Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[C:5]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:45][NH:46][CH2:47][CH2:48][OH:49]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([N:46]([CH2:47][CH2:48][OH:49])[CH3:45])=[O:18])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[C:5]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:4]=1)#[N:2]
Reactant: CNCCO
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-(4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-1-(3-(trifluoromethyl)-phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 19, 23 mg, 43 μmol) and triethylamine (18 μL, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) is stirred at room temperature for 5 min and treated with N,N,N′,N′-tetramethyl-0-(benzotriazol-1-yl)uronium tetrafluoroborate (13 mg, 43 μmol). After 5 min, 2-(methyl-amino)ethanol (10 μL, 0.13 mmol) is added. The mixture is stirred at room temperature for 3 h and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 15 mg; ESI mass spectrum [M+H]+=591; Retention time HPLC: 0.89 min (Z011_S03).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14](=[O:23])[NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH:10]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:9]1)=O)(C)(C)C>Cl>[ClH:34].[ClH:34].[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][NH:15][C:14]([CH:12]2[CH2:11][CH:10]([N:24]3[C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=4[C:27]4=[N:35][O:36][C:37]([CH3:38])=[C:26]4[C:25]3=[O:39])[CH2:9][NH:8][CH2:13]2)=[O:23])[CH:18]=1
Reactant: Cc1onc2c1c(=O)n(C1CC(C(=O)NCc3cccnc3)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: Cl
Product: Cc1onc2c1c(=O)n(C1CNCC(C(=O)NCc3cccnc3)C1)c1cccc(Cl)c21
Yield: 297.2 %

Procedure:
Stir a solution of 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-5-[(pyridin-3-ylmethyl)-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) in HCl-saturated HOAc (5 mL) 2 H at room temperature then concentrate to dryness. Dissolve 2× in toluene and concentrate to dryness to yield the title compound (26 mg, 100%) as a white oil as a mixture of cis isomers. MS(IS) 452.1 (M+); HPLC (5–95% (0.1% TFA/CH3CN) in (0.1% TFA/water) in 3.8 min on YMC ODS-A (0.46×50 mm) 5 μL/min; 25° C.) Rt=1.6 (min 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([NH:14][C:15](=[O:16])[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C=NC1CCCCC1
Reactant: CN(C)CCCO
Product: CN(C)CCCOC(=O)NC1CCCCC1

Procedure:
77.3 g of 3-dimethylamino-1-propanol are reacted with 94 g of cyclohexyl isocyanate in accordance with Example 13. Distillation of the reaction product yields 153.4 g (92.8%) of analytically pure product (analysis by gas chromatography) with a boiling point of 105° C./0.015 torr. IR spectrum: 3320 cm-1NH, 1700 cm-1C=O, no bands between 2000 and 2500 cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:37])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34](O)=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:37])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:56][S:53]([CH:50]5[CH2:52][CH2:51]5)(=[O:55])=[O:54])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCOC(=O)N4C3)nc(Cl)cc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCOC(=O)N4C3)nc(Cl)cc2c1
Temperature: 25 °C
Yield: 15.8 %

Procedure:
A solution of 16 (120 mg, 0.23 mmol) and carbonyldiimidazole (44 mg, 0.27 mmol) in dry THF (25 mL) was refluxed for 3 h under nitrogen. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (33 mg, 0.27 mmol) and DBU (52 mg, 0.34 mmol) were added. The reaction mixture was heated at 50° C. for 24 h, then cooled down at room temperature and partitioned between water and CH2Cl2. The organic layers were dried (MgSO4), filtered, and the solvent was evaporated. The crude material was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05) to give a solid which was successively triturated in water, filtered, dried, triturated in ether and dried again under high vacuum to give 23 mg (16%) of the title product 17 as a white powder: m/z=530 (M+H)+; 1H NMR (CDCl3): 8.10 (d, J=9.3 Hz, 1H), 7.50 (s, 1H); 7.39 (s, 1H); 7.25 (dd, J=9.3 Hz, 2.5 Hz, 1H); 7.39-7.30 (bs, 1H); 5.90-5.83 (bs, 1H); 5.71 (dd, J=8.0 Hz, 17.9 Hz, 1H); 5.18 (t, J=10.1 Hz, 1H), 4.79 (dd, J=7.3 Hz, 9.0 Hz, 1H), 4.1 (s, 3H), 4.09-3.97 (m, 1H), 3.81-3.66 (m, 2H), 3.62 (d, J=11.6 Hz, 1H), 3.19-3.05 (m, 1H); 2.59-2.22 (m, 4H); 2.01-1.90 (m, 1H), 1.89 (dd, J=5.8 Hz, 8.6 Hz, 1H), 1.70 (dd, J=6.1 Hz, 9.8 Hz, 1H), 1.67-1.58 (m, 2H), 1.75-0.76 (m, 7H).
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][OH:32])=[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(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-]>O1CCOCC1.O>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH2:31][OH:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CCO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(CCO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 100 °C

Procedure:
To a solution of racemic 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol, 82a, (0.187 g, 0.363 mmol) in dioxane (4 mL) was added LiOH (0.91 mL of 2 M solution, 1.81 mmol). The reaction mixture was heated at 100° C. for 2 hours. The mixture was diluted with water (30 mL) and extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was washed with Hexanes to afford 76 mg of the desired product: 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 1H), 8.47 (dd, J=9.3, 2.7 Hz, 1H), 8.13 (d, J=11.2 Hz, 1H), 8.10 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 4.89 (d, J=9.0 Hz, 1H), 4.26 (t, J=9.9 Hz, 1H), 3.65 (d, J=9.2 Hz, 1H), 3.54 (td, J=11.4, 2.9 Hz, 1H), 2.17-1.99 (m, 1H), 1.40 (dd, J=14.0, 11.9 Hz, 1H), 0.96 (d, J=18.4 Hz, 9H), 0.90-0.73 (m, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 362.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)[N:8]=[CH:7]2.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:36][S:37]([N:40]1[CH2:44][CH:43]=[CH:42][CH2:41]1)(=[O:39])=[O:38]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:36][S:37]([N:40]1[CH2:44][CH2:43][C:42]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[N:8]=[CH:7]3)=[CH:41]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)N1CC=CC1
Reactant: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1C=C(c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)CC1

Procedure:
To a shlenk tube was added trans-4-[(8-bromoquinazolin-2-yl)amino]cyclohexanol (322 mg, 1 mmol), followed by Pd(OAc)2 (48 mg, 0.2 mmol), (o-Tol)3P (60 mg, 0.2 mg), Ag2CO3 (192 mg, 0.7 mmol), toluene (8 mL) and iPr2NEt (516 mg, 4 mmol), followed by 1-(methylsulfonyl)-2,5-dihydro-1H-pyrrole (560 mg, 3.8 mmol). The mixture was refluxed overnight under Ar. TLC showed that several new spots were formed with small amount of starting material remaining. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (4×15 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by chromatography (eluting with DCM, then DCM/EA 3/1, then DCM/EA=2/1) to afford the title compound (88 mg, 23%) as an off white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.97 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.21 (dd, J=8.8, 7.2 Hz, 1H), 6.60-6.58 (m, 1H), 5.51-5.49 (m, 1H), 5.22-5.19 (m, 1H), 5.16-5.11 (m, 1H), 4.36 (t, J=10.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.58 (dd, J=10.8, 6.0 Hz, 1H), 2.85 (s, 3H), 2.30-2.24 (m, 2H), 2.12-2.08 (m, 2H), 1.41-1.26 (m, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:3])=[O:17])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCOc1ccc(C(=O)Cl)cc1
Yield: 97.9 %

Procedure:
Thionyl chloride (485 g of 98%, 4.00 mol) was added dropwise to 300 g (1.35 mol) of 4-hexyloxybenzoic acid. The resulting mixture was refluxed under nitrogen for 2 hours. Distillation yielded 318 g (98%) of 4-hexyloxybenzoyl chloride [boiling point 149°-153° C. (7.5 mm)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[N:13]=[N:14][N:15]=[C:8]1[CH2:7][CH2:6]2.C1N2CN3CN(C2)CN1C3.[C:26](O)(C(F)(F)F)=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:26]=[O:27])[N:9]1[N:13]=[N:14][N:15]=[C:8]1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCc1nnnn1-2
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)-n1nnnc1CC2
Yield: 50 %

Procedure:
To a stirred solution of Compound 1 (160 mg, 0.79 mmol) in TFA (16 ml) was added hexamethylenetetramine (1.1 g, 7.9 mmol), and refluxed for 3 days. The solvent was evaporated, and the residue was diluted with AcOEt. This organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 2 (90 mg, 0.39 mmol, 50%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)[C:6](=O)[CH3:7])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:7])=[O:19])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Yield: 79.9 %

Procedure:
A mixture of 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester (6.979 g, 26.21 mmol)), aniline (2.9 mL, 31.45 mmol) and p-toluenesulfonic acid (TsOH) monohydrate (249 mg, 1.31 mmol) in toluene (60 mL) was refluxed overnight while the generated water was separated with Dean-Stark distillation head. Then the reaction mixture was diluted with EtOAc, washed with saturated sodium hydrogen carbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified with column chromatography to give the title compound (6.768 g); The title compound, ESI MS (m/z): 324 (M+H+).
Reaction SMILES: [H-].[Li+].[H-].[Li+].[Al+3].[H-].[H-].[H-].Cl[CH2:10][C@@H:11]1[C:20]([CH3:22])([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]([CH3:25])([CH3:24])[CH2:12]1.Cl>O1CCCC1>[CH3:24][C:13]1([CH3:25])[C:14]2[C:19](=[CH:18][C:17]([CH3:23])=[CH:16][CH:15]=2)[C:20]([CH3:22])([CH3:21])[C@@H:11]([CH3:10])[CH2:12]1
Reactant: Cc1ccc2c(c1)C(C)(C)[C@@H](CCl)CC2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C)(C)[C@@H](C)CC2(C)C
Yield: 73 %

Procedure:
To a suspension of lithium hydride (4.52 g; 0.569 mol) and aluminum lithium hydride (1.81 g; 0.048 mol) in tetrahydrofuran under nitrogen, (S)-3-chloromethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (94.69 g; 0.378 mol) was added dropwise, and the resultant mixture was heated while refluxing for 36 hours. The reaction mixture was treated with dilute hydrochloric acid and extracted with n-hexane. The extract was washed with saturated sodium chloride solution, dried, concentrated and distilled to give (S)-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (59.7 g; 0.276 mol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccccc1OCc1ccccc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A mixture of 2-benzyloxybenzaldehyde (5 g, Apin) and sodium borohydride (1.4 g) in ethanol (50 ml) was stirred under argon for 1 hour. The solvent was evaporated, the residue dissolved in ethyl acetate and added dropwise to 0.1M hydrochloric acid solution (200 ml) at 0° C. The organic solution was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filtered and evaporated to give 2-benzyloxybenzyl alcohol (4.91 g) as an oil.
Reaction SMILES: CC(O)=O.[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[CH2:8][O:9][C:10]1[C:11]([N+:16]([O-])=O)=[N:12][CH:13]=[CH:14][CH:15]=1>[Fe].CCO>[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[CH2:8][O:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ncccc1OCc1c(Cl)cccc1Cl
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of AcOH (650 mL) and EtOH (500 mL) was suspended 3-(2,6-dichloro-benzyloxy)-2-nitro-pyridine (37.4 g, 0.11 mol) and iron chips (69.4 g, 0.11 mol). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then filtered through a pad of celite. The resulting filtrate was neutralized with conc. NH4OH (600 mL) and then extracted with EtOAc (3×500 mL). The combined organic extracts were washed with saturated NaHCO3 (2×100 mL), H2O (2×100 mL) and brine (1×100 mL) then dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol, 99%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.56 (m, 3H), 7.46 (dd, 2H), 7.36 (d, 1H), 6.62 (dd, 1H), 6.18 (br s, 2H, NH2), 5.24 (s, 2H); MS m/z 270 [M+1].
Reaction SMILES: [CH3:1][C:2]([S:17][C:18](=O)[CH3:19])([C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1)[CH3:3].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32]C(CBr)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C[O-].[Na+]>C(O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:1]([C:2]([S:17][CH2:18][CH3:19])([CH3:3])[C:4](=[O:16])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)SC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCSC(C)(C(=O)Nc1ccc(C(F)(F)F)cn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 124.2 %

Procedure:
To a solution of 200 mg (0.654 mmol) of thioacetic acid S-[1-methyl-1-(5-trifluoromethyl-pyridin-2-ylcarbamoyl)-ethyl]ester (synthesized according to Method F, step 1) in ethanol (2 mL) were added 363 mg (1.31 mmol) of 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester and 141 mg (2.61 mmol) of sodium methoxide at room temperature. The reaction was heated to 130° C. for 0.5 h within a microwave (CEM Discover). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (4 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to yield 375 mg of 4-[1-methyl-1-(5-trifluoromethyl-pyridin-2-ylcarbamoyl)-ethylsulfanylmethyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]1=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of (3S)-2-oxo-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.94 g, 3.38 mmol) in 20 ml of anhydrous THF and stirred for 30 min. Methyl bromoacetate (0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to RT. The reaction was diluted with 100 ml of EtOAc and washed with 0.3N KHSO4 (50 ml), H2O (2×50 ml), and brine. The combined organics were dried over anhydrous Na2SO4, filtered, and evaporated to afforded a gum that was purified by flash chromatography eluzing with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][O:16][CH:15]3[N:12]([C:13](=[O:23])[CH:14]3[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[NH:24][C:25](=[O:43])[CH2:26][C:27]([O:29]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]>C(O)=O.C(O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][O:16][CH:15]3[N:12]([C:13](=[O:23])[CH:14]3[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[NH:24][C:25](=[O:43])[CH2:26][C:27]([OH:29])=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(c4cccs4)C3OC2)s1
Solvent: CCO
Solvent: O=CO
Product: CC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(c4cccs4)C3OC2)s1
Yield: 16.4 %

Procedure:
A solution of 3-(2-acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl)-acetamido-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.1 g) in formic acid (5 cc) is heated at 50° C. for 30 minutes, with stirring. The mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C., and the residue is dissolved in ethanol (5 cc). The suspension obtained is stirred at 50° C. for 5 minutes and the solvent is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 50° C.; this operation is repeated once, and the residue thus obtained is taken up in ethanol (2 cc). The solid in suspension yields, on filtration, 3-(2-acetylamino-thiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl)-acetamido-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (12 mg) in the form of a beige powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[CH:27]1[C:36]2[C:31](=[C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccc2cnccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4cccc5cnccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.630 g, 1.59 mmol), isoquinoline-5-boronic acid (0.331 g, 1.91 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol), 1 N aqueous sodium carbonate solution (2.5 mL) and acetonitrile (7.5 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in methanol and filtered through celite. The filtrates were concentrated then purified by chromatography (C-18 reverse phase column, 5 to 95% acetonitrile in water containing 0.1% TFA). The fractions containing the desired product were concentrated then dissolved in MeOH/dichloromethane, basified with solid sodium carbonate then filtered and concentrated to furnish 109 (0.386 g, 50%) as a white foam. MS m/e 489 [M+H]; 1H NMR (300 MHz, MeOH-d4) δ ppm 1.61-1.91 (m, 2 H) 1.99-2.15 (m, 2H) 2.17-2.36 (m, 2 H) 2.88 (s, 6 H) 3.04-3.28 (m, 3 H) 3.73-3.87 (m, 4 H) 3.91 (s, 2 H) 3.96-4.07 (m, 4 H) 7.33 (s, 1 H) 7.69-7.83 (m, 1 H) 8.18 (d, J=8.3 Hz, 1 H) 8.30 (d, J=7.2 Hz, 1 H) 8.43 (d, J=6.4 Hz, 1 H) 8.57 (d, J=6.0 Hz, 1 H) 9.28 (s, 1 H)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][CH3:44])(=[O:42])=[O:41]
Reactant: CCS(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCS(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C29H32N4O5S