.9 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 3-fluoro-4-methoxyphenylboronic acid (0.56 g, 3.3 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.60 g, 97%, m.p. 223-26° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:28])P(=O)(N(C)C)N(C)C>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:19]([CH3:28])[CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Product: CN(C)c1cc2nc(C(C)(C)C)sc2cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of 16.2 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, in 150 ml hexamethyl phosphoric triamide is heated at 200° for 10 hours and poured into ice-water. The liquid separated is extracted with ether, dried over anhydrous sodium sulphate and the ether is evaporated under reduced pressure to give a red oil which is purified by silica gel column chromatography. Elution with benzene hexane (1:1) gives 2-tert-butyl-5-[N,N-dimethyl]amino-6-nitrobenzothiazole, melting at 65°-68°.
Reaction SMILES: [Na].Cl.[CH:3]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4]1.C([O:11][C:12](=O)[CH:13]([F:19])[C:14](OCC)=[O:15])C.Cl>CO.O>[CH:3]1([C:6]2[N:7]=[C:14]([OH:15])[C:13]([F:19])=[C:12]([OH:11])[N:8]=2)[CH2:5][CH2:4]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1nc(C2CC2)nc(O)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60° C. for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro-4,6-pyrimidinediol 3 (3.6 g, 76%) is obtained as a white powder and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:21]1([C@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Cl:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:29][C@@H:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:28])=[O:6]
Reactant: O=C(O)C1CC1(F)Cl
Reactant: C[C@@H](N)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)C1CC1(F)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-2-fluorocyclopropanecarboxylic acid (112 g, 809 mmol) in THF (2.0 L) was added 1,1′-carbonyldiimidazole (170 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 1 hour and then (R)-(+)-1-phenylethylamine (117.5 g, 971 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was extracted with ethyl acetate. The organic extract was washed with 2N aqueous HCl, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography on silica gel (solvent gradient: 15-33% ethyl acetate in petroleum ether) to yield 2-chloro-2-fluoro-N—((R)-1-phenylethyl)cyclopropanecarboxamide as a white solid (149 g, 50% yield over three steps).
Reaction SMILES: [CH2:1]([N:8]([CH2:28]C1C=CC=CC=1)[CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[N:19]=2)[C:14](=[O:22])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]1)C1C=CC=CC=1.C(N(CC1C=CC=CC=1)CCBr)C1C=CC=CC=1>>[CH3:28][N:8]([CH3:1])[CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[N:19]=2)[C:14](=[O:22])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]1
Reactant: CCOC(=O)c1cn(CCN(Cc2ccccc2)Cc2ccccc2)c2nc(C)ccc2c1=O
Agent: BrCCN(Cc1ccccc1)Cc1ccccc1
Product: CCOC(=O)c1cn(CCN(C)C)c2nc(C)ccc2c1=O

Procedure:
1-[2-(Dibenzylamino)ethyl]-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p. 170°-174° (72%) (2-Dibenzylaminoethyl bromide).