Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.Cl[C:19]1[N:20]=[CH:21][C:22]2[CH:27]=[C:26]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[N:25]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:23]=2[N:24]=1>>[CH:33]1([N:25]2[C:23]3[N:24]=[C:19]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH:14]6[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]6)[CH2:10][C:9]5=[O:17])=[CH:6][N:7]=4)[N:20]=[CH:21][C:22]=3[CH:27]=[C:26]2[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: Nc1ccc(N2C(=O)CN3CCC2CC3)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C(=O)CN5CCC4CC5)cn3)nc2n1C1CCCC1
Yield: 86 %

Procedure:
Following general N—C coupling procedure 1, 4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one was combined with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and gave 7-cyclopentyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, 99 mg in 86% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.55 (d, J=9.09 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 8.09 (s, 1H), 7.55 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.47 (s, 1H), 4.81 (m, 1H), 3.93 (s, 2H), 3.82 (m, 1H), 3.19 (m, 10H), 2.59 (m, 2H), 2.41 (m, 2H), 2.07 (m, 6H), 1.74 (m, 2H); HRMS m/z 489.2740 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[N:17]1[N:18]=[C:19]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[NH:20][CH:21]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:19]4[NH:18][N:17]=[CH:21][N:20]=4)=[O:25])[CH2:12][CH:11]3[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4ccccc4-c4ncn[nH]4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI): mass calculated for C21H23N7O, 389.46; m/z found 390.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH2:26][CH3:27])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH2:26][CH3:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.7 %

Procedure:
tert-butyl(3R)-6-cyclohexyl-3-{3-[(ethylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 74) (288 mg, 0.76 mmol) was treated with TFA (5 ml) and stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and the solvents removed under reduced pressure. The residue was azeotroped from toluene (×3) and DCM (×3) to afford the title compound (373 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][C:15](=[O:17])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1)=[O:20].[CH:30]1([Mg]Br)[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([C:15]2([OH:17])[CH2:16][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:18][C:19]([C:21]5[N:25]6[CH:26]=[CH:27][CH:28]=[CH:29][C:24]6=[N:23][CH:22]=5)=[O:20])[CH:4]=4)[N:12]=3)[CH2:14]2)[CH2:32][CH2:31]1
Reactant: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(O)(C4CC4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10) (250 mg, 0.645 mmol) in anhydrous THF (10 mL) at −78° C. under Argon was added cyclopropylmagnesium bromide (2.6 mL, 1.3 mmol). The reaction was stirred for 30 minutes at room temperature and quenched with 1N HCl at 0° C. The crude product was extracted with ethylacetate. The organic layer was washed with saturated ammonium chloride, water and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to give N-(5-(5-(3-cyclopropyl-3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F31). 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.47-9.45 (m, 1H), 8.59 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.55-7.52 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 5.19 (s, 1H), 4.37-4.35 (m, 1H), 3.46-3.40 (m, 1H), 2.45-2.40 (m, 2H), 2.36 (s, 3H), 1.54-1.41 (m, 2H), 1.19-1.14 (m, 1H), 0.34-0.26 (m, 2H), 0.22-0.11 (m, 1H). MS m/z 430.47 (M+1)+.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)[CH:2]=[CH2:3].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:6](=[O:8])[CH:5]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[C:20]2=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: C=CCNC(C)C(=O)OC
Solvent: Cc1ccccc1
Product: C=CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C1C
Yield: 114.5 %

Procedure:
To a solution of 10.5 g (0.073 mole) of methyl 2-allylaminopropionate in 50 ml of toluene is added 15 g (0.08 mole) of 3,5-dichlorophenylisocyanate in small portions. The resulting mixture is heated to reflux for 2 hours. The reaction mixture is cooled and filtered. The filtrate is concentrated under vacuum to give 25 g of a yellow oil. This material is further purified by passing it through a silica gel column using 40/60 ethyl acetate/hexane as the solvent followed by trituration with hexane/ether to give 18 g of a light yellow solid., m.p. 78°-80°.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15]Br)[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC(C)=O>[OH:4][C:5]1[CH:14]=[C:13]([CH2:15][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:12]([C:17]([F:18])([F:19])[F:20])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(C(F)(F)F)c(CBr)cc1OC(C)=O
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1O
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-(bromomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 47; 309 mg, 0.87 mmol) in acetone (5 ml) was added triethylamine (0.24 ml, 1.74 mmol) and morpholine (0.10 ml, 1.13 mmol) the solution was stirred for 2 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound. 300 mg.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and acetic anhydride, to give the desired product as a light yellow solid (43%).
Reaction SMILES: [C:1]([C:3]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])[CH3:4])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([C:3]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(OC(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 3-(1-cyano-1-methylethoxy)benzoate (2.07 g, 9.44 mmol) in methanol (12 mL)/tetrahydrofuran (4 mL) was added 2N aqueous sodium hydroxide solution (9.44 mL, 18.9 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 6N hydrochloric acid (5 mL), 1N hydrochloric acid (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50), and the fraction containing the object product was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give the title compound (1.01 g, 51%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:14][C:13](=[O:15])[CH2:12][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:16])([F:1])[F:17])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)Cn1ccc2ccc(C(F)(F)F)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cn1ccc2ccc(C(F)(F)F)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (90 mg, 0.370 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (130 mg, 0.308 mmol), EDC (83 mg, 0.432 mmol) and DMAP (75 mg, 0.617 mmol) in dry DCM (5 ml) was stirred at room temperature overnight. Aqueous 1N HCl was added to the reaction mixture and the organic phase was separated, washed with brine and dried over sodium sulfate. The solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel column (DCM/MeOH 96/4) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (95 mg, 0.147 mmol, 48% yield). MS/ESI+ 645.03 [MH]+; [αD]=−2.157, c=0.510; DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.67-7.85 (m, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.87 (dd, 1H), 7.03 (t, 1H), 6.61 (dd, 1H), 5.98 (dd, 1H), 5.38 (d, 1H), 5.25 (d, 1H), 3.82 (d, 2H), 3.39 (dd, 1H), 3.19 (dd, 1H), 1.10-1.22 (m, 1H), 0.46-0.70 (m, 2H), 0.15-0.46 (m, 2H)
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3][CH2:4]C.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([O:42][CH3:43])[N:36]=2)=[O:34])=[CH:29][C:28]=1[Cl:44])(C(C)(C)C)(C)C.O>O1CCCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH:3]([CH3:4])[CH3:2])=[C:28]([Cl:44])[CH:29]=2)=[O:34])=[N:36][C:37]=1[O:42][CH3:43]
Reactant: COc1nc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1Cl
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C(=O)c2ccc(OC(C)C)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.39 mL) was added to a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-chloro-6-methoxypyridin-2-yl)methanone (700 mg) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at room temperature for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 mL), and 2-iodopropane (333 μL) and potassium carbonate (464 mg) were sequentially added at room temperature, followed by stirring at 65° C. for three hours. The reaction solution was returned to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the title compound as a colorless oil (538 mg, 93%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][C@H:14]([CH3:21])[CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:12])=[CH:7][CH:6]=1)(=O)C.CN>C1(C)C=CC=CC=1.CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][C@H:14]([CH3:21])[CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:12])=[CH:9][CH:10]=1
Reactant: CCC(CC)C[C@@H](C)OC(=O)c1ccc(OC(C)=O)cc1
Agent: CN
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC(CC)C[C@@H](C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
63 Grams (0.215 mol) of (R)-4-acetoxy-1-(3-ethyl-1-methylpentyloxycarbonyl)benzene was dissolved in 900 ml of dehydrated toluene, 25 g of a solution of 40% methylamine in methanol was dropwise added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with 2N hydrochloric acid and washed with water. The resultant organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off, to give 49 g (0.195 moll yield 91%) of an end compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=4[CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[F:31][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[CH3:30])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccc(C)c(-c2cc(F)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cc(OC)ccc3C)c2O1

Procedure:
The title compound was prepared (0.73 g, 50%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.40 mmol) and methylamine (0.124 g, 4.0 mmol). mp 173-174° C.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20](O)=O)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:32][C:31]4[C:26]([N:25]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(c3nc4ncccc4[nH]3)CC2)c1C
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (compound 26, 50 mg, 0.15 mmol) and 2,3-diaminopyridine (33 mg, 0.30 mmol) in CH2Cl2 (0.5 mL) is added polyphosphoric acid (1 mL). The mixture is concentrated to remove CH2Cl2. After being stirred at 150° C. for 1.5 h, the mixture is cooled to 25° C., diluted with water (10 mL), and basified by 10% aqueous solution of sodium hydroxide to pH˜8. The aqueous solution is extracted with CH2Cl2 (5×15 mL). The combined organic layers are concentrated and purified by HPLC (CH3CN/H2O: 22% 45% with 0.1% TFA) to give 2-[1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidin-4-yl]-1H-imidazo[4,5-b]pyridine (33.8 mg, 55%).
Reaction SMILES: [C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2F)[C:6](=[O:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[C:25]([O:35][CH3:36])(=[O:34])[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:6](=[O:23])[C:5]=1[O:24][C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O:35][CH3:36])=[O:34])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CC(=O)C1=C(O)C(=O)N(c2ccc(Cl)cc2F)C1C1CCCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](OC1=C(C(C)=O)C(C2CCCCC2)N(c2ccc(Cl)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) mixture of 4-acetyl-1-(4-chloro-2-fluorophenyl)-5-cyclohexyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (2.05 g, 5.84 mmol), methyl (S)-mandelate (1.36 g, 8.18 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) in THF (50 ml) is added dropwise DIAD (1.6 ml, 7.6 mmol). The reaction is then left to warm to room temperature and is stirred for 12 hours. The solvent is removed under vacuum and the oily residue is plugged through a pad of silica gel (eluent 1/1 hexanes/ethyl acetate). The solvent is removed and the residual oil is purified by radial chromatography (eluent 9/1 hexanes/ethyl acetate) to yield each diastereomer (1 g) as a white foam.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.O1CCCO[CH2:19]1.Cl>C(O)(C)C>[CH:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH2:9][N:10]2[CH2:19][C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH2:12][CH2:11]2)[CH:5]=1.[ClH:1]
Reactant: C1COCOC1
Reactant: Clc1ccccc1CNCCc1cccs1
Agent: Cl
Solvent: CC(C)O
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 80 °C
Yield: 82 %

Procedure:
N-[(2-chlorophenyl-methyl)]-2-(2-thienyl)ethylamine HCl (28.8 g) is suspended in 75 ml of iso-propanol. 1,3-Dioxane (13.2 g) and 0.25 ml of hydrochloric acid (37% concentration) are added. The reaction mixture is heated to 80° C. for 24 hours. Thereafter, the mixture is cooled to 10° C. and the precipitate is filtered and washed twice with 10 ml of frozen iso-propanol. The product is desiccated at 60° C. UV to yield 24.6 g (82%) Ticlopidine hydrochloride with chemical-physical characteristics as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH:10]([CH2:16][CH2:17][O:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:19][O:18][CH2:17][CH2:16][CH:10]([CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)=[O:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 3.09 mmol) and 4-nitro-phenyl boronic acid (0.62 g, 3.70 mmol) dissolved in toluene (30 mL) and dioxane (8.50 mL), followed by addition of saturated aqueous sodium carbonate solution (8.50 mL). A thin-gauge needle was inserted into the bi-phasic mixture and degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino)ferrocene]dichloropalladium(II) (0.13 g, 0.15 mmol) was added, followed by an additional 15 minutes of degassing. The reaction mixture was heated at 85° C. for 16 h, and then the resulting dark-colored reaction mixture was allowed to cool, and was diluted with ethyl acetate (75 mL) and saturated aqueous sodium chloride solution (75 mL). The layers were separated, the aqueous layer was extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. The filtrate was concentrated in vacuo, leaving a dark red-brown oil, that was purified by flash chromatography (4:1 hexane/ethyl acetate, then 3:1 hexane/ethyl acetate, then 2:1 hexane/ethyl acetate) to afford ethyl 2-(2-methoxyethyl)-4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxobutanoate (1.04 g, 88%). LC-MS ret. time 3.38 min, m/z 385.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.27 (t, 3H), 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H), 3.10-3.25 (m, 2H), 3.40-3.58 (m, 3H), 4.17 (q, 2H), 7.67-7.82 (2d, 4H), 8.10 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyanobiphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[NH:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-phenoxy)-piperidin-1-yl]-oxo-acetic acid (Example 29d) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and chloroform:methanol=10:1 as eluent. Melting Point: 286-288° C. (isopropanol)