Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[S:15]([OH:18])(=[O:17])=[O:16].[Cl-].[NH4+]>[Fe].O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([S:15]([OH:18])(=[O:17])=[O:16])[CH:8]=1
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COCCOc1ccc(N)cc1S(=O)(=O)O
Reaction time: 2 h

Procedure:
A mixed solution consisting of 30 g of 2-(2-methoxyethoxy)-5-nitrobenzenesulfonic acid, 30 g of reducing iron, 0.6 g of ammonium chloride and 60 ml of water was kept at a temperature of 80° to 85° C. over a period of 2 hours with stirring. After the completion of the reaction, the insoluble substances were removed by filtration. To the filtrate was added 200 ml of isopropyl alcohol and the mixture was cooled with ice. The crystals thus precipitated were recovered, washed with 50 ml of isopropyl alcohol and air-dried. Yield 23 g m.p. 250° C. or above.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][O:16][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Br:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Br)c1O
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(Br)c1OCC[C@H]1CN(Cc2ccccc2)CCN1
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.5 g, 6.8 mmol), 2-bromo-6-methylphenol (1.4 g, 7.5 mmol), di-tert-butyl azodicarboxylate (DBAD, 2.4 g, 10.2 mmol), polymer supported-triphenylphosphine (3.8 g, 13.6 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH3:14])=[CH:7][CH:6]=1.[OH-].[K+].C(O)C.Cl>O>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH3:14])=[CH:7][CH:6]=2)[C:3]([OH:34])=[O:2])=[CH:25][CH:26]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(COc1ccc(C(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1)Oc1ccc(Cl)cc1
Yield: 91.7 %

Procedure:
A mixture of 6.4 g of methyl(p-tert.-butylphenoxy){p-[2-(p-chlorophenoxy)propoxy]phenyl}acetate, 4 g of potassium hydroxide, 35 ml of ethanol and 35 ml of water is refluxed for 4 hours. The mixture is acidified with concentrated HCl, cooled, diluted with water and extracted with dichloromethane. The extract is washed with saturated NaCl solution, dried (MgSO4) and the solvent removed under reduced pressure to give 5.7 g of gum. Crystallization from hexane-ether gives 4.5 g of white crystals. Recrystallization from chloroform-hexane gives the product as white crystals, mp 135°-138° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH2:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCCCc1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCCc4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-phenyl-1-propylamine, m.p. 183-184° C. MS [(+)ESI, m/z]: 554 [M+H]+ Anal. Calcd for C37H35N3O2: C, 80.26; H, 6.37; N, 7.59. Found: C, 80.18; H, 6.37; N, 7.51.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])([O-])=O.CO.[NH4+].[Cl-]>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(Nc2ccccc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(Nc2ccccc2N)c1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
To a mixture of 3-(2-nitrophenylamino)benzonitrile (2.0 g, 8.40 mmol) in a 3:1 mixture MeOH:water (120 mL) were added NH4Cl (2.70 g, 0.05 mol) and iron powder (1.88 g, 0.03 mol) and the reaction mixture heated at reflux temperature for 1 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% MeOH in DCM) to afford the title compound as a yellow solid (185 mg, 11%). LCMS (Method J): RT 2.99 min [M+H]+ 210.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1cccc(N)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cccc(C)n2)n1
Yield: 57.8 %

Procedure:
To a flask were added 3.1 g of 2-amino-6-methylpyridine, 5.0 g of 2-bromo-6-methylpyridine, 3.6 g of sodium tert-butoxide, and 150 ml toluene. The mixture was purged thoroughly with nitrogen and 160 mg of 1,1′-bis(diphenylphosphino)ferrocene and 65 mg of palladium acetate were added. The reaction mixture was heated to 80 C for 3 hours, and then cooled to 22 C. After quenching with 100 ml of water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 75 ml of 1M hydrochloric acid, and then basified with 3M sodium hydroxide. Following extraction with 75 ml of ethyl acetate and washing with 30 ml of water, the solvent was removed. The product was purified by dissolving in a minimum amount of hot 2-propanol, and after cooling to 5 C, the product was filtered, washed with cold 2-propanol, and dried, resulting in 3.3 g of a tan solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([I:8])=[CH:5]OC.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19].C[O-].[Na+]>C(O)C>[I:8][C:4]1[C:3](=[O:2])[N:19]=[C:11]2[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]2[CH:5]=1
Reactant: COC=C(I)C(=O)OC
Reactant: Nc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1nc2[nH]c3ccccc3n2cc1I

Procedure:
To a mixture of 2-iodo-3-methoxy-acrylic acid methyl ester (1, 1.21 g, 5 mmol), 1H-benzoimidazol-2-ylamine (2, 0.67 g, 5 mmol) and ethanol (30 mL) was added a solution of sodium methoxide (10 mL, 0.5 M in methanol, 5 mmol). The resulted mixture was refluxed for 3 h and concentrated to afford 3-iodo-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-2-one (3). A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]carbamic acid tert-butyl ester (4, 490 mg, 1 mmol), 3 (311 mg, 1 mmol), K2CO2 (414 g, 3 mmol), Pd(PPh3)4 (0) (41 mg, 0.05 mmol), ethanol (6 mL), dioxane (2 mL) and water (2 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-6% MeOH in methanechloride) to give desired product 5 (170 mg, 31%) as light yellow solid. LCMS (EI) m/z: 570 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](=[O:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[CH3:36][Mg]I>>[OH:17][C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([CH3:36])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(=O)CCCc1ccccc1
Reactant: C[Mg]I
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(C)(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 1-{4′-[3-methyl-4-(4-phenyl-butyryl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and methylmagnesium iodide.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: COc1ccccc1O
Product: CCCCOC(=O)c1nc(Oc2ccccc2OC)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 2-methoxy phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=368.13.
Reaction SMILES: C(O)=O.[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:16]=3[C:32]([O:34]C(C)(C)C)=[O:33])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1>ClCCl>[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:16]=3[C:32]([OH:34])=[O:33])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1c(-c2cccc(OCC3CC3)c2)c2ccccc2n1Cc1ccc(F)cc1
Solvent: O=CO
Solvent: ClCCl
Product: O=C(O)c1c(-c2cccc(OCC3CC3)c2)c2ccccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Formic acid (4 mL) was added dropwise to a stirred solution of tert-Butyl 3-[3-(cyclopropylmethoxy)phenyl]-1-[(4-fluorophenyl)methyl]indole-2-carboxylate (Example 72, 431 mg, 0.91 mmol) in dichloromethane (1.0 mL). The reaction was stirred at room temperature for 8 h, then concentrated in vacuo. The resulting solids were placed on a pad of silica gel and purified by chromatography (gradient from 30% ethyl acetate/hexane to 100% ethyl acetate) to afford 3-[3-(cyclopropylmethoxy)phenyl]-1-[(4-fluorophenyl)methyl]indole-2-carboxylic acid (324 mg, 85%): mp=200-202° C., 1H NMR acetone-d6) 0.32-0.37 (m, 2 H), 0.55-0.61 (m, 2 H), 1.21-1.31 (m, 1 H), 3.86 (d, J=7.0 Hz, 2 H), 5.90 (s, 2 H), 6.89-6.93 (m, 1 H), 7.00-7.08 (m, 4 H), 7.11-7.16 (m, 2 H), 7.18-7.24 (m, 2 H), 7.30-7.36 (m, 2 H), 7.52-7.58 (m, 2 H), 11.28 (br s, 1 H); mass spectroscopy gave MH+=416 (60%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:54])[C@H:21]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:48][CH2:47][C:46]5[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=5[NH:44][C:43]4=[O:53])[CH2:38][CH2:37]3)=[O:35])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:54]=[C:20]([N:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16]1)[C@H:21]([NH:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH2:48][CH2:47][C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[NH:44][C:43]2=[O:53])[CH2:40][CH2:41]1)=[O:35])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1
Reactant: [H][H]
Reactant: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 100 mg (0.14 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid [(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide (Example 50) in 10 mL MeOH was hydrogenated in the presence of 20 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][O:11][C:12]#[C:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:26])[C:22]([NH2:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[NH:25][C:15](=[O:17])[C@H:9]([CH2:10][O:11][C:12]#[C:13][CH3:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)C(C)(C)N
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-tert-butoxycarbonyl O-propynyl-L-serine 13 (6.26 g, 25.7 mmol) was dissolved in DMF (50 mL). Aminoisobutyric acid methyl ester hydrochloride 2 (3.95 g, 25.7 mmol) was dissolved in DMF (50 mL) and N,N-diisopropylethylamine (3.32 g, 25.7 mmol) added. The resulting solution was added to the solution of 13 in one portion and the mixture cooled to 0° C. (ice bath). HOBt hydrate (3.94 g, 25.7 mmol) and then EDC hydrochloride (5.43 g, 28.3 mmol) were added in portions together with additional DMF (50 mL). The reaction mixture was stirred for 1 h at 0° C., after which the ice bath was removed and stirring continued for 42 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (300 mL). The solution was washed with 2 M HCl (3×100 mL), 7.5% (w/w) K2CO3 solution (3×100 mL) and brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange, viscous oil which was deemed to be of satisfactory purity to be used in subsequent steps without further purification (7.94 g, 90%); 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H, NH(Aib)), 6.69 (d, J=8.5 Hz, 1H, NH(propSer), rotamer 1), 6.32 (d, 1H, NH(propSer), rotamer 2), 4.21-4.08 (m, 1H, CαH), 4.13 (d, J=2.1 Hz, 2H, CH2CCH), 3.57 (dd, J=9.9, 4.8 Hz, 1H, CHH), 3.54 (s, 3H, OCH3), 3.47 (dd, J=9.6, 7.4 Hz, 1H, CHH) 3.42 (t, J=2.3 Hz, 1H, CCH), 1.38 (s, 9H, (CH3)3), 1.35 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (75 MHz, d6-DMSO) δ 174.0, 169.0, 154.9, 79.9, 78.1, 77.1, 69.3, 57.5, 54.9, 53.7, 51.7, 28.0, 24.6; HRMS (m/z): [M+Na]+ calcd. for C16H26N2O6Na, 365.1688. found, 365.1695; Anal. Calcd. for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.1; H, 7.7; N, 8.0.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CCOCC>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:9][CH:10]=1
Reactant: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccccc1-c1ccc(CN)cc1
Reaction time: 2 h

Procedure:
A solution of 4-azidomethyl-2'-cyanobiphenyl (4.68 g, 20 mmole) in 40 ml of dry tetrahydrofuran (THF) was stirred under N2 at room temperature as 5.3 g (20 mmole) of triphenylphosphine was added in small portions over a period of about 10 minutes. After 2 hours, by which time gas evolution had ceased, 532 μl (532 mg, 29.6 mmole) of H2O was added. After an additional 23 hours, the solution was concentrated in vacuo to give a pale golden gum. This material was chromatographed on a column of silica gel (50×8.5 cm) packed in CH2Cl2. The column was eluted with a gradient of 0-6% methanol in CH2Cl2. Concentration of the product fractions gave a foam which solidified upon trituration with ether. This material was collected on a filter, washed further with some ether, and dried in vacuo at 50° C. to give white crystals, of satisfactory purity; mass spectrum (FAB) m/e 209 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17](=[O:26])[CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2[CH:16]=[C:15]([CH:17]([OH:26])[CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12

Procedure:
The operation was as in Example 1, except that 14 g of 1-(2-phenyl-4-quinolyl)-3-(4-piperidyl)-1-propanone and 2.3 g of sodium borohydride in 300 ml of methanol were used. After recrystallization of the crude product in isopropanol, 7 g of 1-(2-phenyl-4-quinolyl)-3-(4-piperidyl)-1-propanol (racemic) were obtained, which melted at 162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(Oc2ccc(OC(F)(F)F)cc2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1
Yield: 13 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methyl-6-(4-trifluoromethoxy-phenoxy)-pyrimidine in a yield of 13%. MS ISP (m/e): 472.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.44 (s, 1H), 7.35-7.15 (m, 5H), 7.01 (s, 2H), 6.86 (s, 1H), 6.30 (s, 1H), 3.63 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]4[CH:32]=[C:31](Br)[CH:30]=[N:29]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]4[CH:32]=[C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:30]=[N:29]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(Br)cn4)cc3)cc2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(-c5ccccc5)cn4)cc3)cc2)CC1
Temperature: 90 °C

Procedure:
1-{4′-[4-(4-Bromo-pyrazol-1-ylmethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.062 g, 0.122 mmol), phenylboronic acid (0.018 g, 0.146 mmol), tri(o-tolyl)phosphine (0.004 g, 0.0122 mmol) and sodium bicarbonate (0.041 g, 0.488 mmol) were dissolved in DME (1.5 mL) and H2O (0.5 mL) and N2 (g) was bubbled through the mixture for 10 minutes. Palladium(II) acetate (1 mg, 0.002 mmol) was added and the reaction was heated to 90° C. for 1 hour. The reaction was cooled and purified via silica gel chromatography to afford the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[N:36]O)[NH2:35])=[CH:30][C:29]=1[NH:38][C:39]([C:41]1[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]2=[N:43][CH:42]=1)=[O:40]>CN1C(=O)CCC1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[C:12]([CH:10]3[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]3)[O:14][N:36]=2)=[CH:30][C:29]=1[NH:38][C:39]([C:41]1[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]2=[N:43][CH:42]=1)=[O:40]
Reactant: NC(=NO)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(F)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of Boc-azetidine-3-carboxylic acid (162 mg, 0.8 mmol) in anhydrous NMP (4 mL) was added CDI (131 mg, 0.8 mmol). The reaction was stirred for 10 minutes. N-(2-fluoro-5-(N′-hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (50) (125 mg, 0.4 mmol) was added and the reaction was stirred for 15 minutes, then heated via microwave at 125° C. for 15 minutes. The crude was purified via reverse phase HPLC to afford tert-butyl 3-(3-(4-fluoro-3-(imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F27) as a white solid. MS m/z 479.2 (M+1)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.Cl.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[NH:20])=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CO>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[N:21]=[C:8]([OH:10])[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=3[N:20]=2)=[CH:17][CH:16]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCCC2

Procedure:
7.5 g of ethyl 2-oxocyclohexane-1-carboxylate and 9.6 g of 4-chlorobenzamidine hydrochloride were introduced into 50 ml of methanol. 5.6 g of potassium tert-butylate were added with stirring. The reaction mixture was stirred under reflux for 4 hours and then poured onto ice water. The crystalline product was filtered off with suction, washed with water and recrystallized from dimethylformamide. Yield: 8.8 g; m.p.: >300° C.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]2)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>O1CCCC1.[Pt]=O>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCCC#Cc1ccc2cc(C(=O)OC)ccc2c1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CCCCCCCc1ccc2cc(C(=O)OC)ccc2c1
Yield: 96.2 %

Procedure:
A mixture of Methyl 6-(1-heptynyl)naphthalene-2-carboxylate (4.51 g) and platinum oxide (0.4 g) in tetrahydrofuran was stirred under 3.5 atm pressure of hydrogen for 5 hours. The catalyst was filtered off and the filtlate was evaporated to give Methyl 6-heptylnaphthalene-2-carboxylate (4.40 g).