Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:50][CH2:51]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: OCC(F)(F)F
Product: COCCN1CCN(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.4 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 241, step B) (102 mg, 0.37 mmol) and p-toluenesulfonicacid (185 mg, 0.98 mmol) were weighed into a 20 mL vial. 2 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (125 mg, 0.17 mmol, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.33 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=5.31 Hz, 1H), 8.07 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.70, 1.74 Hz, 1H), 7.66 (d, J=8.97 Hz, 1H), 7.45 (s, 1H), 7.33-7.45 (m, 2H), 7.25 (d, J=8.79 Hz, 1H), 7.15 (t, J=8.06 Hz, 2H), 6.89-6.95 (m, 1H), 6.74 (s, 1H), 6.53 (d, J=5.13 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.43 (t, J=5.77 Hz, 2H), 3.21 (s, 3H), 2.83 (t, J=4.40 Hz, 4H), 2.47-2.58 (m, 6H), 2.11 (s, 3H); MS (ESI): 735 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]([CH3:30])[NH2:29]>CO.O1CCCC1.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])/[C:4](=[N:29]/[N:28]([CH3:30])[CH3:27])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: CN(C)N
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)/C(=N/N(C)C)c1ccc(OCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (3.5 g), 1,1-dimethylhydrazine (2.28 mL) in methanol (40 mL), tetrahydrofuran (20 mL) and one drop of glacial acetic acid was refluxed for 48 hours and evaporated to dryness. The crude mixture was separated by HPLC (dichloromethane-ether, 49:1) and the more polar component was crystallized from dichloromethane-methanol to provide 0.9 g of (E)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid methyl ester as a colorless solid, mp 137°-138° C.
Reaction SMILES: C1(=O)N(CC(Cl)=O)C(=O)C2=CC=CC=C12.Br.Br.Cl[C:19]1[CH:20]=[CH:21][C:22](N2C(C)=NN=C2CN)=[C:23]([CH:32]=1)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.CN(C)C=O>[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])[C:23]1[CH:32]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Agent: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 195.9 %

Procedure:
To a solution of 2-phthalimidoacetyl chloride (1.5 g) in benzene (20 ml) and dimethylformamide (10 ml), 5-chloro-2-(3-aminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone dihydrobromide (2.3 g) is added under ice cooling and stirring, and the temperature within the flask is gradually returned to room temperature. The reaction mixture is allowed to stand at room temperature, neutralized with saturated aqueous sodium bicarbonate, and shaken with ethyl acetate. The precipitated crystals are filtered, washed with methanol and dried to give 5-chloro-2-[2-phthalimidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.68 g) as crystals melting at 251°-253° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].Cl.[NH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>C(Cl)Cl>[CH2:14]([O:13][C:11]([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:12])[CH:15]=[CH2:16]
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc([N+](=O)[O-])c1

Procedure:
Diisopropylethylamine (66 ml) and allyl chloroformate (22 ml) in 150 ml of methylene chloride were added at 0° C. to a solution of ethyl 3-amino-3-(3-nitrophenyl)-propionate hydrochloride from II.1b (47 g) in 350 ml of methylene chloride. After a reaction time of 30 min, HCl (1N, 100 ml) was added. The organic phase was separated off, washed with water, dried over MgSO4 and concentrated. A white solid was obtained (yield: 56.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:13]O)=[CH:5][CH:4]=1.ClC(Cl)(Cl)C(O)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][NH:13][C:10](=[O:18])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=NO)CCC2
Reactant: O=C(O)C(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(=O)NCCC2
Temperature: 80 °C
Yield: 22.3 %

Procedure:
Following a procedure of Tomita, et. al., J. Chem. Soc. C 1969, 183, 7-methoxytetralone oxime (45.0 g, 0.235 mol) was mixed with solid trichloroacetic acid (150 g), and the resulting suspension heated to ca. 80° C., at which time a violent exotherm ensued, yielding a black solid mixture. The residue was cooled, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the combined organic layers were concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 10.0 g (22%) of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one. An analytical sample was obtained by recrystallization from CH2Cl2 /hexanes to yield colorless crystals: mp. 99°-101° C. (lit. (see above) 100°-101° C.); 1H NMR (CDCl3) d7.35(brs, 1H), 7.30(d, J=3 Hz, 1H), 7.10(d, J=9 Hz, 1H), 6.95(dd, J=3, 9 Hz, 1H), 3.82(s, 3H), 3.10(q, J=6 Hz, 2H), 2.80(t, J=6 Hz, 2H), 1.98(m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([C:9](O)([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.O1CCOCC1>C(O)(=O)C.O>[Cl:8][C:6]1[N:7]=[C:2]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([N:26]3[CH2:25][CH2:24][CH:23]([N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)[CH2:28][CH2:27]3)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]=1[C:9]([CH3:11])=[CH2:10]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Cl
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3C(F)(F)F)CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: O
Product: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C(F)(F)F)c2)nc1Cl
Temperature: 100 °C
Reaction time: 135 h
Yield: 41.8 %

Procedure:
A mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (1.10 g), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)aniline (Preparation Example 436) (1.58 g), N,N-diisopropylethylamine (0.80 mL) and dioxane (31 mL) was stirred at 100° C. for 135 hours. After cooling, water was added, followed by extraction with ethyl acetate. Further, insoluble materials were separated by filtration, and the insoluble materials were dissolved in methanol and thereafter mixed with the organic layer. The solvent was distilled off under reduced pressure, followed by drying to give a brown solid. A mixture of the brown solid and acetic acid (30 mL) was stirred at 120° C. for 5 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added, and the precipitated solid was collected by filtration and washed with water. The resulting solid was purified by basic silica gel column chromatography (eluent: chloroform) to give 5-chloro-6-isopropenyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide (0.99 g) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([CH2:7][C@@H:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)CN[C@H](CN1CCOCC1)C2

Procedure:
To a solution of 4.9 g of the compound of Step B (13.4 mmol) in 67 mL of ethanol there is added 0.980 g of palladium dihydroxide (20% by mass) at ambient temperature. The reaction mixture is placed under 1.2 bar of hydrogen at ambient temperature for 4 hours. It is subsequently passed over a Whatman filter, and then the palladium is rinsed several times with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[C:83]([NH2:86])(=[O:85])[CH3:84]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=2)=[O:24])=[CH:6][C:7]=1[C:8]1[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:86][C:83](=[O:85])[CH3:84])[CH:12]=2
Reactant: CC(N)=O
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2Cl)cc2cnc(NC(C)=O)cc21
Temperature: 100 °C
Yield: 4.8 %

Procedure:
A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea (178 mg, 0.351 mmol), Xantphos (20.30 mg, 0.035 mmol), Cs2CO3 (229 mg, 0.702 mmol) and acetamide (104 mg, 1.754 mmol) in dioxane (3.5 mL) was sparged with Ar for 10 min, treated with Pd2(dba)3 (16.07 mg, 0.018 mmol) and heated at 100° C. overnight. The mixture was cooled to RT, treated with THF, the solids removed via filtration through diatomaceous earth and rinsed well with THF. The filtrate was washed with brine (3×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was suspended in 4:1 MeCN/H2O, frozen and lyophilized; the resulting solid was triturated with MTBE, collected via filtration and dried to afford N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (9 mg, 4.8% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.48 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J=10.9 Hz, 1H), 7.17 (m, 2H), 6.84-6.83 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 530.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:15][C:16]1[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=1[O:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O.C(OCC)(=O)C>CN(C)C=O.C(N(CC)C(C)C)(C)C>[C:1]([O:5][C:6]1[N:7]=[C:8]([CH2:12][CH2:13][N:23]2[CH2:24][CH2:25][C:20]([CH2:19][O:18][C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[F:15])([OH:26])[CH2:21][CH2:22]2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1(COc2ccccc2F)CCNCC1
Reactant: C=Cc1cccc(OC(C)(C)C)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Oc1cccc(CCN2CCC(O)(COc3ccccc3F)CC2)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 2 %

Procedure:
After dissolving 400 mg of 2-tert-butoxy-6-vinylpyridine and 601 mg of 4-(2-fluorophenoxymethyl)-4-hydroxypiperidine hydrochloride in 5 ml of N,N-dimethylformamide, 0.44 ml of N,N-diisopropylethylamine was added and the mixture was stirred for 24 hours at 100° C. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (18 mg, 2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH3:30])[CH:29]=1)[NH:26][N:25]=[CH:24]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([CH3:30])[CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: Cc1cc(N)cc2cn[nH]c12
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2cc(C)c3[nH]ncc3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
The product of Example 3 Step 2 (180 mg, 0.635 mmol, 1.00 equiv), 5-amino-7-methylindazole (94 mg, 0.635 mmol, 1.0 equiv), and EDC (145 mg, 0.761 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.106 mL, 0.761 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was triturated with EtOAc and CH2Cl2, filtered, and washed with CH2Cl2 to provide 69 mg (26%) of the title compound as an off white solid. MS (ES+) m/e 413 [M+H]+
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N:12]=[C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)[C:16](=[O:27])[C:15](=[C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[S:29]2)[S:14]1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N:12]=[C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[C:16](=[O:27])[C:15](=[C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[S:29]2)[S:14]1)[CH3:2]
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1cccc(O)c1
Temperature: -78 °C
Yield: 26.5 %

Procedure:
To a N2-purged flask was added the product of Example 114 (60 mg, 0.11 mmol) and anhydrous DCM (5 mL). The solution was cooled to −78° C. prior to the addition of a 1.0M solution of BBr3 in DCM (0.50 mL). The solution was allowed to warm to ambient temperature with stirring. After 7 h the solution was quenched by addition of MeOH (10 mL) and then concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to provide the title compound (15 mg, 26%). 1H-NMR (CDCl3): δ 7.40 (1H, d), 7.35 (1H, t), 7.29 (1H, dd), 7.13–7.25 (3H, m), 6.95–7.01 (3H, m), 6.76 (1H, dd), 6.49 (1H, d), 5.08 (2H, s), 3.56 (3H, s), 3.02 (2H, q), 1.05 (3H, t); MS(ESI): 514(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([CH2:10][N+:11]([O-:13])=[O:12])[C:15]([CH3:17])([CH3:16])[CH:14]=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Reactant: CC(C)C=O
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@H](C[N+](=O)[O-])C(C)(C)C=O)cc1

Procedure:
The title compound was prepared from trans-1-methoxy-4-(2-nitrovinyl) benzene and isobutyraldehyde according to general method. The enantiomeric excess was determined by HPLC with Chiralpak AS-H column at 210 nm (2-propanol:hexane=20:80), 1 ml/min; tmajor=12.7 min, tminor=15.8 min, [α]D20=+9.1 (c=1.2, CHCl3);
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]([CH:40]=[O:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]([C@H:40]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=3)[OH:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reaction time: 1 h

Procedure:
1.23 ml of a 2.5 M solution of n-butyllithium in toluene are added dropwise to a solution of 695 mg 2-bromo-5-trifluoromethylpyridine in 10 ml toluene at −80° C. The mixture is stirred for 1 hour and then a solution of 600 mg (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 1 ml toluene is added dropwise. After stirring the mixture for 1 hour at −80° C. the reaction is quenched by addition of a saturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted for three times with ethylacetate. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (pentane/diethylether 100:0 to 70:30).
Reaction SMILES: C1CN([P+](ON2N=[N:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:34]([O:41][CH2:42][C@H:43]([C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])[CH:52]=2)[NH:47][C:46]=1[C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=1)[CH3:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.C12NC(CC1)CC2.C(N(CC)CC)C.O.[Cl-].[Na+].O>ClCCl>[CH:20]12[N:25]([C:55](=[O:56])[C:54]([C:51]3[CH:52]=[C:53]4[C:45]([C@H:43]([CH3:44])[CH2:42][O:41][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:46]([C:60]5[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=5)[NH:47][C:48]4=[N:49][CH:50]=3)([CH3:59])[CH3:58])[CH:23]([CH2:24][CH2:19]1)[CH2:22][CH2:21]2
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Agent: C1CC2CCC1N2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)COCc2ccccc2)c1
Reaction time: 12 h
Yield: 94.4 %

Procedure:
PyBOP (1.51 g, 2.89 mmol) was added to a stirred mixture of the crude (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoic acid (1.20 g, 2.63 mmol), 7-azabicyclo[2.2.1]heptane hydrochloride (0.70 g, 5.26 mmol) and triethylamine (1.47 mL, 10.5 mmol) in dichloromethane (26 mL) at ambient temperature. After approximately 12 h, the reaction mixture was poured into water/brine (1:1) and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient eluton; 60-75% ethyl acetate/hexanes as eluent) to give the title compound as a colourless foam (1.33 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[N:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](=[O:38])[NH:30][CH:31]([C:35](F)=[O:36])[CH:32]([CH3:34])[CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH:10][C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:38])[CH:32]([CH3:34])[CH3:33])=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)F
Reactant: COC(=O)c1cnccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cnccc1NC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Formula 506 where R1, R3 and R4 are H; R6 is Isopropyl; R6′ is H: W, Y and Z are —C═; and X is —N═: To a solution of dichloromethane (100 mL), 4-amino-nicotinic acid methyl ester (4.60 g, 30.2 mmol) and diisopropylethyl amine (8.25 mL, 46.7 mmol), was added (1-fluorocarbonyl-2-methyl-propyl)-carbamic acid benzyl ester (11.8 g, 46.7 mmol) at room temperature and the mixture stirred overnight. The solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography using hexane-EtOAc (stepwise gradient from 3:1 to 1:1) as eluents to obtain the desired amide of Formula 506, 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid methyl ester (10.5 g, 90.1%). MS (Cl) M/E: 386.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].CCCCCC.[H-].[Na+].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22]>C1COCC1.C(O)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:19]([O:20][CH2:21][CH3:22])=[O:23])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 47.9 %

Procedure:
A solution of 4-fluoroacetophenone (100 g, 7.239 mol) in dry THF (100 ml) was added dropwise over 2.5 hours to a refluxing slurry of hexane-washed NaH (68.3 g, 60% oil dispersion, 1.708 mol) and diethyl carbonate (176.0 ml, 1.453 mol) in dry THF (300 ml). This solution was refluxed an additional 0.5 hours, cooled (0° C.), and a solution of ethanol (50 ml) in dry THF (150 ml) was added to quench the excess NaH. 300 ml of water and 100 ml of acetic acid were added, and this mixture was extracted with ethyl acetate (3×300 ml). The combined organics were washed with saturated NaHCO3 (1×500 ml), washed with brine (2×500 ml), dried (MgSO4), concentrated under reduced pressure, and distilled at 10 mm to yield 146.3 g of the title compound.