Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([C:27]#[C:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:36]1[C:45]2[N:44]=[CH:43][N:42]=[C:40]([NH2:41])[C:39]=2[N:38]=[CH:37]1)(=O)C>CO.C(N(CC)CC)C>[CH2:11]([O:10][C@@H:9]1[C@@:8]([C:27]#[C:28][Si:29]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:34][CH3:35])([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:7][C@@H:6]([N:36]2[C:45]3[N:44]=[CH:43][N:42]=[C:40]([NH2:41])[C:39]=3[N:38]=[CH:37]2)[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Compound 20 (0.354 g, 0.565 mmol) in methanol (14 ml), triethylamine (3.3 ml) was added, and the mixture was stirred for one day at room temperature under air-tight condition. The mixture was concentrated under reduced pressure. The residue was applied to a silica gel column (10 g, eluent; ethyl acetate:n-hexane:ethanol 20:10:1), to thereby yield Compound 21 in an amount of 0.283 g (86%).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](OC)=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>O>[C:28]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[CH2:14][CH2:15]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COCCN
Reactant: COc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 51 %

Procedure:
A solution of 20.8 parts of 1-(diphenylmethyl)-4-(4-methoxy-3-nitrophenylmethyl)piperazine dihydrochloride in 50 parts of 2-methoxyethanamine is stirred and refluxed overnight. Water is added and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified twice by columnchromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 11.6 parts (51%) of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-(2-methoxyethyl)-2-nitrobenzenamine; mp. 97.2° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]2[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:27]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cccc(N2CCOCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1cccc(N2CCOCC2)c1)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.18 ml (12.9 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 1.54 g (8.6 mmol) of 3-(4-morpholinyl)-phenol and 3.59 ml (25.8 mmol) of triethylamine in 10 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 2.41 g (90.1% of theory) of the title compound are obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[Cl:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([O:39][CH3:40])=[CH:33][C:30]=1[CH2:31][OH:32].CCOC(C)=O>C(Cl)Cl>[Cl:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([O:39][CH3:40])=[CH:33][C:30]=1[CH:31]=[O:32]
Reactant: COc1cc(CO)c(Cl)c(OC)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1cc(C=O)c(Cl)c(OC)c1
Reaction time: 0.25 h

Procedure:
To a suspension of Dess-Martin periodinane (1.38 g, 32.5 mmol) in CH2Cl2 (120 mL) was added tert-butanol (3.05 mL, 32.5 mmol). After stirring for 15 min, a sol. of 2-chloro-3,5-dimethoxybenzyl alcohol (H. Newman, R. B. Angier, J. Org. Chem., 1966, 31, 1462-1464, 5.06 g, 25.0 mmol) in CH2Cl2 (20 mL) was added. After stirring for 1 h, EtOAc (200 mL) was added and the mixture was washed with aq. 1M NaOH. The org. phase was evaporated, and the crude product was dissolved again in EtOAc (200 mL), and washed successively with aq. 1M NaOH (2×), water (2×) and brine. The org. phase was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The aldehyde was used without further purification. LC-MS: tR=0.92 min.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 81.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{cyclohexyl[5-(4-fluorophenyl)-2-methyl-3-furyl]methoxy}benzoic acid (163 mg) as well as ethyl 3-(methylamino)propanoate (63 mg) to give the title compound (161 mg, 82%) as an amorphous compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[N:13](OCCC(C)C)=[O:14].C(OCC)C.[ClH:26]>C(O)CC>[ClH:26].[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:13]=[O:14])=[C:6]([OH:10])[CH:5]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCCO
Solvent: CCOCC
Product: CCN(CC)c1ccc(N=O)c(O)c1

Procedure:
0.1 mol of 3-diethylaminophenol are dissolved in 50 ml of n-propanol saturated with gaseous hydrogen chloride and, at 0° C., admixed dropwise and with stirring with 0.1 mol of isoamyl nitrite. Stirring is continued for another hour and the reaction solution is then admixed with diethyl ether, and the product which is formed is isolated by filtration with suction.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23]
Reactant: COC(COCCO)OC
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COCCOC(=O)C(C)(C)Br)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2,2-dimethoxy-ethoxy)-ethanol (2.20 g, 14.6 mmol) from Example 9 in dry triethylamine (3.0 mL, 21 mmol) and dry methylene chloride (30 mL) was stirred at 0° C. 2-bromo-2-methylpropionyl bromide (1.7 mL, 14 mmol) methylene chloride (10 mL) was then added to the alcohol over a 15 minute period. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered, the filtrate was washed with saturated sodium bicarbonate, and dried with magnesium sulfate. The solvent was removed and the yellow oil purified by column chromatography. 1H NMR (300 MHz, CDCl3): δ=1.78 (s, 6H), 3.31 (s, 6H), 3.49 (d, 2H), 3.68 (t, 2H), 4.25 (t, 2H), 4.46 (t, 1H) 13C NMR (300 MHz, CDCl3): δ=31.23, 55.85, 56.15, 65.58, 69.55, 71.44, 103.09, 172.07.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:38](=[O:40])[CH3:39])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[(S)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-propionic acid methyl ester (240 mg) in DCM (10 mL) was added pyridine at 0° C. To this mixture was added acetic anhydride. The mixture was stirred for 2-3 h. After completion of the reaction, the mixture was diluted with DCM (50 mL) and was washed with water, 1N HCl and brine solution. The organic layer was dried and concentrated to get the desired product as a white solid (208 mg). LCMS (m/z): 473
Reaction SMILES: C(N1C=C(B2O[C:13]([CH3:16])(C)[C:12]([CH3:18])([CH3:17])O2)C=N1)C(C)C.Br[C:20]1[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.Br[C:39]1[CH:45]=[CH:44]C(N)=[CH:41][CH:40]=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[O:24][C:20]([C:39]4[CH:45]=[CH:44][C:16]([CH2:13][CH:12]([CH3:17])[CH3:18])=[CH:41][CH:40]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)o1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)Cc1ccc(-c2ccc(C(=O)NCc3ccn4ccnc4c3)o2)cc1

Procedure:
The title compound was prepared as described in Example 51A, substituting 4-isobutylphenylboronic acid for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)furan-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.08 (t, J=6.1 Hz, 1H), 8.49 (dd, J=6.9, 0.8 Hz, 1H), 7.92-7.87 (m, 1H), 7.87-7.79 (m, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.45-7.38 (m, 1H), 7.25 (d, J=8.3 Hz, 2H), 7.21 (d, J=3.6 Hz, 1H), 7.04 (d, J=3.6 Hz, 1H), 6.87 (dd, J=7.0, 1.7 Hz, 1H), 4.51 (d, J=6.0 Hz, 2H), 2.49-2.46 (m, 2H), 1.86 (dp, J=13.4, 6.8 Hz, 1H), 0.87 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 374 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([OH:21])=O)=[CH:5][N:4]=1.C1C=CC2N(O)N=[N:28]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>CN(C=O)C.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([NH2:28])=[O:21])=[CH:5][N:4]=1
Reactant: CSc1ncc(C(=O)O)c(NC2(c3ccccc3)CC2)n1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CSc1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylic acid (646 mg, 2.15 mmol) and HOBt.H2O (395 mg, 2.58 mmol) in DMF (3.5 mL), EDC (515 mg, 2.69 mmol) was added. The mixture was stirred at room temperature for 20 min. Ammonium hydroxide (244 mg, 4.30 mmol) was added. It was stirred at room temperature for 1 h. Water was added to induce precipitation, the solids were collected by filtration to give 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (636 mg). MS 301.2 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=[O:5].[CH2:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:18][CH3:19].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C.ClCCl.O>[CH2:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:2][CH2:3][C:4]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=3)=[O:5])=[O:32])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:18][CH3:19]
Reactant: CCOC(=O)c1ccc(C(=O)CN)cc1
Reactant: CCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(-c2ccc(C(=O)NCC(=O)c3ccc(C(=O)OCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a solution of 2-amino-4′-ethoxycarbonylacetophenone hydrochloride (700 mg), 4-(4-propoxyphenyl)benzoic acid (866 mg) and 1-hydroxybenzotriazole (456.5 mg) in triethylamine (0.47 ml) and dichloromethane (7 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) (648 mg), and stirred for 5 hours at ambient temperature. To the reaction mixture was added water (100 ml), and extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate aqueous solution and brine. Then the organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate, and collected by filtration to give 2-[4-(4-propoxyphenyl)benzoylamino]-4′-ethoxycarbonylacetophenone (746 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:38])[CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH2:28][C:29](=[CH:33][C:34]([O:36]C)=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[Cl:22])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=CC=1C(C)CN(CCCOC1CC(=CC(O)=O)C=CC=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:38])[CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH2:28][C:29](=[CH:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[C:13]=2[Cl:22])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2cccc(Cl)c2)C1
Agent: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1cccc(Cl)c1
Product: Cl
Yield: 48 %

Procedure:
The titled compound was prepared from N-(2-[3-Chlorophenyl]-propyl)-N(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in 48% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine in Example 184g. MS (ESI) 554 (MH+).
Reaction SMILES: [NH2:1][C:2](=[S:16])[C:3]([N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH3:4].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)=O>>[Cl:28][C:23]1[CH:22]=[C:21]([C:19]2[N:1]=[C:2]([C:3]([N:6]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]3)([CH3:5])[CH3:4])[S:16][CH:18]=2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cnn(C(C)(C)C(N)=S)c1
Product: CCOC(=O)c1cnn(C(C)(C)c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Yield: 98 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (241 mg, 1.00 mmol) obtained in Example 16b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol), the title compound (402 mg, 98%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)CCNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)cyclopropylamino)propanoate (0.031 g, 0.064 mmol) in tetrahydrofuran (0.2 mL) and methanol (0.1 mL) was added 1 M lithium hydroxide solution (0.19 mL, 0.19 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting slurry was diluted with water and neutralized (to pH=˜7) with aqueous 1 N HCl solution. The aqueous suspension was extracted with 15% MeOH/CHCl3; the organic extracts were combined, dried (K2CO3), filtered, and concentrated in vacuo. Purification via reverse phase prep. HPLC afforded the title compound as an off-white amorphous solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:36])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-methylphenoxy}-2-methylpropionic acid ethyl ester (11.8 mmol) in THF (30 mL) and methanol (60 mL) was treated with 5N aqueous NaOH (20 mL). The solution was heated at 55° C. for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (20 mL), acidified with 5N aqueous HCl (25 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (40 mL), dried (Na2SO4), and concentrated to yield the desired product. mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ8.07 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.62 (dt, J=6.8, 1.2 Hz, 2H), 7.45 (tt, J=6.8, 1.2 Hz, 2H), 7.37 (tt, J=7.2, 2.0 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.71 (d, J=3.2 Hz, 1H), 6.57 (dd, J=8.8, 3.2 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 3.82 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH:17]=O)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].C1COCC1.[CH3:34][NH:35][CH3:36]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH2:17][N:35]([CH3:36])[CH3:34])=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
In a 50 ml round bottom flask 5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.456 gm, 1.0 mmol) was stirred in dichloromethane (5 mL). To this mixture was added a 2M THF solution of dimethyl amine (1.25 ml, 2.5 mmol). The mixture was allowed to stir under nitrogen atmosphere and at room temperature for 2 hours. To this mixture was then added triacetoxy sodium borohydride (0.37 g, 1.75 mmol) followed by two to three drops of acetic acid. The mixture was then stirred at rt overnight. The solvents were then removed by evaporation and the residue was taken up in ethyl acetate (30 ml) and washed with aqueous sodium bicarbonate and brine. The organics were then combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography using a solvent gradient of (3:1) ethyl acetate-hexane to (0:100) ethyl acetate to give 0.14 g (30% yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.58 (m, 2H), 7.42-7.30 (m, 3H), 7.22 (dt, J=8.73, 2.60 Hz, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 3.04 (s, 2H), 1.96 (s, 6H); ES-MS m/z 485.0 (M+H). ES-HRMS m/z 485.0457 (M+H calcd for C21H18BrF4N2O2, requires 485.0489).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1)(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ccccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(4-Pyridin-2-yl-phenyl)-ethyl]-carbamic acid tert-butyl ester was dissolved in a 1:1 mixture of trifluroacetic acid:dichloromethane. The reaction mixture was stirred at room temperature overnight after which the product was recovered upon solvent removal. The TFA salt was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)[CH:2]=[CH2:3].Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:18][OH:19])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN(CC=C)CC(=O)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1cccnc1
Temperature: 70 °C
Yield: 77.8 %

Procedure:
2-(Diallylamino)-1-(3-pyridyl)ethanone (4.75 g, 21.96 mmol) is dissolved in ethanol (47 mL) under a nitrogen atmosphere. Hydroxylamine hydrochloride (3.55 g, 50.51 mmol) and pyridine (2.5 mL, 30.75 mmol) are then added. The resulting solution is heated at 70° C. under nitrogen for 140 minutes. The reaction is then cooled to room temperature and the solvent is partially evaporated under reduced pressure. The resulting residue is partitioned between 1 M aqueous sodium hydroxide (50 ml) and dichloromethane (250 mL). The phases are separated and the aqueous phase is re-extracted with ethyl acetate (250 mL). The organic layers are combined and the solvents are evaporated. The crude material is purified by silica gel column chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (3.95 g, 78%) as a mixture of E/Z isomers. ES/MS (m/e): 232 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10](=[O:27])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:26])[C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:28].[C:29]([OH:36])(=O)/[CH:30]=[CH:31]/C(O)=O.[CH3:37]O>>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:10](=[O:27])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:26])[C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH2:22][CH2:37][C:29](=[O:36])[CH2:30][CH3:31])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:28]
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(C(C)C(=O)C(C)(C)C)CC1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CO
Product: CCC(=O)CCC(C)(C)C(=O)C(C)N1CCC(CCC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1

Procedure:
The title compound was prepared according to the procedure of step 3 in the example 13 using 4-{4-[3-(6-amino-5-chloro-2-methoxypyridin-3-yl)-3-oxopropyl]piperidin-1-yl}-2,2-dimethylpentan-3-one (step 1 in example 104) instead of 6-amino-5-chloro-N-{[1-(cyclohexylmethyl)-4-piperidinyl]methyl}-2-(methyloxy)-3-pyridinecarboxamide. Then treated with equal amount of fumaric acid in methanol and concentrated gave brown solid, which was recrystallized from ethanol/diethyl ether to afford the title compound as a pale brown solid.