Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:8]2[CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2ccc(F)cc2[nH]1
Reactant: OCc1cccc(C(F)(F)F)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: COC(=O)c1cc2ccc(F)cc2n1Cc1cccc(C(F)(F)F)c1
Yield: 81.7 %

Procedure:
This compound was prepared according to a process similar to that described in step 16.1, by reacting 475 mg (2.459 mmol) of methyl 6-fluoro-1H-indole-2-carboxylate with 0.67 mL (4.918 mmol) of 3-trifluoromethylphenylmethanol in the presence of 1.18 g (4.918 mmol) of cyanomethylenetributylphosphorane (CMBP). The crude reaction product is then purified by chromatography on a column of silica in a mixture of heptane and ethyl acetate, to give 706 mg of the expected product in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[CH3:27]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:25]=[C:26](\[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])/[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccccc1F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF (5 mL), Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-1% MeOH-DCM. The product was further purified by HPLC. Yield: 10 mg. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.25 (s, 1H), 7.10 (m, 3H), 6.90 (m, 2H), 6.82 (m, 1H), 6.70 (s, 1H), 4.62 (d, 1H), 4.0 (d, 1H), 3.70 (m, 1H), 3.20 (m, 1H), 2.92 (m, 1H), 2.82 (s, 3H), 2.70 (m, 1H), 2.0 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH3:25]
Reactant: CCOc1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Product: CCOc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-ethoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl-].[Na+].O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccn1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of diethyl 2-(pyrimidin-2-yl)malonate (1.0 g, 4.2 mmol) and sodium chloride (491 mg, 8.4 mmol) in DMSO (6 ml) and water (151 μl, 8.4 mmol) was heated at 180° C. for 20 min. The mixture was cooled to room temperature, water (12 ml) was added, and the solution extracted with EtOAc (2×20 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica, eluting with hexane:EtOAc (2:1), to afford the ester (434 mg, 62%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ 1.27 (3H, t, J=7.1 Hz), 4.04 (2H, s), 4.23 (2H, q, J=7.1 Hz), 7.22 (1H, t, J=5.3 Hz), 8.72 (2H, d, J=5.3 Hz).
Reaction SMILES: C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO)=CC=1)C.OC1C(F)=CC(CCC(OCC)=O)=CC=1F.[CH2:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[S:46][C:45]=2[CH2:53][O:54][C:55]2[C:60]([F:61])=[CH:59][C:58]([CH2:62][CH2:63][C:64]([O:66]CC)=[O:65])=[CH:57][C:56]=2[F:69])=[CH:40][CH:39]=1)[CH3:37]>>[CH2:36]([C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:48]=[C:47]([C:49]([F:51])([F:52])[F:50])[S:46][C:45]=2[CH2:53][O:54][C:55]2[C:60]([F:61])=[CH:59][C:58]([CH2:62][CH2:63][C:64]([OH:66])=[O:65])=[CH:57][C:56]=2[F:69])=[CH:42][CH:43]=1)[CH3:37]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(F)c1
Agent: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCc1ccc(-c2cc(C(F)(F)F)sc2CO)cc1
Product: CCc1ccc(-c2cc(C(F)(F)F)sc2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 by coupling of (3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methanol and ethyl 3-(4-hydroxy-3,5-difluoro phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.28 (d, J=7.6 Hz, 2H), 6.78 (d, J=7.9 Hz, 2H), 5.21 (s, 2H), 2.92 (t, J=5.1 Hz, 2H), 2.70 (m, 4H), 1.28 (t, J=8.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].P(Br)(Br)[Br:13].CCOC(C)=O.C([O-])(O)=O.[Na+]>COCCOC>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]([CH2:10][Br:13])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: COc1ncc(CO)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(CBr)cc1Br
Reaction time: 0.25 h

Procedure:
To (5-bromo-6-methoxy-pyridin-3-yl)-methanol (2.86 g, 13.1 mmol) in DME (30 mL) was added phosphorus tribromide (1.9 mL, 19.7 mmol), and the reaction was stirred for 15 minutes. The mixture was worked up with EtOAc and saturated aqueous NaHCO3, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-bromo-5-bromomethyl-2-methoxy-pyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C[O:14][C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)=[O:16]>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]2[CH2:19][CH:17]2[C:15]([OH:16])=[O:14])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Product: CC(C)Sc1cccc(COc2ccc(C3CC3C(=O)O)cc2F)n1
Yield: 93 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.029 g, 0.14 mmol) obtained in Step C of Preparation Example 16 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.048 g, 93%).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O-2].[Mg+2:20]>O>[C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Mg+2:20].[C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
25 g of powdered palmitic acid (AN 223, titer 60° C., particle size >40μ) and 2.1 g of 96% active magnesium oxide (precipitated, density 70 g/liter, IN 62) are suspended in 500 ml of water at room temperature. This is followed with stirring for 30 minutes at 55° C. and 2 hours at 70° C. The hollow-sphered granulate formed is filtered and dried. The free fatty acid content amounts to 1.3% but if agitation is carried out for 60 minutes only, the granulate still contains 3% of free fatty acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([O:42][C:43]1[CH:47]=[C:46]([CH2:48]OS(C)(=O)=O)[O:45][N:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N.CC#N.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:48][C:46]1[O:45][N:44]=[C:43]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:47]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1cc(OCc2ccccc2)no1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1OCc1cc(OCc2ccccc2)no1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (159 mg, 0.4 mmol, 1 eq.) in MeCN (0.8 mL), potassium carbonate (166 mg, 1.2 mmol, 3 eq.) and methanesulfonic acid 3-benzyloxy-isoxazol-5-ylmethyl ester (113 mg, 0.4 mmol, 1 eq.) were added. The reaction mixture was stirred at 80° C. for 18 hours. The mixture was diluted with MeCN/H2O 1:1 (1 mL) and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-[2-(3-benzyloxy-isoxazol-5-ylmethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH2:17])[CH:2]=1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:23]=1)=[O:21].CO.C(OCC)(=O)C.[ClH:41].C(O)C>C(#N)C>[ClH:41].[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:19][CH:20]([C:22]2[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[OH:21])[CH:2]=1
Reactant: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1
Reactant: NCCOc1ccc2c(c1)sc1ccccc12
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(C(O)CNCCOc2ccc3c(c2)sc2ccccc23)c1
Reaction time: 1.92 h

Procedure:
To a solution of 462 mg of Intermediate 39 in 20 ml of anhydrous acetonitrile, a solution of 320.2 mg of Intermediate 14 in 10 ml of anhydrous acetonitrile was added under argon atmosphere at 0° C. whereupon the reaction mixture was removed from the ice bath and was agitated for 115 minutes. To this mixture was then added a solution of 215 mg of sodium borohydride in 20 ml of absolute ethanol at room temperature. After agitation for 75 minutes, the reaction was terminated using 1 N hydrochloric acid (pH 4) and thereto was added 0.54 g of ethanolamine. After agitation for 10 minutes, the mixture was diluted with ethyl acetate,organic layer was rinsed with saturated aqueous sodium chloride solution and dried, whereupon it was evaporated under a reduced pressure. This was purified by a column chromatography (elution by methanol/ethyl acetate of 1/7), whereby 251.3 mg of fractions containing the free amine product of the above-identified compound were obtained. This was further purified by a PTLC (elution with methanol/ethyl acetate of 1/7), whereby 134.7 mg of free amine product of the above-identified compound were obtained. Rf=0.50 (methanol/ethyl acetate of 1/7). To this, 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanol were added to convert it into hydrochloride salt (the above-identified compound), which was washed with ethanol, ethyl acetate and diethyl ether, successively, with subsequent drying under a reduced pressure, whereby 93.9 mg of the above-identified compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:10]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.C1COCC1>[C:10]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:23])=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCCCC1)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 66.1 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine (260 mg) in acetonitrile (5 ml)/THF (10 ml) were added 6-(4-biphenylylmethoxy)nicotinic acid (500 mg), WSC (380 mg), HOBt (260 mg), and triethylamine (0.7 ml) at room temperature. After stirring at room temperature for 36 hr, the reaction mixture was diluted with 5% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was purified by alumina column chromatography (THF) and recrystallized from ethyl acetate to obtain the titled compound (450 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18].Cl[CH2:28][CH2:29][CH2:30][OH:31].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:28][CH2:29][CH2:30][OH:31])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18]
Reactant: OCCCCl
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1cc(OCCCO)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
Compound 512 (38 mg, 0.1 mmol) was dissolved in acetonitrile (2 mL) in a reaction vial. 3-Chloro-propan-1-ol (11 μL, 0.12 mmol), K2CO3 (17 mg, 0.12 mmol) and NaI (cat. amount) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for 20 min. in a microwave oven. The reaction mixture was allowed to cool to RT and then poured into a mixture of EtOAc/water. The aqueous phase was acidified with HCl (4N) and the layers were separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo affording the crude product. Purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:3 to 1:1) as the eluent, affording the title compound as a yellow solid. 13C NMR (CDCl3) δ 190.8, 159.1 (dd), 155.6 (dd), 155.3 (d), 155.0 (d), 148.0, 134.7, 133.0, 129.4, 127.9 (d), 124.4 (m), 120.4 (d), 117.1 (d), 116.0, 115.1 (d), 112.8, 111.6 (dd), 104.9 (dd), 66.3, 60.0, 32.0
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:38])([F:37])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[CH3:39][NH:40][CH2:41][CH2:42][OH:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:43][CH2:42][CH2:41][N:40]([CH3:39])[C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([C:11]([F:37])([F:10])[F:38])=[N:13][N:14]=4)[N:17]=3)[CH2:26][CH2:25]2)=[CH:36][CH:35]=1
Reactant: CNCCO
Reactant: O=C(O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
DIPEA (0.087 mL, 0.5 mmol) was added to 4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzoic acid (100 mg, 0.25 mmol), 2-(methylamino)ethanol (20.28 mg, 0.27 mmol) and HATU (114 mg, 0.3 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 24 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-hydroxyethyl)-N-methyl-4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzamide (64 mg, 55%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:9]=3[C:8]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:24]1[CH2:25][CH2:26][C:9]2[C:8]3[CH:7]=[C:6]([F:5])[CH:14]=[CH:13][C:12]=3[N:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH2:22][CH2:23]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CCc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
3.1 ml allyl bromide are added dropwise to 9.0 g of 9-fluoro-6-p-fluorophenyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole and 9 g potassium carbonate in 90 ml dimethylformamide. The mixture is stirred for 2 hours at 110° C., cooled to room temperature, poured onto water, and extracted with ether. The ether extracts are concentrated to give the title compound as a residue. M.p. of the hydrochloride 228°-228° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:4]([C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: O=C(C=Cc1ccccc1Cl)c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1ccccc1Cl
Yield: 68 %

Procedure:
Upon boiling a solution of 24.3 g of 2-chlorobenzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 3 hours, 2-amino-6-phenyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 196°C (alcohol) is obtained. Yield: 68 percent of theory.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:9]1[N:4]2[N:3]=[C:2]([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cccc(-c3ccc[nH]3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 9, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 360 mg; 1.20 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (428 mg; 2.41 mmol; 2.0 eq.) as a brown powder (245 mg, 67%). HPLC, Rt: 2.14 min. (purity 100.0%). LC/MS, M−(ESI): 303.3.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:31])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:27](=[CH:28][CH:29]=1)[O:26][C:13]1([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:30]>O.CO>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2([CH2:12][C:11](=[O:30])[C:10]3[C:27](=[CH:28][CH:29]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:31])=[O:4])[CH:9]=3)[O:26]2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
NaOH (160 mg, 4 mmol) in H2O (2 ml) was added to a suspension of (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (462 mg, 1.15 mmol, Intermediate 1, Step B) in MeOH (6 ml). The mixture was stirred at 50° C. After 2 h, MeOH was evaporated and the pH of the aqueous phase was adjusted with 1 M HCl to a pH value of 5. The resulting suspension was extracted with DCM, the organic phase dried over Na2SO4 and concentrated to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (410 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16]=O)=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2.O.[OH-].[Na+].Cl.[CH3:22][C:23]([CH3:25])=[O:24]>>[Cl:1][C:2]1[C:3]([CH:16]=[CH:22][C:23](=[O:24])[CH3:25])=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2
Reactant: CCC1(C)Cc2c(C)c(C)c(C=O)c(Cl)c2C1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)Cc2c(C)c(C)c(C=CC(C)=O)c(Cl)c2C1
Yield: 73.7 %

Procedure:
To a solution of 14.7 g of the 7-chloro-2-ethyl-2,4,5-trimethylindan-6-carboxaldehyde in 45 ml of absolute acetone was added 22 ml of water and 24 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 12.65 g of the title compound as brown oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(#N)C>[Br:27][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:21]
Reactant: BrBr
Reactant: Cc1cc(C)c2c(c1C)OCC2c1ccc(C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of 3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 13 (6.10 g, 21.8 mmol) and sodium acetate (1.97 g, 24.0 mmol) in acetonitrile (30 mL) was added bromine (1.17 mL, 22.9 mmol), and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was crystallized from methanol to obtain 7.90 g (yield 99%) of the title compound. Melting point: 86-87° C. (methanol).