Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]=[C:3]([O:10][CH3:13])[C:2]([F:11])([F:12])[F:1])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(OC)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of ethyl 4,4,4-trifluoroacetoacetate (12 mL, 82 mmol) in DMF (80 mL) is added cesium carbonate (26.4 g, 82 mmol). The reaction mixture is heated to 70° C. A solution of methyl p-toluenesulfonate (13.5 mL, 90 mmol) in DMF (30 mL) is then added dropwise during 30 min and the reaction mixture is stirred for an additional 1 hr. After cooling to room temperature, the reaction mixture is diluted with H2O (150 mL) and extracted with Et2O (2×150 mL). The organic extracts are combined and washed with H2O and brine, then dried (Na2SO4), filtered and concentrated to afford the title compound (9.0 g, 56%) as an oil which is used without further purification.
Reaction SMILES: [CH3:1][O:2]C1C=CC([N+]([O-])=O)=C(C=1)N.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:20](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[C:23]=2[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2c1

Procedure:
Free base of the titled compound was prepared from 5-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[C:21]([C:25](O)=[O:26])=[CH:22][S:23][CH:24]=1>>[CH3:18][O:19][C:20]1[C:21]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:22][S:23][CH:24]=1
Reactant: COc1cscc1C(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: COc1cscc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 109.2 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.2 mg (0.09 mMol) 4-methoxy-3-thienoic acid, 12.1 mg of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[C:23]#[N:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[CH:20]=[N:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: N#Cc1[nH]cnc1N
Product: Cc1ccc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)cc1
Yield: 44 %

Procedure:
Reaction of 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 4-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (133 mg, 44%). MS (ISP) 303.1 [(M+H)+]; mp 197° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH:7]([C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15])[CH3:8].N1C=CC=CC=1>C1COCC1>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]([NH:16][C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])=[CH:10][C:9]=1[CH:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH3:8]
Reactant: CCC(=O)Cl
Reactant: CC(N)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)NC(C)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reaction time: 28 h
Yield: 90.4 %

Procedure:
Propionyl chloride (21 mg, 0.22 mmol, 1.3 eq.) in THF (1 ml) was added to a solution of N-[3-(1-aminoethyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 0.17 mmol) and pyridine (18 mg, 0.22 mmol, 1.3 eq.) in THF (3 ml). After 28 h at room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/ethyl acetate) to give N-{4-chloro-3-[1-(propionylamino)ethyl]phenyl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[OH:8]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(4-chloro-2-fluoro-5-hydroxyphenyl)6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (2.5 g) was added to an ice cooled con. nitric acid (50 ml). After stirring for 1 hr, the reaction mixture was poured into ice-cold water. The yellow crystals were collected by filtration to afford the title compound (0.9 g). The filtrate was extracted by ethyl acetate (200 ml) and washed with brine. The organic phase was dried over anhydrous sodium sulfate. After removal of the solvent, 0.6 g of title compound was obtained as yellow crystal.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][C@@H:4]4[C@:17]3([CH:20]=[O:21])[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:22]
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O
Reaction time: 0.25 h

Procedure:
To a solution of 3β,19-dihydroxy-5α-androstan-17-one in acetone chilled to 10° C. is added exactly two equivalents of Jones reagent. After standing for 15 minutes the upper acetone layer is poured into water with vigorous stirring. The solid which forms is filtered, air dried and crystallized from hexane to yield 5α-androstane-3,17,19-trione.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([C:18]([N:20]([CH3:22])[CH3:21])=O)[C:13](=O)[NH:14]2)=[CH:9][CH:8]=1.Cl>O>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][N:20]([CH3:22])[CH3:21])[CH2:13][NH:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)C1Cc2ccc(Cl)cc2NC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(Cl)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
1M Borane/THF complex (80 ml) was added to a THF (180 ml) suspension of 7-chloro-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (5.055 g). The reaction mixture was heated under ref lux and left standing for cooling. The reaction mixture was ice-cooled, to which was added water (5 ml) and 6N hydrochloric acid (50 ml). The mixture was stirred at room temperature for one hour, then concentrated. A methanol solution (100 ml) of the residue was heated under reflux for 75 minutes and then concentrated. 3N Aqueous sodium hydroxide solution was added to the residue to make basic, which was extracted with ethyl acetate. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4). The obtained crude crystals were washed with hexane to give the entitled compound (3.991 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][N:20]1[C:24]([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)=[CH:23][CH:22]=[N:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:24]4[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=4)[O:29][N:28]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1nccc1-c1cc(C(=O)O)no1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccnn2C)on1
Yield: 28.2 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.69 mmol) and 5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxylic acid (173 mg, 0.898 mmol). The product was purified by triturated using acetonitrile and methanol. Yield 28.2%. 1H-NMR (400 MHz; DMSO): δ 1.19 (d, 3H), 4.06 (s, 3H), 4.35 (d, 2H), 4.43-4.57 (m, 1H), 6.91 (d, 1H), 6.96 (d, 1H), 7.20 (s, 1H), 7.59 (d, 1H), 7.85 (d, 1H), 7.93 (dd, 1H), 7.97 (d, 1H), 8.09 (d, 1H), 8.94 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=O)[C:3]=1[N+]([O-])=O.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(N)c([N+](=O)[O-])c(=O)[nH]1
Product: CC(C)c1cc(N)cc(Cl)n1

Procedure:
A mixture of 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one (555 mg, 2.81 mmol) in POCl3 (10 mL) is stirred at reflux under N2 for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath, and crushed ice (˜20 g) is added to the residue. The mixture is swirled vigorously for several minutes and then stirred at room temperature for 30 min. The mixture is then extracted with EtOAc. The extract is washed with an additional 20 mL of H2O. The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4 and concentrated, yielding 2-chloro-6-isopropyl-pyridin-4-ylamine as an orange oil. This material is used without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 7.27 (br s, 2H), 6.65 (s, 1H), 2.77 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[C:5]([C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:26]=3)=[CH:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C.[C:44](Cl)(=[O:46])[CH3:45].C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:44]([O:1][C:2]1[C:3]2[C:4]3[C:5]([C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:26]=3)=[CH:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:46])[CH3:45]
Reactant: Cc1ccccc1-n1nc2c3c(O)cccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1c1nn(-c3ccccc3C)c(=O)c-1cn2Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
9-Hydroxy-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 724, 56 mg, 0.12 mmol) was dissolved in dichloromethane (2.5 mL), treated with N,N-dimethyl-4-aminopyridine (1.5 mg, 0.013 mmol, 0.1 equiv) and N,N-diisopropylethylamine (0.033 mL, 0.19 mmol, 1.5 equiv) and cooled to 0° C. To the mixture was added acetyl chloride (0.012 mL, 0.17 mmol, 1.4 equiv), and after 15 minutes the mixture was warmed to ambient temperature. After 15 minutes at ambient temperature, the mixture was poured into sodium bicarbonate (5 mL, aqueous saturated) and extracted with dichloromethane (2×15 mL). The combined organic extracts were washed with hydrochloric acid (2×15 mL, 1 N aqueous) and brine (1×10 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.47 (1H, s), 7.91 (1H, d, J=2.6 Hz), 7.73 (1H, d, J=1.7 Hz), 7.72 (2H, d, J=8.6 Hz), 7.47 (1H, t, J=8.2 Hz), 7.44-7.42 (1H, m), 7.34-7.26 (6H, m), 7.17 (1H, d, J=7.9 Hz), 6.47 (1H, dd, J=2.3, 1.9 Hz), 5.45 (2H, s), 2.33 (3H, s), 2.32 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 490.1900 [(M+H)+; calculated for C29H24N5O3: 490.1874].
Reaction SMILES: [NH2:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH2:54][C:55](O)=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH2:54][C:55]([NH:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)=[O:56]
Reactant: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)n3)cc2)cc1
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Prepared using General Procedure 6. To a suspension of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 (60 mg, 0.104 mmol) and 2-(2,5-dimethoxyphenyl)acetic acid (20.48 mg, 0.104 mmol) stirring in DMF (2 mL) were added HATU (43.7 mg, 0.115 mmol) and TEA (36.4 μL, 0.261 mmol). After stirring at room temperature for 2 h the reaction mixture was diluted with EA (25 mL) and washed with NaHCO3 (2×25 mL), 1 M HCl (2×25 mL) and brine (25 mL). The organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EA/hexanes) to afford 56 mg (71%) of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-65. LCMS-ESI (m/z) calculated for C45H44N4O7: 752; found 753 [M+H]+, tR=2.76 min (Method 10).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[N:7][N:6]=[C:5]2[CH2:15]O)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20](=[O:31])[CH:21](P(OCC)(OCC)=O)[CH3:22])[CH3:18].C1CCN2C(=NCCC2)CC1>C(#N)C.O=[Mn]=O>[CH2:17]([O:19][C:20](=[O:31])[C:21]([CH3:22])=[CH:15][C:5]1[N:4]([CH:1]2[CH2:2][CH2:3]2)[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[N:7][N:6]=1)[CH3:18]
Reactant: OCc1nnc(-c2ccncc2)n1C1CC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)=Cc1nnc(-c2ccncc2)n1C1CC1
Temperature: 80 °C

Procedure:
(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (6.8 g, 31.4 mmol) was mixed with MnO2 (40 g, 0.46 mol) in acetonitrile at r.t. for 2 hours and then heated at 80° C. for another 30 min. The reaction mixture was filtered through celite. The filtrate was mixed with 2-(diethoxy-phosphoryl)-propionic acid ethyl ester (12.35 g, 51.8 mmol) and DBU (7.17 g, 47 mmol) at 80 to 90° C. for 4 h. The reaction mixture was concentrated, dissolved in EA and washed with water and brine. The organic layer was dried, concentrated and triturated with hex. to give the title compound in 5.76 g (61%) yield. 1H-NMR: 8.78(d, 2H), 7.78 (d, 2H), 7.67 (s, 1H), 4.32 (q, 2H), 3.43 (m, 1H), 2.53 (s, 3H), 1.38 (t, 3H), 1.24 (m, 2H) and 0.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:16])([F:15])[F:14].Cl.C[O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:38][CH2:37][CH2:36][CH2:35][C:34]([OH:33])=[O:39])=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:14])([F:15])[F:16]
Reactant: CC(c1cc(C(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)CCCN
Agent: Cl
Product: CC(c1cc(C(=O)NCCCC(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 19, step 2, 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-benzoic acid (Example 19, step 1) was coupled with methyl-4-aminobutyrate hydrochloride. The product of this reaction was hydrolyzed in analogy to Example 2, to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=527.2 [M−H+].
Reaction SMILES: [Li+].[OH-].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][NH:29][C:28]=4[N:27]=3)=[CH:19][CH:18]=2)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:4]=1.Cl>C1COCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][NH:29][C:28]=4[N:27]=3)=[CH:19][CH:18]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: CCOC(=O)C[C@H](Cc1ccc(OCCc2ccc3c(n2)NCCC3)cc1)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](Cc1ccc(OCCc2ccc3c(n2)NCCC3)cc1)c1cccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
1.0 M LiOH (2.6 mL, 2.6 mmole) was added to a solution of ethyl (S)-3-(pyridin-3-yl)-4-[4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl]butanoate (572 mg, 1.28 mmole) in THF/H2O (8 mL), and the mixture was heated at 50° C. After 18 hr, the reaction was cooled to RT and acidified to pH 6.0 with 10% HCl. The precipitated solid was collected by suction filtration, washed with H2O, and dried in vacuo to afford the title compound (414 mg, 77%): 1H NMR (400 MHz, MeOH-d4) δ 8.28 (dd, J=4.9, 1.4 Hz, 1 H), 8.21 (d, J=1.8 Hz, 1 H). 7.68 (d, J=8.0 Hz, 1 H), 7.25-7.27 (m, 2 H), 6.91 (d, I=8.6 Hz, 2 H), 6.71 (d, J=8.6 Hz, 2 H), 6.53 (d, J=7.3 Hz, 1 H), 4.08-4.22 (m, 2 H), 3.30-3.45 (m, 3 H), 2.90-3.05 (m, 3 H), 2.70-2.85 (m, 3 H), 2.68 (dd, J=15.2, 6.7 Hz, 1 H), 2.58 (dd, J=15.2, 8.5 Hz, 1 H), 1.80-1.97 (m, 2 H); MS (ES) m/e 418 (M+H)+. Anal. Calcd for C23H25N3O3.0.25H2O: C, 71.15; H, 6.57; N, 9.96. Found: C, 71.11; H, 6.66; N, 9.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>O1CCOCC1.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: COc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
0.73 g of 2-methoxyphenylboronic acid and then 1.66 g of potassium carbonate are successively added to a solution of 0.78 g of 4-bromoindole in 15 ml of dioxane and 5 ml of water under argon. The reaction mixture is stirred at ambient temperature for 15 minutes, and then 0.16 g of dichlorobis(tri-o-tolylphosphine)palladium(II) is added. The reaction mixture is stirred at ambient temperature for 16 hours, and then at 60° C. for 18 hours, and, finally, at 110° C. for 3 hours. After returning to ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 15 ml of a 2N sodium hydroxide solution and 30 ml of ethyl acetate. The mixture is filtered through Clarcel®, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×30 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 30 g cartridge of 15-40 μm silica, elution being carried out with a 60/40 v/v cyclohexane/dichloromethane mixture, at a flow rate of 30 ml/min. 0.44 g of 4-(2-methoxyphenyl)indole is thus obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2=[N:17][CH:18]=[C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)[N:20]=[C:15]2[CH:14]=1.O1CCOCC1.Cl>CCOC(C)=O>[NH:21]([C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:16]2=[N:17][CH:18]=1)[NH2:22]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(NNC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(-c1cc3nc(NN)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a round bottom flask were added tert-butyl 2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.272 g, 0.505 mmol) and 1,4-dioxane (5 mL). To the mixture was added HCl (4 N in 1,4-dioxane, 1.26 ml, 5.05 mmol) and the reaction mixture was heated to about 60° C. for about 1 h. The reaction mixture was cooled to room temperature and was diluted with EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 2-hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.19 g, 84%): LC/MS (Table 1, Method d) Rt=1.55 min; MS m/z: 439 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH:20]=O>C(O)C.[Pd]>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:5]=1
Reactant: COC(C=O)OC
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(NCC(OC)OC)cc1N1CCN(C)CC1
Yield: 93.3 %

Procedure:
A suspension of 4-methoxy-3-(4-methyl-1-piperazinyl) benzenamine (5 g, 0.023 mol) in ethanol (150 ml) and dimethoxyethanal (9.5 g, 1.2 eq) was hydrogenated over 10% Palladium on charcoal (3 g) at standard temperature and pressure for 3 h. The suspension was filtered through kieselguhr, washed with methanol and evaporated to give a pale yellow oil. Purification by Fcc, eluting with 2% methanol/dichloromethane afforded the title compound (6.64 g, 95%).