Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[C:26]([CH3:33])[C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:6][C:5]1[C:26]([CH3:33])=[CH:27][C:28]([O:31][CH3:32])=[C:29]([CH3:30])[C:4]=1[O:3][CH3:2])[CH3:35]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OC)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1OC

Procedure:
By the procedure of Example 1, 2,4-dimethoxy-3,6-dimethyl-benzyltriphenyl-phosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(2,4-dimethoxy-3,6-dimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([CH3:33])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:25][CH:26]=1)=[O:8])[CH3:5].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH3:33][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:25][CH:26]=1)=[O:8])([CH3:5])[C:3]([OH:34])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To 124 mg 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid methyl ester in 4 mL THF and 1 mL methanol was added 1.3 mL of 1M aqueous sodium hydroxide solution. After stirring at room temperature for 1 h the mixture was poured into cold water, acidified to pH 2 with 2 M HCl and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated to provide a yellow oil, which could be crystallized from diisopropylether to yield 43 mg of 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 81.3 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.15 g, 0.56 mmol) was reacted with 4-hydroxybenzaldehyde (0.067 g, 0.56 mmol) in the presence of glacial acetic acid (0.034 g, 0.56 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.042 g, 0.67 mmol) in methanol (5 ml) (Procedure D) to give compound 16h (0.17 g, 80%) as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][CH:19]([C:21](O)=[O:22])[CH3:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[CH3:1][NH:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:21](=[O:22])[CH:19]([CH3:20])[NH:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1
Reactant: CNC(=O)[C@@H](N)C(C)C
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CNC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Following General Procedure D and using L-valine N-methyl amide (from Example E above) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=145-160° C.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2c(Cl)ccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Yield: 75 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-chloro-quinolin-8-ylamine (Intermediate 464) (1.5 g, 8.43 mmol), 2-nitrobenzene-1-sulfonyl chloride (2.43 g, 11.0 mmol), DMAP (cat), pyridine (2 ml, 25.28 mmol) in DCM (70 ml) for 3 h at room temperature gave the title compound (2.3 g, 74%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[C:13](=O)[CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:23]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[C:13]([CH3:14])[C:3]=2[CH:4]=1
Reactant: COCCOc1ccc(O)c(C(C)=O)c1
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2oc(C(=O)C(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.2 %

Procedure:
To a solution (10 mL) of 1-[2-hydroxy-5-(2-methoxyethoxy)phenyl]ethanone (0.55 g) synthesized in Example A79(1) in N,N-dimethylformamide were added potassium carbonate (1.1 g) and 1-bromo-3-methylbutan-2-one (0.56 g) synthesized in Example A75(1) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was filtered through celite, water (200 mL) was added and the mixture was extracted with diethyl ether (10 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) was added to the solution at room temperature. The reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with diethyl ether (10 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.71 g, 98%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1(OCC1C=CC=CC=1)[CH2:13][O:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=[O:26])C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:26])[CH2:10][CH:9]1[CH2:13][O:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1(OCc2ccccc2)CCCN1C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Product: COCC1CC(O)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
The benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (217.00 mg, 0.68 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 148.35 mg. 1H NMR (CDCl3, 300 MHz): δ 1.42 (s, 9H), 1.80-2.10 (m, 2H), 3.05 (bs, 1H), 3.30 (s, 3H), 3.34-3.50 (m, 3H), 4.00 (bs, 1H), 4.33-4.40 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[F-].[Cs+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[CH:26]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]3[C:9](=[O:19])[C:10]([CH3:18])([CH3:17])[O:11][C:12]([CH3:15])([CH3:16])[C:13]3=[O:14])[CH:7]=2)=[C:27]([F:34])[CH:26]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 77.9 %

Procedure:
To a mixture of 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.278 g, 0.79 mmol), cesium fluoride (1.19 g, 7.90 mmol), 4-chloro-2-fluorophenylboronic acid (0.194 g, 1.11 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.102 g, 0.12 mmol) is added degassed dimethoxyethane (2 ml), and the resulting suspension is stirred under nitrogen for 45 minutes then heated at 80° C. for 20 hours. After cooling to room temperature the reaction mixture is partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous phase is further extracted with ethyl acetate, then all organic fractions are combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting material is purified by column chromatography on silica gel (hexane/ethyl acetate 3:1 ratio) to afford 4-(4′-chloro-4-ethyl-2′-fluorobiphenyl-3-yl)-2,2,6,6-tetramethyl-pyran-3,5-dione (0.248 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organiclayer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:6]([C:7]3[CH:8]=[CH:9][C:10]([NH2:17])=[CH:11][C:12]=32)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:16][CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1CC2CCC(C1)c1cc(N)ccc12
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)C)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trien-4-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 271d. Product isolated as a light brown foam (35 mg, 60%). LCMS (m/e) 491 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.67 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.47 (dd, 1H, J=1.3 and 7.8 Hz), 7.46-7.42 (m, 2H), 7.33 (d, 1H, J=2.2 Hz), 7.26-7.23 (m, 1H), 7.10-7.03 (m, 1H), 7.00 (d, 1H, J=7.9 Hz), 6.87 (s, 1H), 6.18 (bs, 1H), 3.03 (d, 3H, J=4.9 Hz), 2.98-2.91 (m, 1H), 2.91-2.79 (m, 4H), 2.35-2.30 (m, 2H), 2.18-2.15 (m, 2H), 1.60-1.55 (m, 2H), 0.95 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([NH:14][CH2:15][C:16]1[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C.C([O-])(O)=O.[Na+]>ClCCCl.O.CC(O)=O>[CH2:1]([N:8]([CH3:34])[C:9]1[C:10]([C:28]([F:31])([F:29])[F:30])=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([NH:14][CH2:15][C:16]1[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cccc(NCc3ccccc3)c2C(F)(F)F)c(=O)[nH]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: CC=O
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cccc(N(C)Cc3ccccc3)c2C(F)(F)F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
To a solution of 3-(benzylamino)-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-(trifluoromethyl)benzamide (100 mg, 0.23 mmol) in DCE (5 ml) was added acetic acid (27 μl, 0.47 mmol) followed by paraformaldehyde (7 mg, 0.23 mmol) after which the reaction was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (74 mg, 0.35 mmol) was added in one portion and the reaction was stirred at room temperature for 16 h. Further treatment with acetaldehyde (35 mg), sodium triacetoxyborohydride (250 mg) and AcOH (100 ml) was performed. After a further 24 h further acetaldehyde (445 mg) and sodium triacetoxyborohydride (250 mg) were added and the reaction was stirred for a further 3 h. Water (20 ml) was then added to the reaction mixture and the aqueous phase was neutralised by the portionwise addition of NaHCO3. The aqueous phase was extracted with DCM (2×50 ml), then the combined organic phases were washed with brine, dried (Na2SO4) and evaporated. The product was purified using FCC over a 5 g Isolute, eluting with 0-5% MeOH in DCM to afford the title compound as an off-white powder (24 mg, 22%). LC-MS 95%, 4.12 min (7 minute LC-MS method), m/z=444.2, 1H NMR (500 MHz, Chloroform-d) δ 11.10 (br. s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.38-7.29 (m, 5H), 7.27-7.23 (m, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.04 (t, J=5.6 Hz, 1H), 5.92 (s, 1H), 4.52 (d, J=5.9 Hz, 2H), 4.09 (s, 2H), 2.60 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21](O)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 107A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 24 mg (19% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([NH:16][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:25]=2)[CH:21]=[N:22]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2c1
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 159.8 mg (1.2 mmol) of 6-aminoindazole in 10 mL of 2-ethoxyethanol was added 115.6 mg (1.0 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr. After cooling, most of solvent was evaporated off and the residue was diluted with ether. The precipitate was collected by filtration and was taken into water. The aqueous suspension was neutralized to PH 7-8 by addition of sat. sodium carbonate aqueous solution and stirred for 15 min. The separated solid was filtered off and washed with water and ether. After drying in vacuo, 297.5 mg (94.3%) of the product was obtained as a deep yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 315.8. HRCIMS m/z: cacld 315.112 for C18H13N5O (M+), obsd 315.1124
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2>[Pd].CO>[NH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(N)cccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 3-methyl-5-nitroisoquinoline (1.3 g, 0.0069 mol—prepared according to the procedure in WO 2004/024710), 10% Pd—C (100 mg) and MeOH (100 mL) was stirred under an atmosphere of hydrogen (1 atm) at rt for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a light yellow solid (1.1 g, 100%). LC-MS: 0.64 min, 159.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[CH3:19][N:20]=[C:21]=[O:22]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:19][NH:20][C:21](=[O:22])[O:13][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[OH:1])=[C:11]([CH3:12])[CH:10]=1
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cc(C)c(N=Cc2ccccc2O)c(C)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 68 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 6.03 grams (0.025 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol prepared in Part A, 1.71 grams (0.030 moles) of methyl isocyanate, 50 milliliters of ethyl acetate and 5 drops of dibutyltin diacetate. The resulting reaction mixture was stirred for 65 hours at room temperature and then washed twice with a 1% aqueous sodium bicarbonate solution followed by a single wash with saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was collected by filtration and concentrated under reduced pressure to give a brown oil. The oil was triturated with hexane to give 5.21 grams (0.017 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenyl methylcarbamate in the form of a yellow solid having a melting point of 116°-118° C. and the following structural formula: ##STR8##
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH:12]=3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH3:19]>CO.CO.N>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C:11]([C:8]1[O:9][C:10]3[C:2]([NH2:19])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[CH:12]2
Reactant: N
Reactant: Brc1cccc2cc(C3=CN4CCC3CC4)oc12
Solvent: CO
Product: Nc1cccc2cc(C3=CN4CCC3CC4)oc12
Temperature: 120 °C

Procedure:
3-(7-Bromo-1-benzofuran-2-yl)-1-azabicyclo[2.2.2]oct-2-ene (300 mg, 0.986 mmol; Intermediate 25) was dissolved in methanol (2 mL). A solution of concentrated aqueous ammonia (25%; 10 mL) and CuCl2 (15 mg) were added and the resulting mixture was heated at 120° C. for 48 h. The mixture was run through a silica plug using methanol/ammonia solution (9:1) as eluent. Concentration in vacuo furnished 236 mg of the crude title product. This material was used directly in subsequent experiments.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]([CH:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=[N:15]2)=[C:10](I)[N:9]=1)=[O:7].[CH3:35][O:36][CH2:37]/[CH:38]=[CH:39]/B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]([CH:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=[N:15]2)=[C:10]([CH:39]=[CH:38][CH2:37][O:36][CH3:35])[N:9]=1)=[O:7]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COCCNC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCC=Cc1nc(C(=O)NCCOC)c(OCc2ccccc2)c2ncc(Cc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To Compound 10 (286 mg, 0.5 mmol) and tetrakistriphenyl phosphine palladium (30 mg, 0.026 mmol) was added a dimethylformamide (4 ml) solution of 2-((E)-3-methoxy-propenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (142 mg, 0.65 mmol), followed by an aqueous solution of 2 moles of potassium carbonate (0.66 ml, 1.32 mmol), and after vacuum deaeration under stirring at room temperature, and replacement with nitrogen, the reaction was heated under stirring in an oil bath at 100° C. After 3 hours, to the reaction mixture were added and dissolved ethyl acetate and water, and was added 10% citric acid (8 ml), and then the mixture was shaken for separation, washed twice with water, dried over sodium sulfate, and subjected to distillation under reduced pressure. The residue was subjected to high flash column chromatography (toluene:acetone (4:1)), and the obtained residue (170 mg) was crystallized from diisopropyl ether, to give 8-benzyloxy-3-(4-fluorobenzyl)-5-(3-methoxypropenyl)[1,6]naphthyridine-7-carboxylic acid (2-methoxyethyl)amide b-11 (135 mg) in 52.3% yield.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, light brown solid (98 mg, 78%), MS (ISP) m/z=499.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.