Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: CC(C)Nc1ccccc1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(c3ccccc3)C(C)C)c2)C[C@H]1C

Procedure:
N-Isopropylaniline was then coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-phenylbenzamide as an off-white solid. NMR (200 MHz, DMSO-d6): δ 0.92 (d, J=6.1 Hz, 3H); 0.99 (d, J=5.9 Hz, 3H); 1.11 (d, J=6.9 Hz, 6H); 1.70 (dd, J1 =7.2 Hz, J2 =11.1 Hz, 1H); 2.07 (dd, J1 =7.6 Hz, J2 =10.6 Hz, 1H); 2.33 (br d, J=9.9 Hz, 1H); 2.42-2.54 (m, 2H); 2.68 (br d, J=10.4 Hz, 1H); 2.85 (dd, J1 =6.5 Hz, J2 =13.9 Hz, 1H); 3.16 (dd, J1 =4.9 Hz, J2 =14.1 Hz, 1H); 4.75 (s, 1H); 4.85 (m, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.18 (d, J=16.8 Hz, 1H); 5.70-5.84 (m, 1H); 6.50 (d, J=7.1 Hz, 1H); 6.59 (s, 1H); 6.65 (d, J=8.2 Hz, 1H); 7.03-7.32 (m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 498 (M+1, 100%), 344 (43%), 153 (76%). [α]D20 =+6.4° (abs. ethanol, c=1.4). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic off-white powder. Calc. for C32H39N3O2HCl 0.5 H2O: C, 70.76; H, 7.61; N, 7.74; Cl, 6.53. Found: C, 71.01; H, 7.83; N, 7.49; Cl, 6.41.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([CH:42]=[CH:43][C:44]=1[N+:45]([O-])=O)[O:10][C:11]1[C:12]([CH:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:41])[CH3:40])=[CH:13][C:14]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:16][C:15]=2[CH:33]=1)([O-])=O>[Ni].C(O)C>[NH2:4][C:7]1[CH:8]=[C:9]([CH:42]=[CH:43][C:44]=1[NH2:45])[O:10][C:11]1[C:12]([CH:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:41])[CH3:40])=[CH:13][C:14]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:16][C:15]=2[CH:33]=1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(N)c(N)c1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.030 ml of hydrazine monohydrate and 20 mg of developed Raney nickel catalyst were added to an ethanol (1 ml) solution of 72 mg of 1-(2-(6-(3,4-dinitro-phenoxy)-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone, and the reaction liquid was stirred at room temperature for 2 hours. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:40]=[CH:39][CH:38]=[CH:37][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]3)[N:10]=1.O.[OH-].[Li+:44]>C1COCC1.O>[C:33]([O:32][C:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:37]=[CH:38][CH:39]=[CH:40][C:5]=4[CH2:4][C:3]([O-:41])=[O:2])[C:14]([C:15]([F:17])([F:16])[F:18])=[CH:13][N:12]=3)[CH:21]=2)[CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35].[Li+:44]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)ccc2C1
Yield: 80.9 %

Procedure:
tert-Butyl 6-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I80) (520 mg, 0.91 mmol) was dissolved in THF (20 mL) and a solution of lithium hydroxide hydrate (76 mg. 1.8 mmol) in water (5 mL) was added. After 18 hours the THF was removed under reduced pressure, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulfate) and evaporated to give the title compound (I81) (414 mg, 81% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.36 (s, 1H), 8.65 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.20-7.02 (m, 5H), 4.45 (s, 2H), 3.54 (t, J=5.8 Hz, 2H), 3.17 (s, 2H), 3.14-2.98 (m, 4H), 2.76 (t, J=5.7 Hz, 2H), 1.43 (s, 9H). LCMS Method C: rt 6.51 min; m/z 557.1 [M-Li+2H]+, 501.1 [M-tBu-Li+3H]+, 457.1 [M-Li-Boc+3H]+; m/z 555.1 [M-Li]−.
Reaction SMILES: C(=O)([O-])O.[Na+].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:15]([NH2:25])(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[C:18]1(/[CH:17]=[CH:16]/[C:15]2[O:24][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
Synthesis was conducted in accordance with the report (J. Org. Chem., 1996, Vol. 61, p. 6496) by Panek et al. Sodium hydrogencarbonate (22.8 g) and ethyl bromopyruvate (10.5 ml) were added to a solution of cinnamamide (10.0 g) in tetrahydrofuran (250 ml) at room temperature, and the mixture was heated under reflux for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite and then concentrated under reduced pressure to obtain residue. Trifluoroacetic anhydride (30 ml) was added to a solution of this residue in tetrahydrofuran (30 ml) at 0° C., and the mixture was gradually warmed to room temperature. After the mixture was stirred for 63 hours, a saturated aqueous solution (500 ml) of sodium hydrogencarbonate and ethyl acetate (150 ml) were added to the reaction mixture, and a water layer was separated. The water layer was extracted with ethyl acetate (150 ml). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (150 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1→3:1) to obtain the title compound (10.9 g).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.C=O.[C:27]([BH3-])#[N:28].[Na+].[C:31](O)(=O)C>C(#N)C>[CH3:31][N:28]([CH3:27])[C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Amino-2-(2-phenylchroman-6-yloxy)pyridine (ORM-10543) (0.20 g, 0.63 mmol) and 37% formaldehyde (0.73 ml, 0.80 mmol) were dissolved in acetonitrile (12 ml). Sodiumcyanoborohydride (0.16 g, 2.51 mmol) was added and the mixture was stirred for 30 minutes at the room temperature. The pH was adjusted to 6-7 with acetic acid and the reaction mixture was stirred additional 30 minutes. The solvent was evaporated. The residue was solvated to 10% potassiumhydroxide solution and extracted with methylene chloride. Organic phase was dried and evaporated. Recrystallization from diethylether yielded dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]-amine in 92% purity. Recrystallization filtrate was evaporated. The residue was solvated in methylene chloride and 1M HCl-diethylether was added. Dimethyl-[2-(2-phenylchroman-6-yloxy)-pyridin-4-yl]-amine precipitated as a hydrochloride in 95.3% purity.
Reaction SMILES: [N:1]1([C:6]2C=CN=[C:8]([CH3:12])[CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[F:27])[CH:18]=[N+:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.BrC1C=C(C=CC=1F)C=O.[NH:38]1CC[CH2:40][CH2:39]1>>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:5]2[N:1]([CH2:6][C:7]3[CH:8]=[CH:12][CH:40]=[CH:39][N:38]=3)[CH:2]=[CH:3][CH:4]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Fc1ccc(C=[N+]2CCCC2)cc1Br
Reactant: Cc1cc(-n2cccc2)ccn1
Reactant: C1CCNC1
Agent: O=Cc1ccc(F)c(Br)c1
Agent: [Cl-]
Product: Fc1ccc(C(c2cccn2Cc2ccccn2)N2CCCC2)cc1Br

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-pyrrol-1-yl-methyl-pyridine and 1-(3-bromo-4-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 3-bromo-4-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1cccc(Br)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
3-(6-Bromo-pyridin-2-yl)-acrylic acid (4.5 g, 19.5 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23.4 mmol), HOBT (5.3 g, 39.1 mmol), EDAC (7.5 g, 39.1 mmol) and triethylamine (5.4 mL, 39.1 mmol) were added to dichloromethane (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 3.2 g of the titled compound as a white solid.
Reaction SMILES: C([NH:8]/[C:9](/[NH:18][CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:10]/C(OC(C)(C)C)=O)(OC(C)(C)C)=O.C1(C)C=CC=CC=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>O>[F:35][C:36]([F:41])([F:40])[C:37]([O-:39])=[O:38].[NH2:8][C:9]1[NH:10][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][NH+:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)/N=C(\NCC(=O)c1ccccc1)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1[nH]c(-c2ccccc2)c[nH+]1
Product: O=C([O-])C(F)(F)F
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 81.3 %

Procedure:
To a flask charged with ketoguanidine 73 (57.9 mg, 0.153 mmol, 1 equiv) was added toluene (4 mL) and trifluoroacetic acid (120 μL, 1.53 mmol, 10.0 equiv) via syringe and the reaction mixture was heated to 85° C. After 13.5 h, the reaction mixture was allowed to cool to 23° C. and was concentrated under reduced pressure. Water (2 mL) and trifluoroacetic acid (120 μL, 1.53 mmol, 10.0 equiv) were added via syringe to the residue and the resulting mixture was heated to 85° C. After 1.5 h, the reaction mixture was allowed to cool to 23° C. and was concentrated under reduced pressure to give 2-aminoimidazole 74 (34 mg, 82%) as a pale yellow solid. 1H NMR (500 MHz, CD3OD, 21° C.): δ 7.56 (app-d, J=7.2 Hz, 2H), 7.43 (app-t, J=7.7 Hz, 2H), 7.34 (app-tt, J=7.4, 1.2 Hz, 1H), 7.13 (s, 1H). 13C NMR (125.8 MHz, CD3OD, 21° C.): δ 163.1, 149.7, 130.3, 129.7, 129.2, 129.1, 125.6, 109.9, 101.4. FTIR (neat) cm−1: 3182 (br-s), 1682 (br-s), 1204 (s), 1139 (s), 842 (m). HRMS (ESI) (m/z): calc'd for C9H10N3, [M+H]+: 160.0869, found: 160.0867.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:12][CH:11]=1>C1COCC1>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Lithium aluminum hydride (15.5 mL of a 1.0 M solution in THF) is added slowly to a cooled (ice-water bath) solution of the title B compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzoic acid methyl ester (2.0 g, 6.18 mmol) in THF (30 mL). The mixture is stirred at 0° C. for 3 h, then quenched with saturated sodium bicarbonate, and extracted with EtOAc. The organic solution is washed with brine, dried over magnesium sulfate, and concentrated under vacuum to give the crude product. The product is purified by silica gel chromatography using 30% EtOAc in hexane as the eluent to give [4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-methanol as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](=[O:20])([O-])[O-].[Na+].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:5][N:4]1[C@H:1]2[C@@:23]([CH3:27])([C:23]3[CH:27]=[CH:8][C:7]([C:9]4[CH:8]=[C:7]5[C:12](=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=4)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:6][C:24]=3[CH2:25][CH2:2]2)[CH2:24][CH2:25][C:17]1=[O:20]
Reactant: CC(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc(-c3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)cc([N+](=O)[O-])c21
Yield: 22 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 1-acetyl-5-bromo-7-nitroindoline (185 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 63 mg (22%) of the title compound a yellow solid. mp 235°-240°. FDMS: m/e=433. α[D]589 =+65.72 (c=0.99, chloroform).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([CH3:38])[CH:24]=1>C1(C)C=CC=CC=1>[CH3:29][C:27]1[CH:28]=[C:23]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:11]=3)[CH2:16]2)[CH:24]=[C:25]([CH3:38])[C:26]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 30 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3 mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.55 g, 79%).
Reaction SMILES: [SH:1][CH2:2][C:3]1[NH:4][C:5]([CH3:25])=[C:6]([C:23]#[N:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[CH2:27][C:28]#[N:29]>CCO>[C:28]([CH2:27][S:1][CH2:2][C:3]1[NH:4][C:5]([CH3:25])=[C:6]([C:23]#[N:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:29]
Reactant: CCOC(=O)C1=C(CS)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Reactant: N#CCCl
Solvent: CCO
Product: CCOC(=O)C1=C(CSCC#N)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of 2-mercaptomethyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (3 g), 2-chloroacetonitrile (1 g) and 1,4-diazabicyclo-2,2,2-octa ne (0.8 g) in EtOH (30 ml) is heated at reflux temperature for six hours. Then the reaction is cooled to room temperature and after usual work-up and purification by columnchromatography (SiO2 90 g; eluent Et2O/AcOEt 90/10) gives 1.8 g of 2-(cyanomethylthio)methyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: Clc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-chlorobenzylamine (0.5 ml) as described above; yield: 0.063 g (20.4%);
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH3:4].[Mg].[CH2:12](O)[CH3:13].Cl.C[CH2:17][O:18][CH2:19][CH3:20]>[Pd]>[CH3:17][O:18][C:19]1[CH:20]=[C:5]([CH:12]([CH2:4][CH2:3][CH2:2][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:13])[CH:2]=[CH:3][CH:4]=1
Reactant: CCO
Reactant: CCC(Br)c1ccccc1
Reactant: CCOCC
Agent: [Pd]
Agent: Cl
Agent: [Mg]
Product: COc1cccc(C(C)CCCc2ccccc2)c1

Procedure:
A solution of 1-bromopropylbenzene (51.7 g.) in ether (234 ml.) is added dropwise over a 2-hour period to a refluxing mixture of magnesium (7.32 g.) in ether (78 ml.). The reaction mixture is refluxed for 30 minutes longer and then a solution of 3-methoxy-acetophenone (46.3 g.) in ether (78 ml.) is added dropwise and heated to reflux for 1.5 hours. The reaction is quenched by addition of saturated ammonium chloride (234 ml.), the ether layer is separated and the aqueous phase extracted with ether (3×200 ml.). The combined ether extracts are dried over magnesium sulfate and concentrated under vacuum to yield an oil. The oil is hydrogenated in a mixture containing ethanol (600 ml.), concentrated hydrochloric acid (4 ml.) and 5% palladium-on-carbon (10 g.). The catalyst is filtered off and the ethanol removed under vacuum. The residue is distilled under vacuum yielding 2-(3-methoxyphenyl)-5-phenylpentane.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:12][C:7]1[C:6]2[C:10](=[CH:11][C:3]([OH:2])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: COc1ccc2c(C)n[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1n[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To an ice cold solution of 6-methoxy-3-methyl-1H-indazole (620 mg, 3.82 mmol) in CH2Cl2 (25 mL) was added a solution of BBr3 in CH2Cl2 (1 M, 17 mL). The ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The solution was carefully quenched by slowly pouring into iced saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were concentrated and the crude material was purified Biotage (40S column, 45-60% acetone/heptane) to provide 3-methyl-1H-indazol-6-ol (458 mg, 81%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]2[NH:10][CH:11]=[CH:12][C:7]2=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C)C=O>[Cl:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:11]=[CH:12][C:7]2=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. and under an atmosphere of argon, 1.34 g (28.3 mmol) of sodium hydride (60% in mineral oil) are added in small portions to a solution of 5.6 g (28.3 mmol) of 6-chloro-4-nitro-1H-pyrrolo[2,3-b]pyridine in dimethylformamide (50 ml), and the suspension is stirred at RT for 30 minutes. The mixture is once more cooled to 0° C., 5.3 ml (29.8 mmol of 2-(trimethylsilyl)ethoxymethyl chloride are added dropwise and the mixture is allowed to stir at room temperature for 2 h. The suspension is poured into ice-water (250 ml) and stirred until the mixture has reached RT. The mixture is then extracted with ethyl acetate (three times 50 ml) and the organic phase is washed with saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:13](O)[CH3:14]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH3:14])=[O:5]
Reactant: CCO
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)c(C)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 2,5-difluoro-4-methylbenzoic acid (595 mg, 3.89 mmol) in ethanol (30 mL) was added a catalytic amount of thionyl chloride (2 drops). The reaction was stirred for 18 hours at 70° C., and cooled to room temperature. The solvent was removed in vacuo to afford the title compound as a clear oil (500 mg, 86%). No further purification undertaken.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.O.O.[O-:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].CN(C=O)C>CCOCC>[O:17]([C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [O-]c1ccccc1
Reactant: N#Cc1ncc(C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: N#Cc1ncc(C(F)(F)F)cc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
3-Chloro-5-(trifluoromethyl)picolinonitrile (0.220 g, 1.07 mmol) was combined with sodium phenoxide trihydrate (0.272 g, 1.60 mmol) and DMF (5 mL). The resulting mixture was heated to 80° C. and agitated for one hour. The mixture was then cooled, diluted with ether and washed with 1M NaOH, water (3×), brine, dried and evaporated to give crude 3-phenoxy-5-(trifluoromethyl)picolinonitrile (0.190 g, 67.5% yield) as red oil.