Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][C:39]([O:52][CH3:53])=[C:40]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:41]=3)[N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[CH:69]=[C:68]([C:70](O)=[O:71])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][C:39]([O:52][CH3:53])=[C:40]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:68]5[O:67][N:66]=[C:65]([CH3:64])[CH:69]=5)=[O:71])[CH2:50][CH2:51]4)[CH:41]=3)[N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2nc(Nc3cccc(Cl)c3F)ncc2cc1OC1CCNCC1
Reactant: Cc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nc(Nc3cccc(Cl)c3F)ncc2cc1OC1CCN(C(=O)c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolinamine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-5-isoxazolecarboxylic acid (0.126 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)carbonyl]piperidin-4-yl}oxy)quinazolinamine as a white solid (0.145 g). 1H NMR Spectrum: (DMSO d6 373K) 1.89 (m, 2H), 2.10 (m, 2H), 2.35 (s, 3H), 3.64 (m, 2H), 3.88 (m, 2H), 3.99 (s, 3H), 4.82 (m, 1H), 6.73 (s, 1M), 7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.93 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Br)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2ccccc2Br)cc1C
Product: Cc1cc(Oc2ccccc2Oc2ccc(Cl)cc2Oc2ccccc2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(2-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.039 g (8%). 1H NMR (400 MHz, CDCl3); MS (ES−) m/z mass calculated for C28H23O5Cl 474, found 473 and 475 (M−1, and M+1).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@:13]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH3:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C(F)(F)F>[CH3:16][C@:13]1([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:11]2[C@@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1
Reactant: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [H][H]
Solvent: OCC(F)(F)F
Product: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CNC[C@@H]21

Procedure:
N-[(3aR,4R,6aS)-2-benzyl-4-methyloctahydrocyclopenta[c]pyrrol-4-yl]benzamide from Example 2 (250 mg, 0.747 mmol) and trifluoroethanol (10 mL) were added to 20% Pd(OH)2—C, wet (50.0 mg, 0.356 mmol) in a 50 mL pressure bottle and stirred for 2 hours under 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give the title compound as a white solid: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.40 (s, 1H), 8.22-8.15 (m, 2H), 7.46-7.38 (m, 3H), 3.15 (dd, J=10.2, 1.3, 1H), 2.91-2.86 (m, 1H), 2.83-2.77 (m, 1H), 2.75-2.66 (m, 2H), 2.54 (qd, J=9.1, 2.0, 1H), 2.38 (dd, J=11.8, 4.4, 1H), 1.92-1.84 (m, 1H), 1.75 (s, 3H), 1.49-1.41 (m, 1H), 1.32 (ddt, J=13.0, 10.5, 6.6, 1H); MS (ESI+) m/z 245 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)([O-])=O.[CH3:25]O>[Pd]>[NH:15]1[CH2:14][CH2:13][CH:12]([N:11]2[C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[N:1]=[CH:25]2)[CH2:17][CH2:16]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c[n+]([O-])ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Product: c1cc2ncn(C3CCNCC3)c2cn1

Procedure:
To a solution of tert-butyl 4-[(4-nitro-1-oxidopyridin-3-yl)amino]piperidine-1-carboxylate (4 g) in methanol (100 ml) was added 10% palladium on carbon (50 mg) and the mixture was placed under a hydrogen atmosphere (60 psi) for 48 hours. The mixture was filtered through Celite and evaporated to dryness to give the title compound as a solid, which was used without further purification. Yield 3.21 g. MS 293 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](OCC)=[O:9])=[O:5].C1COCC1.[H-].[Na+]>O>[CH2:13]([C@H:7]1[C:8](=[O:9])[NH:1][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4](=[O:5])[NH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccnc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N[C@@H](Cc2ccccc2)C(=O)Nc2ncccc21
Reaction time: 8 h

Procedure:
(S)-Ethyl 2-(2-aminonicotinamido)-3-phenylpropanoate (5.7 g, 18.1 mmol) was dissolved into THF (125 mL) under argon. Sodium hydride (1.07 g, 60% dispersion in oil, 26.8 mmol) was added and the reaction was stirred overnight. Water (5 mL) was carefully added and the resulting white precipitate was collected. The precipitate was dissolved into ethyl acetate (200 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to a yellow solid (2.1 g, 44%): ESI MS m/z 268 [C15H13N3O2+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:24]([O:31][CH2:32][C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:24]([O:31][CH2:32][C:33]([O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=1[O:11][CH3:12])=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c(OC(=O)COCc2ccccc2)c(OC)c1OC
Reaction time: 2 h

Procedure:
6-Nitro-2,3,4-trimethoxyphenol (1.25 g) and triethylamine (1.12 mL) were dissolved in dichloromethane (20 mL), benzyloxyacetyl chloride (1.1 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 2 hours as it is. The reaction mixture was extracted with chloroform, and the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound. Yield: 1.38 g (66.5%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:29][C:30]1[S:34][C:33]([CH:35]=[CH:36][S:37](Cl)(=[O:39])=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[N:16]([S:37]([CH:36]=[CH:35][C:33]4[S:34][C:30]([Cl:29])=[CH:31][CH:32]=4)(=[O:39])=[O:38])[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1S(=O)(=O)C=Cc1ccc(Cl)s1
Reaction time: 8 h
Yield: 2.3 %

Procedure:
(3S,5R)-1-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (43 mg, 0.123 mmol), minor epimer from EXAMPLE 88, Part D, is taken up in methylene chloride to this is added triethylamine (0.034 ml, 0.25 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3. The reaction is stirred overnight, and the crude material is purified by preparative thin layer chromatography (15% methanol/CH2Cl2). The product (1.4 mg, 2.3%) is isolated as a yellow wax. C21H22ClN5O3S2 MS m/z: 492, 494. 1H NMR (CD3OD) δ8.36 (s, 1H); 8.03 (d, 1H, J=7.5 Hz); 7.61 (s, 1H); 7.49-7.44 (m, 2H); 7.19 (d, 1H, J=3.83 Hz); 6.98 (d, 1H, J=3.75 Hz); 6.76 (d, 1H, J=15.1 Hz); 4.86-4.71 (m, 2H); 4.45-4.39 (m, 1H); 4.13-4.09 (m, 1H); 3.64-3.7 (m, 2H); 1.63 (d, 3H, J=7.09 Hz); 1.33 (d, 3H, J=6.80 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:10][C:7]1[CH:8]=[N:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(O)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(OCc2ccccc2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a flame dried flask under N2 was placed 2-chloro-5-hydroxynicotinonitrile (2.0 g, 0.012 mol), DMF (60 mL), NaH (50% oil dispersion, 0.75 g, 0.013 mol) and the mixture cooled to 0°-4° C. A solution of benzyl bromide (1.5 mL, 0.013 mol) in DMF (2 mL) was then added and the solution allowed to stir at room temperature overnight. The mixture was poured into H2O and extracted with Et2O (3×). The organic layer was concentrated to yield 2.0 g (100%) of 5-benzyloxy-2-chloronicotinonitrile. An analytical sample of 5-benzyloxy-3-chloronicotinonitrile was prepared by trituration with C6H14, mp 114°-15° C.; 1H NMR (CDCl3) δ5.2 (2H, s) 7.4 (5H, s), 7.5 (1H, d, J=3) and 8.35 (1H, d, J=3); IR (nujol) 2220 cm-1 ; MS m/e M+ 244.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[N:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[NH:5][C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:26][C:27]1[N:28]([CH3:32])[N:29]=[CH:30][N:31]=1>CN(C=O)C>[CH3:32][N:28]1[C:27]([CH2:26][O:8][C:6]2[N:5]=[C:4]3[N:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:10]=[CH:11][C:3]3=[C:2]([NH2:1])[CH:7]=2)=[N:31][CH:30]=[N:29]1
Reactant: Cn1ncnc1CCl
Reactant: Nc1cc(=O)[nH]c2c1cnn2-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1cc(N)c2cnn(-c3ccccc3)c2n1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a solution of 4-amino-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.30 g, 1.33 mmol) in DMF (8 ml) under nitrogen was added cesium carbonate (0.95 g, 2.92 mmol) followed by 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.27 g, 1.61 mmol). The resulting suspension was heated at 60° C. for 17 h. The mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous phase extracted a second time with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (0.41 g, 96%), m.p. 164-166° C. δH (400 MHz; CDCl3) 3.91 (3H, s), 4.70 (2H, br s), 5.58 (2H, s), 5.89 (1H, s), 7.28-7.31 (1H, m), 7.48-7.52 (2H, m), 7.88 (1H, s), 7.98 (1H, s), 8.15-8.18 (2H, m); m/z (ES+) 322 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[NH:34][C:33]([CH:35]=O)=[CH:32][N:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]3[NH:34][C:30]([CH3:29])=[N:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(C=O)[nH]1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ncc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)[nH]1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-methyl-3H-imidazole-4-carbaldehyde. MS (ESI) m/z 473.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:13][CH2:14][N:15]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:16][CH2:17]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Yield: 94.4 %

Procedure:
Following the procedure in Example 1, step 6, 4-[3-(4-fluoro-phenoxy)-benzylidene]-piperidine hydrochloride (200 mg, 0.625 mmol, from Example 18, Step 3) and phenyl pyridin-3-ylcarbamate (147 mg, 0.688 mmol) were used to provide the title compound (238 mg). MS (APCI 10 V) AP+ 404.3, AP− 402.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.43 (td, J=5.79, 1.10 Hz, 2H) 2.52 (td, J=5.89, 1.01 Hz, 2H) 3.51-3.55 (m, 2H) 3.60-3.66 (m, 2H) 6.40 (s, 1H) 6.78-6.84 (m, 2H) 6.95-6.98 (m, J=7.67, 1.53, 0.75, 0.75 Hz, 1H) 6.98-7.04 (m, 2H) 7.05-7.15 (m, 2H) 7.30 (t, J=7.77 Hz, 1H) 7.34 (ddd, J=8.41, 4.84, 0.76 Hz, 1H) 7.91 (ddd, J=8.38, 2.60, 1.45 Hz, 1H) 8.16 (dd, J=4.85, 1.46 Hz, 1H) 8.58 (dd, J=2.62, 0.67 Hz, 1H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:26][CH:25]=2)=[CH:32][CH:33]=1
Reactant: NCc1ccc(COc2ccc(Cl)cc2)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCc2ccc(COc3ccc(Cl)cc3)cc2)c(Nc2ccncc2)c1=O
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 4-(4-chlorophenoxy-methyl)-benzylamine.
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([CH2:7][CH2:8][C:9]#[CH:10])[C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(#N)C>[Si:28]([O:1][C@H:2]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:3]([CH2:7][CH2:8][C:9]#[CH:10])[C:4]([OH:6])=[O:5])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCC[C@@H](C(=O)O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 4 h
Yield: 86.5 %

Procedure:
To a stirred solution of 32.0 g (147 mmol) of (2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoic acid from Step C above in 500 mL of anhydrous acetonitrile at ambient temperature under an atmosphere of nitrogen was added 77.0 mL (513 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene 22 mL followed by 66.3 g (440 mmol) of tert-butyldimethylsilyl chloride in three portions over 10 min. The reaction mixture was stirred for 4 h then evaporated in vacuo to remove all volatiles. The residue was diluted with 300 mL of dichloromethane and 100 mL of water. A 1.0 M aqueous hydrogen chloride solution was added to the mixture until a pH of 3 was achieved in the aqueous layer. The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organics were washed with water (50 mL), brine (50 mL) then dried over magnesium sulfate. After filtration and evaporation in vacuo the residue was dissolved in 350 mL of methanol and 350 mL (280 mmol) of a 0.8 M aqueous potassium carbonate solution was added. The resulting mixture was stirred for 1.5 h then evaporated in vacuo to remove all volatiles. The residue was diluted with 300 mL of dichloromethane and the aqueous phase was acidified with a 5.0 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organics were washed with water (50 mL), brine (50 mL) then dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 3-15% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (42.3 g, 86.6%). 1H NMR (500 MHz, CDCl3): δ 7.36-7.27 (m, 5H), 4.78 (d, J=8.7, 1H), 2.90-2.86 (m, 1H), 2.19-2.11 (m, 1H), 2.10-2.03 (m, 1H), 1.90 (t, J=2.6 Hz, 1H), 1.75-1.67 (m, 1H), 1.41-1.34 (m, 1H), 0.83 (s, 9H), 0.02 (s, 3H), −0.27 (s, 3H). LC-MS: m/z (ES) 333.2 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[C:31](Cl)=[O:32]>O1CCOCC1>[CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:31](=[O:32])[C:30]3[CH:29]=[C:28]([Cl:27])[CH:36]=[C:35]([Cl:37])[CH:34]=3)[CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cc1nc2cccnc2n(-c2cccc(N)c2)c1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 2-methyl-4-(3-aminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (7.4 g) and triethylamine (5.72 ml) in dioxane was added 3,5-dichlorobenzoyl chloride (6.14 g) in dropwise. The mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched by water and extracted with ethyl acetate (100 ml). The crude product was purified by chromatography to obtain 2-methyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][CH3:5].CC(C)([O-])C.[K+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][CH2:2][C@@H:3]([OH:6])[CH2:4][CH3:5]
Reactant: CC[C@H](O)CN
Reactant: Clc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC[C@H](O)CNc1ccccn1

Procedure:
(S)-1-Aminobutan-2-ol (35 millimoles), potassium tertiary butoxide (77 millimoles) and 2-chloropyridine (38.5 millimoles) were used in a similar manner to Example 1(a) to obtain the title compound, [α]D26=+10° (1.12% concentration in trichloromethane).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:41][C:40]([C:42]23[CH2:49][N:46]([CH2:47][CH2:48]2)[CH2:45][CH2:44][O:43]3)=[N:39][CH:38]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:46]12[CH2:49][C:42]([C:40]3[S:41][C:37]([C:9]4[N:8]([S:12]([C:15]5[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=5)(=[O:14])=[O:13])[C:5]5=[N:6][CH:7]=[C:2]([F:1])[C:3]([C:22]6[S:26][C:25]([C:27]7([OH:31])[CH2:28][CH2:29][CH2:30]7)=[N:24][CH:23]=6)=[C:4]5[CH:10]=4)=[CH:38][N:39]=3)([CH2:48][CH2:47]1)[O:43][CH2:44][CH2:45]2
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C23CCN(CCO2)C3)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnc(C45CCN(CCO4)C5)s3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (150 mg, 0.263 mmol), 5-(5-(tributylstannyl)thiazol-2-yl)-4-oxa-1-azabicyclo[3.2.1]octane (192 mg, 0.395 mmol), and bis(triphenylphosphine)palladium dichloride (0.013 g, 0.025 mmol) in N,N-dimethylformamide (1.8 mL) was heated to 70° C. for 2 hours. The reaction was quenched by the addition of an aqueous potassium fluoride solution (1.0 g in 2.5 mL water) and ethyl acetate (5 mL). The mixture was stirred vigorously overnight and was then filtered through diatomaceous earth, eluting with ethyl acetate. The layers were separated, and the organic layer was washed with aqueous saturated sodium bicarbonate and water. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 638.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH3:16])[CH:10]=2)[CH2:26][CH2:25]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
85 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propanal (58 mg, 0.268 mmol), 1-(2-fluorophenyl)piperazine (52 mg, 0.289 mmol), DIPEA (0.070 mL, 0.403 mmol) and NaBH(OAc)3 (171 mg, 0.805 mmol).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([O:34][CH3:35])[CH:31]=1)[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: COc1cc(CNC(=O)C(C)C(=O)O)cc(OC)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: COc1cc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc(OC)c1

Procedure:
The title compound, MS: m/e=488.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3,5-dimethoxy-benzyl)-malonamic acid.