Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=O)[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1[C:56]2C=CC=CC=2N=N1.CN>C1COCC1.[Pd]>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:52][CH3:56])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: [Pd]
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(NC1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% Pd/C and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 h. The reaction mixture was filtered without exposure to air into another flask containing polystyrene-carbodiimide (260 mg, 0.29 mmol) and the mixture was stirred for 10 min. A solution of 1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) and methylamine (0.08 mL, 2.0 M solution in THF, 0.16 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (7.5 mg, 7%) and as a dark red solid: 1H NMR (500 MHz, CD3OD) δ 8.11 (s, 1H), 6.59 (s, 1H), 6.15 (s, 0.3H), 5.99 (s, 0.7H), 5.19-5.17 (m, 0.3H), 4.94 (s, 0.7H), 3.75 (s, 3H), 3.57 (s, 3H), 3.54 (s, 1H), 3.51 (s, 1H), 3.48-3.35 (m, 6H), 3.26-3.21 (m, 1H), 3.08 (t, J=9.0 Hz, 0.3H), 3.04 (t, J=9.0 Hz, 0.7H), 2.78 (s, 3H), 2.22 (s, 3H), 1.27 (d, J=9.0 Hz, 2H), 1.22 (d, J=6.5 Hz, 1H); MS (ESI+) m/z 697 (M+H); HPLC >99% (AUC), tR 10.63 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[CH3:22][N:23]([CH3:31])[CH2:24][CH2:25][C:26](=O)[C:27]([OH:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:26]([C:27]([OH:29])=[O:28])[CH2:25][CH2:24][N:23]([CH3:31])[CH3:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: CN(C)CCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: CN(C)CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with 4-(dimethylamino)-2-oxobutanoic acid at room temperature to give 7-chloro-2-[[1-carboxy-3-(dimethylamino)propylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1.[CH3:24][S-:25].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([S:25][CH3:24])[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1
Reactant: C[S-]
Reactant: Nc1nc(Cl)nc(OCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(N)nc(OCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a 25 mL recovery flask was added 2-(4-Amino-6-chloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide (33 mg, 0.0950 mmol, 1.0 eq.) and CH2Cl2 (7 mL). Sodium thiomethoxide (20 mg, 0.285 mmol, 3.0 eq.) was added and the resulting solution was stirred at room temperature for 1 h. The reaction was diluted with CH2Cl2 (50 mL) and washed with H2O (1×50 mL) and brine (1×50 mL). The combined aqueous phases were extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown solid. The crude material was purified via preparative HPLC to give 2-(4-Amino-6-methylsulfanyl-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (6.2 mg, 24% yield). LC/MSD (HP Series 1100 MSD) Expected MW: 359.07, Observed M+H, 360.1, Retention time: 1.40. Analytical LC: 98%, Retention time: 4.87 (11 minute run). 1H-NMR, CH3OH-d4, Varian 400 MHz δ 8.01 (s, 1H), 7.81 (d, 1H), 7.51 (t, 1H), 7.40 (d, 1H), 4.94 (s, 2H), 2.46 (3H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([CH3:31])[CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1cc(O)cc(Cl)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(C)cc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-5-methylphenol (J. Org. Chem. 1996, 61, 6814): 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.8 Hz), 8.15 (1H, d, J=2.6 Hz), 8.01 (3H, m), 7.42 (2H, d, J=8.1 Hz), 7.12 (1H, m), 6.97 (1H, m), 6.85 (1H, m), 5.36 (1H, m), 3.91 (3H, s), 2.38 (3H, s), 1.59 (3H, d, J=7.5 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:35])([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][C@H:30]([NH:29][C:27]([O:26][C:24]([CH3:35])([CH3:25])[CH3:23])=[O:28])[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Yield: 99.5 %

Procedure:
A solution of 12.5 g (40 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 8.9 g (48 mmol) of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 8.1 g (80 mmol) of triethylamine and 75 ml of acetonitrile was heated at reflux for 18 hours. The reaction mixture was cooled to 5° and the solid was removed by filtration, washed with acetonitrile, ether and dried in vacuo to give 19.0 g of the title compounds, mp 148°-151°.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:36]3[NH:40][C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:38][CH:37]=3)[CH2:14][C@H:15]3[CH2:35][CH2:34][C:17]4(O[C@H](C5C=CC=CC=5)[C@@H](C5C=CC=CC=5)[O:18]4)[CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:36]3[NH:40][C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:38][CH:37]=3)[CH2:14][C@H:15]3[CH2:35][CH2:34][C:17](=[O:18])[CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2ccc(-c3ccccn3)[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)pyridine (70 mg) in tetrahydrofuran (3 mL) was added 1M hydrochloric acid (3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (45 mg, yield 94%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 435 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24](I)[N:23]=[C:22]2[CH:27]([CH3:29])[CH3:28])=[CH:17][CH:16]=1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:24]2[N:23]=[C:22]([CH:27]([CH3:29])[CH3:28])[N:21]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)[CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: CC(C)c1nc(I)cn1-c1ccc(F)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CC(C)c1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=340.1 (M+H+), was prepared in accordance with the general method of example B, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 1-(4-fluoro-phenyl)-4-iodo-2-isopropyl-1H-imidazole and crystallization from methanol and 1.05 eq fumaric acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:28][C:26]1[O:27][C:23]2[CH:22]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:30]=[CH:29][C:24]=2[N:25]=1
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)oc3c2)cc1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (163 mg, 0.744 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (105 mg, 0.709 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (164 mg, 70%), single spot at Rf 0.49 (60:40 hexane:ethyl acetate). mp 101.7-102.3° C., HPLC purity 99% (tR 2.02 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.61 (2H, m), 7.43 (1H, d, J=8.4 Hz), 7.37 (1H, d, J=1.8 Hz), 7.19 (2H, m), 6.83 (2H, m), 2.57 (5H, m), 1.58 (2H, sextet, J=7.3 Hz), 0.88 (3H, t, J=7.3 Hz). LCMS: 329.21 (M−). FAB-MS (MH+, C17H18N2O3S): calcd 331.1116, found 331.1107.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCl.O>[Si:17]([O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OCCOc1ccnc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccnc(Cl)n1
Reaction time: 0.17 h

Procedure:
2-[(2-Chloropyrimidin-4-yl)oxy]ethanol (416 mg, 2.38 mmol) in dichloromethane (9.5 mL) at 0° C. was added to an oven-dried, nitrogen cooled vial containing imidazole (389 mg, 5.72 mmol). The solution was stirred for 10 minutes. TBS-Cl (424 mg, 2.81 mmol) was added and the reaction mixture was stirred at room temperature for 2 h then, diluted with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-chloropyrimidine as a clear, yellow oil. MS ESI calcd. for C12H22ClN2O2Si [M+H]+ 289. found 289. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J=5.7, 1H), 6.67 (d, J=5.7, 1H), 4.62-4.30 (m, 2H), 4.02-3.87 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:11])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ccc2occc2c1Br
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)ccc2occc12
Yield: 67.8 %

Procedure:
Beginning with 1.13 gm (5.26 mMol) 4-bromo-5-fluorobenzofuran and 1.18 gm (6.2 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 1.21 gm (68%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1ccsc1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccsc1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with thiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 8.00 (dd, J=1.2 & 3.3 Hz, 1H), 7.45 (dd, J=0.9 & 5.1 Hz, 1H), 7.35 (m, 2H), 7.27 (m, 2H), 6.91 (dd, J=9.3 & 17.1 Hz, 1H), 6.64 (ddd, 2.1, 4.8 & 8.7 Hz, 1H), 6.34 (dt, J=5.4, 8.7 & 14.1 Hz, 1H), 5.98 d, J=2.1 Hz, D2O exchangeable, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:33])=[CH:39][CH:38]=[CH:37][C:36]=3[F:40])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)cccc1F
Product: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 102), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluorophenyl)boronic acid gave 347. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.94 (s, 1H), 7.69-7.65 (m, 1H), 7.40-7.36 (m, 2H), 5.11-5.09 (m, 1H), 3.85-3.79 (m, 2H), 3.72 (s, 3H), 3.57 (s, 2H), 3.46-3.43 (m, 1H), 3.30 (s, 1H), 3.01 (s, 3H), 2.43-2.37 (m, 1H), 1.74-1.58 (m, 3H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl[CH2:26][CH2:27][C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[C:42]([NH:62][C:63]2[CH:67]=[C:66]([CH3:68])[NH:65][N:64]=2)=[N:43][C:44]([NH:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([CH:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:50][C:49]=2[CH3:61])=[N:45][CH:46]=1>CN(C=O)C>[Cl:40][C:41]1[C:42]([NH:62][C:63]2[CH:67]=[C:66]([CH3:68])[NH:65][N:64]=2)=[N:43][C:44]([NH:47][C:48]2[C:49]([CH3:61])=[CH:50][C:51]([CH:55]3[CH2:60][CH2:59][N:58]([C:28](=[O:30])[CH:27]=[CH2:26])[CH2:57][CH2:56]3)=[C:52]([CH3:54])[CH:53]=2)=[N:45][CH:46]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: O=C(O)CCCl
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: C=CC(=O)N1CCC(c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A solution of HATU (108 mg, 0.28 mmol), 3-chloropropanoic acid (30 mg, 0.28 mmol) and DIEA (0.1 mL) in DMF (1 mL) was stirred at rt. After 3 min, this solution was transferred to a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine solution (111 mg, 0.27 mmol) in DMF (10 mL). The resulting mixture was stirred at rt overnight. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-10% MeOH in DCM gradient with 1% NH3 additive) to give 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)prop-2-en-1-one as a light brown oil; ESMS m/z 466.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:34][CH2:33][CH2:31][OH:32])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCO)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5.00 g 19.98 mmol) in 150 mL THF was treated with 3.65 g CDI (22.5 mmol) and the exothermic reaction let stir for 1 h at room temperature. Ethanolamine (1.35 g, 22.10 mmol) in 50 mL THF was added over 1 h and the solution stirred overnight. The reaction was concentrated, dissolved into 375 mL CH2Cl2 and washed with 250 mL 0.1 M HCl, 250 mL 0.5 M NaHCO3, 2×100 mL saturated NaCl and dried over Na2SO4. The acidic aqueous phase was extracted 3×100 mL CH2Cl2 and washed with 50 mL saturated NaCl and dried over Na2SO4. The combined organics were concentrated and purified by flash chromatography yielding 2.88 g of 6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as an off white impure solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:2]=1.[Br:17]Br>CC(O)=O>[Br:17][C:12]1[CH:13]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[NH2:11]
Reactant: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(Br)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a solution of 4-(pyridin-3-yl)-2-nitroaniline (1.3 g, 9 mmol) in HOAc (25 mL) was added bromine (1.58 g, 9.9 mmol) in HOAc (5 mL). The resulting mixture was stirred at room temperature for one hour and then quenched with ice-water. The solids were collected, washed with water and dried. The solids in EtOAc was then washed with NaOH (2N; 20 mL), water, brine and concentrated in vacuo. The concentrate was purified by chromatography [Silica Gel, ethyl acetate:hexanes (1:1)] to afford the title compound (0.8 g). 1H NMR (CDCl3) δ 8.83 (d, 1H), 8.55 (m, 1H), 8.41 (d, 1H), 8.15 (d, 1H), 7.96 (m, 1H), 7.41 (m, 1H), 6.80 (br s, 2H). (M+1) 294.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[C:8]([O:32]CC2C=CC=CC=2)=[C:9]([O:30][CH3:31])[CH:10]=[C:11]([C@H:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[O:14]2)[CH:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]>C(OCC)(=O)C>[CH2:1]([S:4]([C:7]1[C:8]([OH:32])=[C:9]([O:30][CH3:31])[CH:10]=[C:11]([C@H:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[O:14]2)[CH:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1O

Procedure:
A solution of trans-2-(5-propylsulfonyl-4-benzyloxy-3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (5.0 g) in ethyl acetate (100 mL) was hydrogenated over 10% palladium-over-charcoal (250 mg) for 1 h. The catalyst was filtered off and the filtrate was concentrated to a crystalline mass. Recrystallization from ethyl ether gave pure product: mp 168°-169° C.; NMR (CDCl3) δ 1.0 (t, CH2CH2CH3) 1.7 (m, CH2CH2CH3), 2.0 & 2.49 (2 m, H-3-& H-4), 3.4 (m, CH2CH2CH3), 3.84, 3.89 & 3.93 (3 s, 4 OCH3), 5.20 (m, H-2 & H-5), 6.62 (s, C5ArH), 7.24 & 7.47 (2 d, J=1.5 Hz C2ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7](Cl)[C:6]=2[CH:16]=1.[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](=[S:22])[S-:21])[CH3:18].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7]([S:22][C:20](=[S:21])[N:19]([CH2:23][CH3:24])[CH2:17][CH3:18])[C:6]=2[CH:16]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(SC(=S)N(CC)CC)c2cc(Br)ccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g) in dimethylformamide (2 ml) was treated with sodium diethyldithiocarbamate (0.34 g). The mixture was stirred at room temperature under nitrogen overnight and then poured into water, extracted with diethyl ether and the extract washed with brine, dried and evaporated under reduced pressure to give 6-bromo-4-diethylthiocarbamoylthio-3-propyl-2H-1-benzopyran-2-one, m.p. 135-7°. (compound 16)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]>ClCCl.C(=O)([O-])O.[Na+]>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][CH:28]=1)=[O:31]
Reactant: Nc1nc2ccccc2s1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3ccccc3s2)cc1)OCC
Reaction time: 10 h
Yield: 84.3 %

Procedure:
In 30 ml of dry dichloromethane were dissolved 3.0 g of 2-aminobenzothiazole and 10 ml of pyridine and while the resulting solution was stirred under ice-cooling, a solution of 5.8 g 4-[(diethoxyphosphoryl)methyl]benzoyl chloride in 10 ml dry dichloromethane was slowly added dropwise. The stirring was continued at room temperature for 10 hours, after which the reaction mixture was diluted with 30 ml of 10% aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed serially with 30 ml of 10% hydrochloric acid and 30 ml of water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform-ethyl acetate=1:1) and the resulting crude crystals were recrystallized from ethanol to provide 6.8 g of the title compound as colorless crystals. The structure and melting point of the compound thus obtained are shown in Table 1.