Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20](I)[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:34]3[CH:35]=[CH:36][C:37]([O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:32]([O:31][CH3:30])[CH:33]=3)[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nc([C@H]3CC[C@H](CNC(=O)OCc4ccccc4)CC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-[4-(8-amino-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (80.0 mg, 0.0002 mol), 2-(3-methoxy-4-phenoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (67.0 mg, 0.0002 mol), potassium carbonate (0.076 g, 0.00055 mol) in DME (3.00 mL) and H2O (0.50 mL) was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride DCM (9.0 mg, 0.00001 mol). The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. Solvent was removed under reduced pressure and the product was purified by flash chromatography (2% MeOH in DCM). MS (ES+): m/z: 577.95 [MH+]. HPLC: tR=2.72 min (OpenLynx: polar—5 min).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[F:8][C:9]1[C:14](O)=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:8][C:9]1[C:14]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19]
Reactant: O=C(O)CCCBr
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCBr)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a solution of 4-bromobutyric acid (0.91 g, 5.4 mmol), pentafluorophenol (1.00 g, 5.4 mmol) and DMAP (0.13 g, 1.1 mmol) in CH2Cl2 (10 ml) cooled to 0° C. under nitrogen, N,N-dicyclohexylcarbodiimide (1.70 g, 8.1 mmol) was added in portions. After 1 h the reaction was slowly warmed to room temperature and stirred for 5 hours. The dicyclohexylurea was filtered off and the mother liquor was concentrated and purified by flash chromatography (n-Hexane/EtOAc 98:2) affording 4-bromobutyric acid pentafluorophenyl ester as a colourless oil (1.40 g, 78%). A mixture of 4-bromobutyric acid pentafluorophenyl ester (0.65 g, 1.9 mmol) and AgNO3 (0.83 g, 4.9 mmol) in CH3CN (8 ml) was warmed at 70° C. for 20 minutes at the microwave. The formed salts were filtered off, the solvent was concentrated and the residue purified by flash chromatography (n-Hexane/EtOAc 95:5) affording 4-nitrooxybutyric acid pentafluorophenyl ester as a clear oil (0.38 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:37][C:38]1([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([N:41]1[CH2:42][CH2:43][C:38]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)([F:37])[CH2:39][CH2:40]1)=[O:9]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: Cc1cc(C)c(C(=O)O)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)N2CCC(F)(c3ccc(C#N)cc3)CC2)cc1N
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 5-amino-2,4-dimethylbenzoic acid (compound 42.1, 2.264 g, 13.71 mmol, 1.00 equiv), HBTU (7.803 g, 20.59 mmol, 1.50 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 2.8 g, 13.71 mmol, 1.00 equiv), and DIEA (3.541 g, 27.45 mmol, 2.00 equiv) in DMF (50 mL) was stiffed at room temperature. After 1 h, the mixture was diluted with 100 mL of EtOAc and washed with 1×100 mL of water followed by 1×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 3.51 g (73%) of the title compound as a white solid.
Reaction SMILES: CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:23][C:24]1[C:25]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[C:34](=O)[CH3:35]>C(Cl)Cl>[Si:8]([O:15][C:34]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[N:26]=[C:25]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:24]([CH3:23])=[CH:33]2)=[CH2:35])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc2cc(C)c(Oc3ccccc3)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cc(C)c(Oc3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Et3N (0.105 mL, 0.751 mmol) and TBSOTf (0.146 mL, 0.635 mmol) were sequentially added (TBSOTf: dropwise, over 2 min) to a solution of 1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (160.1 mg, 0.577 mmol) in DCM (3.0 mL) at 0° C., and the resulting was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to provide 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-phenoxy quinoline (214.0 mg, 0.547 mmol, 95% yield) as a colorless oil. This material was taken up in THF (3.0 mL), water (0.166 mL, 9.24 mmol) and NBS (103 mg, 0.577 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 15 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo to provide 2-bromo-1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (240 mg) as a light-yellow oil: m/z (ESI, +ve) 356.0 (M+H)+. NH4OAc (178 mg, 2.309 mmol) and piperidine-2,4-dione (78 mg, 0.693 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (3.0 mL) and stirred at 25° C. for 5 min. The reaction vial was sealed under argon and heated at 50° C. for 14.5 h. The mixture was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(3-methyl-2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.4 mg, 0.145 mmol, 25% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 11.28 (1H, br. s.), 7.92-8.00 (2H, m), 7.50-7.58 (3H, m), 7.34-7.43 (2H, m), 7.29 (2H, d, J=7.8 Hz), 7.08 (1H, d, J=1.8 Hz), 5.36 (1H, br. s.), 3.50 (2H, t, J=6.7 Hz), 2.56 (3H, s), 2.42 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 370.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC([O-])(C)C.[Na+]>O1CCOCC1>[C:2]1([NH:21][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
Following general procedure F, a mixture of chlorobenzene (102 μL, 1.0 mmol), N1-phenylbenzene-1,4-diamine (221 mg, 1.2 mmol), NaOt-Bu (192 mg, 2.0 mmol), 10 (8 mg, 1 mol %), 1 (5 mg, 1 mol %), and dioxane (1 mL) was heated to 80° C. for 2 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 0-50% EtOAc/Hexane) to provide the title compound as a off-white solid (260 mg, 99%), mp 152-154° C. 1H NMR (300 MHz, CDCl3) δ: 7.27 (t, J=7.5 Hz, 4H), 7.08 (s, 4H), 7.00 (d, J=8.0 Hz, 4H), 6.90 (t, J=7.5 Hz, 2H), 5.59 (s, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ: 144.7, 137.4, 129.6, 121.2, 120.2, 116.5 ppm. IR (neat, cm−1): 3389, 1601, 1512, 1496, 1382, 1313, 1271, 820, 742, 695. Anal. Calcd. for C18H16N2: C, 83.04; H, 6.19. Found: C, 82.81; H, 6.22.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[N:18]1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]3[CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[N:18]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1F
Yield: 41 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-68, 0.050 g, 0.094 mmol), ethynylcyclopropane (0.009 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol), bis(triphenylphosphine)palladium(II) chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.018 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 0.75 (m, 2H), 0.77-0.91 (m, 2H), 1.36 (s, 9H), 1.53-1.59 (m, 2H), 7.38 (t, J=5.9 Hz, 1H), 7.46-7.52 (m, 3H), 8.79 (d, J=4.4 Hz, 2H), 8.19 (t, J=4.3 Hz, 1H); MS (m/z): 467.15 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>O1CCCC1>[O:18]=[C:15]([N:3]1[C@@H:2]([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: C[C@@H]1NC(=O)OC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC(C)(C)[C@@H]1C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Reaction of the auxiliary (5) (0.577 g, 4.47 mmol) in solution in tetrahydrofuran (20 ml) at -78° C. with butyllithium (1.6M, 2.82 ml, 4.52 mmol) and propionyl chloride (0.427 ml, 4.92 mmol) for 30 minutes and then at room temperature for 1 hour, with work-up and recrystallisation from 40-60 petroleum ether furnished the title compound (17) as a solid (0.780 g, 94%); mp 86° C.; v. (CHCl3) 1703 and 1781 cm-1 ; [α]D 25 (c 0.9 in CHCl3)=+58.1; (Found: C, 58.08; H, 7.85; N, 7.53. C9H15NO3 requires C, 58.36; H, 8.16; N, 7.56%); δH (CDCl3 ; 300 MHz) 1.05 (3H, t, J=7.4, CH3CH2), 1.18 (3H, d, J=6.5, CHCH3), 1.31 (3H, s, C(CH3)2), 1.34 (3H, s, C(CH3)2), 2.82 (2H, q, J=7.3, CH2CH3), 4.09 (1H, q, J=6.5, CHCH3); δC (125 MHz; CDCl3) 8.08 (CH3), 14.41 (CH3), 21.30 (CH3), 27.58 (CH3), 29.09 (CH2), 58.72 (CH), 81.36 (C), 152.91 (CO), 174.49 (CO) ; m/z (CI+, NH3) 186 (M+ +1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:34]1([C@@H:39]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:40]([OH:42])=O)[CH2:38][CH2:37][CH2:36][CH2:35]1.[NH2:50][C:51]1[CH:52]=[C:53]([CH:65]=[CH:66][CH:67]=1)[CH2:54][C:55]1([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:57][CH2:56]1>CN(C=O)C>[CH:34]1([C@@H:39]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:40]([NH:50][C:51]2[CH:52]=[C:53]([CH:65]=[CH:66][CH:67]=2)[CH2:54][C:55]2([C:58]([O:60][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:59])[CH2:57][CH2:56]2)=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Cc1ccc([C@@H](C(=O)O)C2CCCC2)cc1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([C@@H](C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
At RT, 453 mg (1191 μmol) of HATU and 479 μl (2750 μmol) of N,N-diisopropylethylamine were added to a solution of 200 mg (916 μmol) of (+)-(2S)-cyclopentyl(4-methylphenyl)acetic acid in 1 ml of DMF. The mixture was stirred for 30 min. 249 mg (1008 μmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were then added. The reaction mixture was stirred overnight and then directly separated into its components by preparative HPLC. This gave 328 mg (80% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[N:30]([CH2:33][C@@H:34]([C:36]1[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=1)[OH:35])=[N+]=[N-]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:30][CH2:33][C@@H:34]([C:36]4[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:41]=4)[OH:35])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)(=[O:27])=[O:28])=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1Cl
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(Cl)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and N-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide (which was obtained in Example 25) according to the procedure of Example 95 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.90 (m, 2 H), 2.50–2.80 (m, 5 H), 2.97 (s, 3 H), 3.40–3.55 (m, 2 H), 3.69 (s, 3 H), 4.63 (dd, J=8.0; 3.8 Hz, 1 H), 4.87(s, 2 H), 6.77 (d, J=9.0 Hz, 2 H), 6.87 (d, J=9.0 Hz, 2 H), 7.03 (d, J=9.0 Hz, 2 H), 7.17 (dd, J=8.3, 1.7 Hz, 1 H), 7.43 (d, J=8.3 Hz, 1 H), 7.43 (d, J=1.7 Hz, 1 H), 7.62 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 667.0 (MH+); HRMS Calcd. for C29H36ClN4O8S2 (MH+): 667.1657. Found: 667.1651.
Reaction SMILES: C[C:2]1([C:9]2[C@H:10]([C:14]([N:16]3[C@@H:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][O:18][C:17]3=[O:28])=[O:15])[NH:11][CH2:12]C=2)[CH2:7][C:6](=O)[CH:5]=[CH:4][CH2:3]1.CC1(C2[C@@H](C(N3[C@@H](CC4C=CC=CC=4)COC3=O)=O)NCC=2)CC(=O)C=CC1.[CH3:57][CH2:58][OH:59]>[Pd].CCOC(C)=O>[CH3:12][N:11]1[C:58](=[O:59])[CH2:57][C@H:9]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:10]1[C:14]([N:16]1[C@@H:20]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][O:18][C:17]1=[O:28])=[O:15]
Reactant: CCO
Reactant: CC1(C2=CCN[C@H]2C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)CC=CC(=O)C1
Agent: [Pd]
Agent: CC1(C2=CCN[C@@H]2C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)CC=CC(=O)C1
Solvent: CCOC(C)=O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 48 h

Procedure:
To a slurry of 10% palladium on carbon (7.0 g) in EtOAc (700 mL) was added a solution of diastereomers 3-[((2R)-1-methyl-5-oxo-3-phenyl(3-pyrrolin-2-yl)carbonyl](4S)-4-benzyl-1,3-oxazolidin-2-one and (4S)-3-[((2S)-1-methyl-5-oxo-3-phenyl(3-pyrrolin-2-yl))carbonyl]-4-benzyl-1,3-oxazolidin-2-one (78.5 g, 0.208 mol) in EtOH (100 mL) and the reaction mixture was stirred under a H2 atmosphere (1 Atm) for 2 days. The reaction mixture was filtered through a pad of Celite® with the aid of EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (gradient from 15% to 65% EtOAc/hex) to give diastereomer 3-[((2R,3R)-1-methyl-5-oxo-3-phenylpyrrolidin-2-yl)carbonyl](4S)-4-benzyl-1,3-oxazolidin-2-one as a single diastereomer (41.02 g, 52%): TLC (15% i-PrOH/hex) Rf0.25; 1H NMR (CDCl3) δ 1.39 (dd, J=11.4, 13.6 Hz, 1H), 2.45-2.51 (dd, J=3.3, 13.6 Hz, 1H), 2.87-2.91 (m, 5H), 3.91 (dd, J=9.2, 2.9 Hz, 1H), 4.03-4.23 (m, 3H), 4.36-4.43 (m, 1H), 5.75 (d, J=9.2 Hz, 1H), 7.01-7.03 (m, 2H), 7.21-7.39 (m, 8H); HPLC ES-MS m/z (rel abundance) 377 (MH+, 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].O[C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:1][CH2:2][CH2:3][C@H:4]([O:5][C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O[C@H](CCCl)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Reaction time: 8 h
Yield: 53.2 %

Procedure:
(1R)-3-Chloro-1-phenyl-1-propanol (1.000 g, 5.86 mmol), 1-(3-hydroxyphenyl)ethanone (0.797 9, 5.86 mmol), triphenylphosphine (1.54 g, 5.86 mmol) and diethylazodicarboxylate (1.53 g, 8.79 mmol) were combined in a flask, which was immediately flushed with argon. THF (20 mL) was added and the mixture was stirred overnight under argon. THF was removed in vacuo, the crude product was dissolved in 50 mL of CH2Cl2/H2O (1:1) and the organic layer was separated and dried over MgSO4. After removing the solvent in vacuo, the residue was purified by flash chromatography using 10% ethyl acetate/hexane to yield the desired product (900 mg, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.40-7.26 (m, 6H), 7.07-7.04 (m, 1H), 5.46-5.43 (dd, 1H, J=4.4 Hz, 8.8 Hz), 3.84-3.78 (m, 1H), 3.64-3.59 (m, 1H), 2.52 (s, 3H), 2.51-2.46 (m, 1H), 2.29-2.22 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:24](=[O:25])[CH2:23][O:22][CH3:21])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: COCC(=O)Cl
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (54 mg, 177 μmol) and 2-methoxyacetyl chloride (25 mg, 230 μmol) in DCM-pyridine (0.5 mL each) was stirred at rt. More 2-methoxyacetyl chloride (25 mg, 230 μmol) was added after overnight, resulting in a solution. The reaction was complete after 1 h. The mixture was concentrated, and diluted with NaHCO3 (saturated, 5 mL). After agitating for 30 min, the mixture was filtered, and washed with H2O (3×3 mL) to give a green solid (55 mg, 82%). LCMS: calc'd for C17H17ClN4O2S:376.0. found: 377.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.86 (s, 6H) 3.32 (s, 3H) 4.23 (s, 2H) 7.76-7.88 (m, 3H) 8.36 (s, 1H) 8.43 (s, 1H) 12.39 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:3][CH:4]=1)#[N:20]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(C#Cc2ccc(NC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1H, was dissolved in THF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) was added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This was stirred at room temperature for 1 h. The reaction mixture was partitioned between H2O and EtOAc. The organic layer was dried and concentrated. Purification by silica chromatography (9/1, CH2Cl2/EtOAc) yielded N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[F:33][C:34]1[CH:45]=[CH:44][C:37]([N:38]([CH2:40][CH:41]([NH2:43])[CH3:42])[CH3:39])=[CH:36][CH:35]=1>C(Cl)Cl.O>[F:33][C:34]1[CH:45]=[CH:44][C:37]([N:38]([CH2:40][CH:41]([NH:43][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH3:42])[CH3:39])=[CH:36][CH:35]=1
Reactant: CC(N)CN(C)c1ccc(F)cc1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(CN(C)c1ccc(F)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
1.6 g of N-methylpiperidine was added to a solution containing 3.9 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 2.2 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.0 g of 2-(4-fluoro-N-methylanilino)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a white crystal (yield: 19%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]=[C:20]([NH2:30])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O>C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(N)ncc3-c3ccccc3)cc2)CCC1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)cn4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 48.4 %

Procedure:
A mixture of 5-1 (150 mg, 0.36 mmol) and 2-Bromo-1-phenyl-ethanone (110 mg, 0.54 mmol) in ethanol (2 mL) was heated to 100° C. and stirred for 45 mins under microwave radiation. The mixture was cooled to r.t. and diluted with 20 mL of DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 90 mg of 5-2.