Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH:27]([CH3:29])[CH3:28])[CH3:14])=[CH:8][C:7]=1[CH3:30].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:25][C:20]([C:18]2[O:19][C:15]([CH:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[C:7]([CH3:30])[CH:8]=3)[CH3:14])=[C:16]([CH:27]([CH3:29])[CH3:28])[N:17]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(Br)cc3)nc2C(C)C)cc1C
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(OC(C)c2oc(-c3ccc(-c4ccccc4)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 85 °C

Procedure:
A solution of 3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (150 mg, 0.308 mmol) in toluene (4 ml) and THF (0.5 ml) is bubbled with nitrogen for 10 minutes. To this solution is added phenyl boronic acid (56 mg, 0.46 mmol), Pd(OAc)2 (10 mg), and sodium carbonate (1.0 ml, 2.0 N). The suspension is heated to 85° C. for 8 hours and the mixture is then extracted with EtOAc (3×10 mL). The combined organics are dried over Na2SO4 and concentrated, purified by silica gel chromatography (Hexanes/EtOAc, 7.5/2.5) to afford the biphenyl intermediate as a colorless oil. The ester is then dissolved in MeOH (1.0 ml) and THF (0.5 ml) and treated with NaOH (2.0 N, 1.5 ml). The mixture is stirred at room temperature for 2 hours and concentrated to an aqueous residue. It is then neutralized with 5 N HCl to pH˜4 and extracted with EtOAc (3×5 ml). The combined organics are dried over Na2SO4 and concentrated, purified by silica gel chromatography (Hexanes/EtOAc, 5/5, then Hexanes/EtOAc/HOAc 5/5/0.02) to afford the acid as a colorless oil (35 mg, 24%). MS (ES): 470.1 (M++1).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].O=S(Cl)Cl.[CH3:18][CH2:19]O>>[CH2:18]([O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH3:19]
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(N)Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 2-amino-3-(4-bromophenyl)propanoic acid (40 g, 164 mmol) in EtOH (100 mL) was added SOCl2 (30 ml, 422 mmol) dropwise at 80° C. The mixture was stirred at 80° C. for 2 hrs. After the solvent was evaporated, the residue was extracted by EA. The combined organic layers were washed with aqueous NaCl, dried by anhydrous Na2SO4, and concentrated in vacuo to afford ethyl-2-amino-3-(4-bromophenyl)propanoate as a yellow liquid (32 g, yield: 72%).
Reaction SMILES: [CH3:1][C:2]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:42])[CH:40]=[O:41])=[CH:3][CH2:4][CH:5]([O:15][C:16](=[O:35])[CH2:17][CH:18]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:19]([CH3:26])([CH3:25])[C:20](=[O:24])[CH:21](Br)[CH3:22])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1.[Li+].[I-].[NH4+].[Cl-]>O1CCCC1>[C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH:18]1[C:19]([CH3:26])([CH3:25])[C:20](=[O:24])[CH:21]([CH3:22])[CH:40]([OH:41])[CH:39]([CH3:42])[CH2:38][CH2:37][CH2:36][C:2]([CH3:1])=[CH:3][CH2:4][CH:5]([C:6]([CH3:14])=[CH:7][C:8]2[N:9]=[C:10]([CH3:13])[S:11][CH:12]=2)[O:15][C:16](=[O:35])[CH2:17]1)([CH3:33])([CH3:32])[CH3:34]
Reactant: CC(=CCC(OC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)Br)C(C)=Cc1csc(C)n1)CCCC(C)C=O
Agent: [Cl-]
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=CCC(C(C)=Cc2csc(C)n2)OC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 80 mg (0.117 mmol) 6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-heptanoic acid 4,8-dimethyl-1-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-9-oxo-non-3-enyl ester in 5.0 ml absolute tetrahydrofurane was added to a suspension of 35 mg (0.285 mmol) CrCl2 and 30 mg (0.224 mmol) LiI in 25 ml dry tetrahydrofurane within 80 min using a syringe pump. After addition was completed, the resulting suspension was stirred for another 2 hrs at ambient temperature. Then, 20 ml semiconcentrated NH4Cl solution was added, and the organic phase was extracted with diethylether (5×15 ml). The organic phases were combined, and washed twice with 15 ml demin. water as well as twice with 15 ml saturated NaCl solution, dried over Na2SO4, filtered, and concentrated in vacuo. This gave 67 mg of a yellow oil.
Reaction SMILES: [K+].[Br-].C([O:5][C:6]([C:8]1[C@@H:16]2[C@@H:12]([O:13][C:14]([CH3:18])([CH3:17])[O:15]2)[C@H:11]([NH:19][C:20](=[O:22])[CH3:21])[C:10](=NO)[CH:9]=1)=[O:7])C.C(N[C@H]1[C@@H]2OC(C)(C)O[C@@H]2C(C([O-])=O)=C/C/1=N\O)(=[O:27])C.[Na+:45].C(OC(C1C[C@H](NC(OC(C)(C)C)=O)[C@@H](NC(=O)C)[C@H](O)C=1)=O)C.C(OC(C1[C@@H]2[C@@H](OC(C)(C)O2)[C@H](NC(=O)C)[C@@H](NC(OC(C)(C)C)=O)C=1)=O)C>CO.C(Cl)Cl.CO>[C:20]([NH:19][C@H:11]1[C@@H:12]2[O:13][C:14]([CH3:18])([CH3:17])[O:15][C@@H:16]2[C:8]([C:6]([O-:5])=[O:7])=[CH:9][C@H:10]1[OH:27])(=[O:22])[CH3:21].[Na+:45]
Reactant: CCOC(=O)C1=CC(=NO)[C@@H](NC(C)=O)[C@@H]2OC(C)(C)O[C@H]12
Reactant: CC(=O)N[C@@H]1/C(=N/O)C=C(C(=O)[O-])[C@H]2OC(C)(C)O[C@H]21
Agent: CCOC(=O)C1=C[C@@H](O)[C@H](NC(C)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCOC(=O)C1=C[C@H](NC(=O)OC(C)(C)C)[C@@H](NC(C)=O)[C@@H]2OC(C)(C)O[C@H]12
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@H]1[C@@H]2OC(C)(C)O[C@@H]2C(C(=O)[O-])=C[C@H]1O

Procedure:
RF=0.15 (DCM/MeOH 3/1); [α]D20=−57.471 (c 0.5, MeOH); IR (KBr) ν 3419, 2929, 1691, 1595, 1552, 1384, 1240, 1214, 1045, 869 cm−1; 1H NMR (300 MHz, MeOD) δ 8.00 (d, 1H, J=7.5 Hz), 6.97 (d, 1H, J=3.9 Hz), 5.01 (d, 1H, J=5.4 Hz), 4.44 (t, 1H, J=3.9 Hz), 4.42-4.31 (m, 2H), 2.01 (s, 3H), 1.39 (s, 1H) ppm; 13C NMR (75 MHz, MeOD) δ 172.7, 109.1, 73.8, 70.5, 64.0, 51.8, 26.6, 24.7, 21.2 ppm; MS (FAB+) m/z %: 294 (M+H) (8), 272 (M−Na++2H+) (100), 214 (85), 176 (17), 126 (12), 84 (7), 60 (10), 43 (26); HRMS Calc'd for C12H18NO6: 272.11341 found: 272.11381.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][O:24][C:25](=[O:41])[CH:26]([NH:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39])[CH2:27][CH:28]=[CH2:29].I[C:43]1[CH:48]=[CH:47][C:46]([N:49]([CH3:56])[C:50]2[N:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:41])[CH:26]([NH:30][C:31](=[O:40])[C:32]1[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:27]/[CH:28]=[CH:29]/[C:43]1[CH:48]=[CH:47][C:46]([N:49]([CH3:56])[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][N:55]=2)=[CH:45][CH:44]=1
Reactant: CN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
Under an argon atmosphere, palladium acetate (170.8 mg) and tris(2-methylphenyl)phosphine (222.2 mg) were added to a suspension of 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (2.20 g), N-(4-iodophenyl)-N-methylpyrimidin-2-amine (2.27 g) and potassium carbonate (1.51 g) in DMF (20 ml), and the resulting mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, ethyl acetate was added to the reaction solution, and the resulting mixture was washed twice with water and once with saturated brine, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=1/1→chloroform). The obtained crude product was purified again by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=4/1→2/1) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (2.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[C:11]([C:19]([OH:21])=[O:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O.[CH2:23](O)[CH2:24][OH:25]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[C:11]([C:19]([O:21][CH2:23][CH2:24][OH:25])=[O:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: OCCO
Reactant: O=C(O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CC(c2ccccc2Cl)=Nc2c1cccc2C(=O)OCCO

Procedure:
2-(2-Chlorophenyl)-4-quinolone-8-carboxylic acid (10 grams) was stirred overnight at 95° to 98° C. in a mixture of 10 ml of concentrated sulfuric acid and 100 ml of ethylene glycol. The reaction solution was poured over into water and separated crystals were collected by filtration and then washed with water. After dried, the crystals were re-crystallized from acetone to give 8.2 grams of the title compounds, pale yellow prisms, melting point 170° to 171° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:5].N(C(N(C)C)=O)=NC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:5][N:4]1[CH2:6][C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:15]2[O:16][CH2:2][CH2:3]1)[NH:11][CH:10]=[CH:9]3
Reactant: CN(CCO)Cc1c(O)ccc2[nH]ccc12
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCOc2ccc3[nH]ccc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
4-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-1H-indol-5-ol (Intermediate 5, 0.44 g, 2.0 mmol), 1,1′-Azobis(N,N-dimethylformamide) (0.52 mg, 3.0 mmol) and triphenylphosphine (0.79 mg, 3.0 mmol) was dissolved in THF (10 mL) and stirred at room temperature overnight. The mixture was evaporated and the crude material was purified by flash chromatography on silica gel using a MeOH-ethylacetate gradient, 4-32% MeOH, to give 136 mg of the title compound. MS m/z 203 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([OH:15])[CH:9]=1)(C)(C)C.[CH3:17][N:18]1[CH2:22][CH2:21][C@H:20](O)[CH2:19]1.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[O:15][C@@H:20]1[CH2:21][CH2:22][N:18]([CH3:17])[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(O)c1
Reactant: CN1CC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2cc(N)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
To a cooled (0° C.) solution of 4-chloro-3-hydroxyphenylcarbamic acid tert-butyl ester (55 g, 0.23 mol), (S)-1-methyl-pyrrolidin-3-ol (24 g, 0.24 mol), and triphenylphosphine (89 g, 0.34 mol) in THF (1.1 L) was added dropwise via addition funnel a solution of DIAD (67 mL, 0.34 mol) in THF (100 mL) over 1 h. The resultant solution was allowed to slowly warm to ambient temperature and maintained for 16 h. The THF was removed in vacuo and the residue treated with 6 N HCl (650 mL). The resultant mixture was stirred at room temperature for 4 h, at which time it was diluted with water (500 mL) and the filtered to remove the triphenylphosphine oxide. The filtrate was washed with EtOAc (3×1 L) and chloroform (5×1 L) to remove additional reaction by-products. The aqueous layer was then basified with solid NaOH pellets and extracted with ether (2×1 L) and EtOAc (2×1 L). The combined organic layers were washed with saturated NaHCO3 (2×1 L) and brine (1 L), dried (MgSO4), and concentrated to give 40 g (80%) of the title compound: MS (ES+) m/e [M+H]+227.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([I:20])[CH:12]=[C:13]2[C:18]=1[NH:17][CH:16]=[CH:15][C:14]2=O)=[O:8])[CH3:2].[Cl:23]C1C2C(=CC=C(I)C=2)N=CC=1C(NCCN(CC)CC)=O>>[Cl:23][C:14]1[C:13]2[C:18](=[C:9]([C:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[O:8])[CH:10]=[C:11]([I:20])[CH:12]=2)[N:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: CCN(CC)CCNC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Product: CCN(CC)CCNC(=O)c1cc(I)cc2c(Cl)ccnc12
Yield: 73 %

Procedure:
This compound was prepared, starting from compound 100 (2.00 g, 4.84 mmol), according to the procedure developed for compound 95. Reaction time at 100° C.: 15 min; the purification was performed using column chromatography (Al2O3, AcOEt/cyclohexane, 9/1, v/v) to give compound 101 (1.52 g, 3.52 mmol) as a beige solid. Yield 73%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.49; mp 76-78° C.; IR (KBr) ν 1555, 1654, 2962 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.09 (t, 6H, J=7.1 Hz), 2.64 (q, 4H, J=7.1 Hz), 2.75 (t, 2H, J=6.4 Hz), 3.66 (q, 2H, J=6.4 Hz), 7.54 (d. 1H, J=4.7 Hz), 8.68 (d, 1H, J=2.1 Hz), 8.76 (d, 1H, J=4.7 Hz), 9.07 (d, 1H, J=2.1 Hz), 11.01 (m, 1H); MS m/z 433 (M+2, 1), 431 (M+, 1), 360 (1), 358 (1), 317 (1), 315 (3), 289 (1), 287 (1), 191 (1), 189 (2), 161 (3), 126 (2), 99 (9), 86 (100), 71 (2), 58 (9).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH:11]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[CH:20]=[CH:19]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O>[CH:11]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[C:20]([CH:8]=[O:9])=[CH:19]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1cccc2ccn(CC3CCCCC3)c12
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc2c(C=O)cn(CC3CCCCC3)c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Phosphorous oxychloride (12 ml, 0.13 mol) was added slowly over 30 minutes to dimethylformamide (30 ml) at −10° C. The solution was allowed to warm to 0° C. over 1 h, then 1-(cyclohexyl)methyl-7-methoxy-1H-indole (prepared as in Example 26; 3.2 g, 13 mmol) was added portionwise and the solution stirred at room temperature for 16 h. The solution was cooled in an ice bath and diluted with water, then neutralised carefully with sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The organic extracts were combined and the solvent removed in vacuo. The residue (3.5 g) was dissolved in aqueous sodium hydroxide solution (5 M; 100 ml) and the mixture refluxed at 100° C. for a further 16 h. The solution was cooled and extracted with ethyl acetate (3×50 ml), the organic extracts combined and the solvent removed in vacuo to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (2.2 g, 8.12 mmol) as a white solid.
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:13][CH2:12][C:11]([C:24]([O:26][CH3:27])=[O:25])=[CH:10][C:9]=2[CH:28]=1.B([O-])([O-])O[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:38]([O:37][C:34]1[CH:35]=[CH:36][C:31]([C:5]2[CH:6]=[CH:7][C:8]3[N:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[CH2:13][CH2:12][C:11]([C:24]([O:26][CH3:27])=[O:25])=[CH:10][C:9]=3[CH:28]=2)=[CH:32][CH:33]=1)[CH2:39][CH3:40]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2OC)CC1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OC)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
In toluene (25 ml), ethanol (2.5 ml) and water (2.5 ml) were suspended methyl 7-bromo-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (712 mg), 4-propoxyphenyl borate (416 mg) and potassium carbonate (636 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the suspension was added tetrakistriphenylphosphinepalladium (143 mg) and the mixture was heated under argon atmosphere at 100° C. for 5 hours. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-propoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (663 mg) as yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:39])([F:38])[F:40])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 5.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thio-phene-2-carboxylate and 500 ml of a 7 N solution of ammonia in methanol is stirred in an autoclave at 125° C. for 4 hours. The mixture is allowed to cool down to room temperature and concentrated to dryness. During the reaction the TBDMS group of the title product is partially removed. The crude is purified by flash chromatography [silica gel, eluent: cyclohexane/ethyl acetate/methanol, elution gradient of 40/60/0 (v/v/v) to 0/100/0 (v/v/v) and then to 0/90/10 (v/v)] to give the title compound. Additionally, 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide is obtained.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:1]1[C:10]2[C@H:9]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: N[C@@H]1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCN[C@@H]1CCCc2cccnc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of (R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amine (70.0 g, 0.47 mol) and 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (102.59 g, 0.47 mol) in tetrahydrofuran (160 mL) at room temperature was added potassium carbonate (65.28 g, 0.47 mol) and the mixture stirred for 1 hour. The suspension was then filtered and chilled to −20° C. The cold filtrate was slowly added to Solution A via canula over 35 minutes. The resulting mixture was stirred at −20° C. for 1 hour, until reaction was complete by NMR aliquot. The reaction was then neutralized by the careful addition of 6N HCl until pH=2-3, keeping the temperature below −7° C. The solution was then warmed to 22° C. and basified with 13w/v % Na2CO3(aq) until pH=4. The tetrahydrofuran was removed under reduced pressure and the concentrate diluted with water (700 mL) and CH2Cl2 (530 mL). The phases were separated and the organic phase washed with concentrated ammonium hydroxide (1×230 mL) and water (1×315 mL). The organic phase was then concentrated to 200-250 mL and filtered through a conditioned silica gel pad (14 g). The silica gel was rinsed with CH2Cl2 (2×20 mL). The combined filtrate was concentrated to 100-150 mL and diluted with diisopropyl ether (1000 mL). The solution was concentrated to 300-350 mL and chilled to −10° C., at which temperature the product began to precipitate. Mechanical stirring was continued for 45 minutes at −10° C., after which time the product was collected by filtration. The product was washed with diisopropyl ether (100 mL) and dried under reduced pressure to give pure 2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione (135.3 g, 82%). 1H NMR (300 MHz, CDCl3, δ ppm) 1.55-1.85 (m, 6H), 1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.50 (b, 1H), 2.65-2.85 (m, 4H), 3.65-3.80 (m, 3H), 7.04 (dd, 1H, J=4.5 & 7.5 Hz), 7.35 (d, 1H, J=7.5 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.36 (d, 1H, J=4.5 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>CCO.Cl>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:15]=2[F:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(I)cc1F
Temperature: 90 °C

Procedure:
Ethyl 4,6-dichloronicotinate (18.60 g, 84.40 mmol) and 2-fluoro-4-iodoaniline (20.0 g, 84.40 mmol) were dissolved in EtOH (80 mL), to which was added conc. HCl (6 drops). This mixture was heated, in an oil bath at 90° C., for 24 h. The solvent was evaporated under reduced pressure. The residue was partitioned between water (100 mL) and EtOAc (400 mL). The organic layer was washed sequentially with saturated NaHCO3 and saturated NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on SiO2 using flash chromatography (eluent:5-10% EtOAc/Hexanes) to afford ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate as an off white solid (22.0 g, 62%). 1H NMR [(CD3)2SO, 400 MHz] δ 9.62 (s, 1H), 8.69 (s, 1H), 7.82 (dd, J=9.9, 1.9 Hz, 1H), 7.61-7.66 (m, 1H), 7.33 (t, J=8.5 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). Anal. Calcd for C14H11ClFIN2O2: C, 39.98; H, 2.64; N, 6.66. Found: C, 40.4; H, 2.38; N, 6.59.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CN(C)C=O>[F:26][C:22](=[C:23]([F:25])[F:24])[CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)=C(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 21.6 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 6 ml of N,N-dimethylformamide, 98 mg of sodium hydride (60% in oil), and 0.46 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.16 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (73)).