Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C:9]([OH:11])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:39][C@@H:40]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][C@H:41]1[OH:50].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[C:3]1([C@@H:2]([CH3:1])[C:9]([NH:39][C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@H:41]2[OH:50])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](C(=O)N[C@@H]1Cc2ccccc2C[C@H]1O)c1ccccc1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
Under argon to a solution of R-(-)-2-phenylpropionic acid (505 mg) in methylene chloride (10 ml) at 0° C. was added hydroxybenzotriazole, hydrate (530 mg) and dicyclohexylcarbodiimide (718 mg). The mixture was stirred at 0° C. for 10 minutes before addition of racemic trans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (723 mg) and N-methylmorpholin (438 mg) in methylene chloride (5 ml). Stirring was maintained at 0° C. for 3 hours and at room temperature overnight. The reaction mixture was diluted with ethyl acetate and filtered. Evaporation of solvent gave the crude mixture of diastereoisomer A and diastereoisomer B. The diastereoisomer separation was achieved by chromatography on silica gel [160 g, elution with ethyl acetate: cyclohexane, 1:9 (700 ml), 2:8 (1 1), 3:7 (1 1) 2:3 (1 1) and 1:1 (1 1)]. Diastereoisomer A obtained as a white solid (232 mg) was recrystallized in ethyl acetate/cyclohexane, m.p. 158° C., Rf=0.30 (silica gel, ethyl acetate:cyclohexane, 1:1). Diastereoisomer B was recovered as a white solid (250 mg) and recrystallized in ethyl acetate, m.p. 179-180° C., Rf=0.40 (silica gel, ethyl acetate:cyclohexane, 1:1).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]Br)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:19]([NH2:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22].C([O-])(=O)C.[Na+]>O>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]([NH2:28])=[O:27])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(N2CCN(CCBr)CC2)cc1
Reactant: NC(=O)c1ccccc1N
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccccc1NCCN1CCN(c2ccc(O)cc2)CC1
Yield: 40 %

Procedure:
A mixture of 61 g 1-(p-hydroxyphenyl)-4-(2-bromoethyl)piperazine dihydrobromide, 18.5 g anthranilamide, 33.5 g sodium acetate, and 250 ml water was refluxed 16 hours, cooled, filtered and the solid washed with water and isopropanol. The solid was suspended in water and made alkaline with Na2CO3. The solid was filtered, suspended in 75% ethanol and added dilute HCl until acidic. The solution was cooled and the solid filtered and recrystallized from 1200 ml water to give 18.5 g product, m.285.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7](=[O:12])(=[O:11])[N:8]([CH3:10])[CH3:9])=[C:5]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])[C:4]([CH3:19])=[N:3]1.[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([CH3:29])[N:22]=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH3:29])[N:22]=[C:21]([NH:20][C:17]([NH:16][S:13]([C:5]2[C:4]([CH3:19])=[N:3][N:2]([CH3:1])[C:6]=2[S:7](=[O:11])(=[O:12])[N:8]([CH3:10])[CH3:9])(=[O:15])=[O:14])=[O:18])[N:26]=1
Reactant: Cc1nn(C)c(S(=O)(=O)N(C)C)c1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(N)n1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2c(C)nn(C)c2S(=O)(=O)N(C)C)n1

Procedure:
From the compound as prepared above, following the procedures of Examples 1 and 2, there was synthesized 1,3-dimethyl-5-dimethylsulfamoylpyrazole-4-sulfonyl isocyanate, which was in turn allowed to react with 2-amino-4-methoxy-6-methylpyrimidine to obtain the title compound. m.p. 215°-217° C.,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([S:16]([Cl:19])(=[O:18])=[O:17])[S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[C:13]([S:16]([Cl:19])(=[O:18])=[O:17])[S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)c2csc(S(=O)(=O)Cl)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccc(CBr)cc2)cs1

Procedure:
A solution of 18.0 g (0.053M) of 4-(4-methylphenylsulfonyl)-thiophene-2-sulfonyl chloride, 46.0 g (0.258 m) N-bromosuccinimide and 100 mg benzoyl peroxide in 175 ml CHCl3 was heated at reflux and irradiated with a sun lamp for 45 minutes. The cooled mixture was then extracted with 3×100 ml portions of water, 5% sodium thiosulfate, brine and dried. The solvent was stripped to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]1[CH2:33][O:32][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:29]([CH2:28][CH2:27][CH2:26][CH2:33][OH:32])(=[O:31])=[O:30])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S1(=O)CCCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCO)CC2)nc1N
Temperature: 150 °C
Yield: 85.9 %

Procedure:
The mixture of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (100 mg, 0.290 mmol, Example 59), 1,4-butane sultone (81 uL, 0.870 mmol, Aldrich) and triethylamine (41 uL, 0.290 mmol) in tetrahydrofuran (3 mL) was heated at 150° C. for 1 hour using the Smith Creator microwave synthesizer. Upon cooling to room temperature, the reaction mixture was concentrated. Purification of the crude residue by reverse phase HPLC (C18, eluting with water and acetonitrile) gave [4-amino-2-[1-(4-hydroxy-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as white solids (120 mg, 86%). HR-MS (ES, m/z) calculated for C21H29N5O5SF [(M+H)+] 482.Example 221, observed 482.1874.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22].Br[C:33]1[C:34]([NH2:39])=[N:35][CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.[Cu]I>[CH3:22][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:33]2[C:34]([NH2:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CC(C)c1ccc(CO)cc1
Reactant: Nc1ncccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(COc2cccnc2N)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A mixture of cesium carbonate (2.82 g), 1,10-phenanthrolin (0.208 g), (4-isopropylphenyl)methanol (8.68 g), 3-bromopyridin-2-amine (1 g) and copper (I) iodide (0.110 g) in toluene (10 mL) was stirred under a nitrogen atmosphere at 110° C. overnight, and at 130° C. for 5 hr. The reaction mixture was added to saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.92 g) as a pale-yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2]>CO.[Pd]>[NH2:10][C:8]1[C:7]([CH3:13])=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CNC(=O)c1ccc(-c2cc(C)c([N+](=O)[O-])cc2C(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc(-c2cc(C)c(N)cc2C(C)C)cc1
Reaction time: 8 h

Procedure:
2′-isopropyl-N,5′-dimethyl-4′-nitrobiphenyl-4-carboxamide is dissolved in methanol (20 mL). To this solution is added Pd/C (10%). The reaction mixture is degassed and purged with H2 for several times and then stirred under H2 (1 atm.) overnight. The mixture is filtered and concentrated to afford the title compound 4′-amino-2′-isopropyl-N,5′-dimethylbiphenyl-4-carboxamide as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 7.87 (d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.31 (s, 1H), 7.14 (s, 1H), 3.00 (m, 1H), 2.95 (d, 3H), 2.36 (s, 3H), 1.15 (d, 6H, J=6.8 Hz); ESMS m/z 283.2 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](#[N:31])[CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N12CCCN=C1CCCCC2.C(#N)C>>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][C:23]#[N:31])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CCCCCC=CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Yield: 89.89 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (prepared substantially as described in Example 65 of U.S. Pat. App. Pub. No. 2007/0135461 or International App. No. PCT/US2006/047369 (published as WO 2007/070514); 12 g, 0.038 mol), oct-2-enenitrile (6.0 g, 0.049 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 mL, 0.030 mol) in acetonitrile (120 mL, 2.3 mol) was stirred at room temperature overnight. After being concentrated in vacuo, the resultant residue was purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (15 g, 89.89%). The enantiomers (first peak retention time 11.02 min, second peak retention time 14.10 min) were separated on a ChiralCel OD-H column (30×250 mm, 5 μM), eluting with mobile phase of 15% ethanol and 85% hexane at 25 mL/min. MS calculated for C23H35N6OSi(M+H)+: m/z=439.264. Found: 439.4. 1H NMR (300 MHz, CDCl3) δ 8.91 (1H, s), 8.38 (1H, s), 8.37 (1H, s), 7.46 (1H, d, J=3.8 Hz), 6.86 (1H, d, J=3.8 Hz), 5.73 (2H, s), 4.59 (1H, m), 3.60 (2H, t, J=8.3 Hz), 3.06 (2H, td, J=16.8 and 7.5 Hz), 2.21 (1H, m), 2.01 (1H, m), 1.40-1.21 (6H, m), 0.98 (2H, t, J=8.3 Hz), 0.91 (3H, t, J=6.3 Hz), 0.00 (9H, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9](=S)[NH:10][C:4]=2[CH:3]=1.[CH3:23][O:24][CH2:25][C:26]([NH:28][NH2:29])=O>C(O)CCC>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9]3[N:10]([C:26]([CH2:25][O:24][CH3:23])=[N:28][N:29]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)NC(=S)CN=C2c1ccc(C(C)C)cc1
Reactant: COCC(=O)NN
Solvent: CCCCO
Product: COCc1nnc2n1-c1cc(C)ccc1C(c1ccc(C(C)C)cc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-8-methyl-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 9-methyl-1-(methoxymethyl)-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.063 g, 0.19 mmol) and 4-butyl-piperidine (0.053 g, 0.38 mmol) in MeCN (12 mL) were reacted according to GP10 shaking at 50° C. for 1 day and at 70° C. for 2 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50) to give the title compound (108LM22-20) (0.051 g, 79%). 1H NMR (CDCl3) δ 7.18-7.15 (m, 1H), 7.02-6.96 (m, 3H), 4.60 (ABq, J=15.0 Hz, J=31.3 Hz, CH2), 3.99 (dd, J=8.1 Hz, 13.8 Hz, 1H), 3.92 (dd, J=5.0 Hz, 13.8 Hz, 1H), 2.88 (bd, J=10.0 Hz, 1H), 2.72 (bd, J=10.0 Hz, 1H), 2.26-2.02 (m, 3H), 2.00-1.92 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.59 (m, 2H), 1.32-1.14 (m, 9H), 0.92-0.85 (m, 6H); HPLC-MS (ammonium acetate) [M+H]+=345.3.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 121.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.98 min, m/z=459.1 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.38 (m, 2H) 1.52-1.61 (m, 1H) 1.76-1.87 (m, 1H) 2.58 (dd, J=12.23, 9.05 Hz, 1H) 2.68-2.78 (m, 1H) 3.34-3.41 (m, 1H) 3.41-3.51 (m, 1H) 3.54-3.62 (m, 1H) 4.72 (d, J=3.67 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.51 (dd, J=7.95, 4.77 Hz, 1H) 7.83-7.89 (m, 2H) 7.99-8.04 (m, 1H) 8.10 (d, J=2.20 Hz, 1H) 8.58 (d, J=4.65 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 8.79-8.83 (m, 1H) 10.29 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reaction time: 20 h

Procedure:
2-(4-Benzyloxybenzyl)-2-phenoxybutyric acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH2:31]O)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.[N+:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Se:46]C#N)([O-:39])=[O:38].C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:36][C:33]([CH3:34])([CH3:35])[CH:29]([NH:28][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)[N:4]=1)[CH2:30][CH2:31][Se:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[N+:37]([O-:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CCO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC[Se]c4ccccc4[N+](=O)[O-])C(C)(C)C)n3)c3cc(F)cnc32)cc1
Reaction time: 8 h

Procedure:
To a solution of racemic 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentan-1-ol, 82a, (1.093 g, 2.120 mmol) and (2-nitrophenyl) selenocyanate (0.722 g, 3.180 mmol) in THF (8 mL) was added tributylphosphane (0.792 mL, 3.180 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The crude residue was purified by silica gel (0 to 100% EtOAc/Hexanes gradient) to afford 1.20 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[C:17]([OH:19])=O.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][CH2:6][C:5]3[CH:20]=[CH:21][CH:22]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:11]2=[O:13])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: COc1cccc(COc2cccc(C(=O)O)c2C(=O)O)c1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(COc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Yield: 12.2 %

Procedure:
A mixture of 3-(3-methoxy-benzyloxy)-phthalic acid (1.5 g, 5.2 mmol), alpha-amino-glutarimide hydrochloride (0.89 g, 5.4 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(3-methoxy-benzyloxy)-isoindole-1,3-dione as a white solid (0.25 g, 12% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.41 min (99.1%); mp, 197-201° C.: 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.59-2.62 (m, 2H, CH2), 2.83-2.90 (m, 1H, CHH), 3.77 (s, 3H, CH3), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.35 (s, 2H, CH2), 6.89-7.85 (m, 7H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.95, 30.92, 48.75, 55.01, 69.80, 112.72, 113.27, 115.55, 116.66, 119.17, 120.21, 129.61, 133.25, 136.98, 137.74, 155.42, 159.35, 165.32, 166.77, 169.90, 172.74. Anal Calcd For C21H18N2O6+0.1H2O: C, 63.67; H, 4.63; N, 7.07. Found: C, 63.49; H, 4.40; N, 7.00.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4].[NH:24]1[CH2:31][CH2:30]C[C@H:25]1[C:26](O)=[O:27].N1CCOCC1>CS(C)=O.O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:24]3[CH2:25][CH2:26][O:27][CH2:30][CH2:31]3)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Solvent: O
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
The mixture of 4,4-dimethyl-2-(3-bromo-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester as prepared according to Example 1 (374 mg, 1 mmol), CuI (60 mg, 0.3 mmol), L-proline (70 mg, 0.6 mmol) and morpholine (440 mg, 5 mmol) in DMSO (5 mL) was stirred at 120° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3) and washed with brine (100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-60% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (200 mg, 52.6%) as a white solid. MS (ESI+) [(M+H)+] 381.1.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+:16]>C(O)C>[NH2:16]/[C:1](/[CH2:2][CH2:3][CH3:4])=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCC/C(N)=C\C(=O)OCC
Temperature: 25 °C

Procedure:
Ethyl butyrylacetate (2.7 g, 17 mmol) in ethanol (7 mL) was treated with ammonium acetate (2.0, 26 mmol) and heated to reflux in a seated tube for 16 hours, cooled to ambient temperature and concentrated. The residue was purified by chromatography eluting with 2% methanol in ammonia saturated dichloromethane to provide the title compound.
Reaction SMILES: [CH:1]1([C@H:7]([NH:28]C(=O)OC(C)(C)C)[C:8](=[O:27])[N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C@H:10]2[C:18](=[O:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([NH:19][C:18]([C@H:10]2[N:9]([C:8](=[O:27])[C@@H:7]([NH2:28])[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
For Intermediate 3: In a 100 mL round-bottomed flask, tert-butyl (S)-(1S)-1-cyclohexyl-2-oxo-2-(2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethylcarbamate (130 mg, 272 μmol, Eq: 1.00) was combined with DCM (2.6 mL) to give a colorless solution. TFA (2.6 mL, 33.7 mmol, Eq: 124) was added and the reaction was stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (20 mL), washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give (S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a colorless oil (80 mg), m/z=379 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=O)[CH:28]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:35](=[O:37])[CH2:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(O)CCc1cccnc1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCc2cccnc2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and 3-pyridinepropionic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(3-pyridin-3-yl-propionyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[C:29]([F:39])=[CH:30][C:31]([F:38])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1>>[F:38][C:31]1[CH:30]=[C:29]([F:39])[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)=[CH:33][C:32]=1[S:34]([NH2:37])(=[O:36])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cc(S(N)(=O)=O)c(F)cc3F)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.9) (0.40 g, 1.1 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (0.635 g, 2.3 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 27%). MS (ISP) 505.1 [(M+H)+]; mp 227° C.