Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][N:32]([CH:38]1[CH2:40][CH2:39]1)[CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([NH:20][C@:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:46](Cl)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][N:32]([CH:38]1[CH2:40][CH2:39]1)[CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:14][C@H:13]1[C:18]([NH:20][C@:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:19])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate (1.55 g, 2.75 mmoL) in 10 mL of DMF was added imidazole (0.47 g, 6.88 mmoL) and tert-butyldimethylsilyl chloride (826 mg, 5.50 mmoL). The mixture was stirred at rt for 18 h, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. Flash chromatography (eluting with methylene chloride and then ethyl acetate) gave ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-(tert-butyldimethylsilyloxy)pyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate as a white solid (1.75 g, 94%):
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](=[O:27])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1ccccc1-c1ccncc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccccc1-c1ccncc1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), 2-pyridin-4-yl-phenylamine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([2-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 22%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[C:16]([O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].C(#N)C>CCCCCCC.CCOC(C)=O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:37])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc(C(=O)OC)c1
Yield: 98.7 %

Procedure:
5-Hydroxy-isophthalic acid dimethyl ester (420 mg, 2 mmol), 15-bromo-pentadecanoic acid tert-butyl ester (755 mg, 2 mmol) and K2CO3 (415 mg, 3 mmol) were placed in a flask with acetonitrile (25 ml) and refluxed under N2. The reaction was followed by TLC (4:1 heptane/AcOEt), which indicated reaction completion after 6 h. The sample was concentrated to near dryness. AcOEt (50 ml) and water (25 ml) were added to the residue. The phases were separated and the organic phase was washed with water and brine (25 ml each), dried over MgSO4 and concentrated to yield a white crystalline solid (1.0 g, 100%).
Reaction SMILES: [NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH3:42])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH3:41])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C[OH:51]>>[NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([OH:25])=[O:51])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH3:42])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH3:41])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CO
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
Using 0.35 g of BOC-Tyr-(D)-Met(O)-Gly-MePhe-NHNH-CO-CH3, in a similarmanner to (IV) of Example 36 is obtained 0.19 g of the desired product, [α]D22 0° (c=0.25, MeOH), Rf2 =0.16, amino acid analysis: Gly 1.00, Met 1.00, Tyr 1.20.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[N:25]([CH3:34])[C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([F:33])=[CH:28][CH:27]=4)(=[O:23])=[O:22])=[C:16]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39].C(OCC)(=O)C>CCOCC>[ClH:39].[CH3:38][S:35]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][C:17]=1[NH:20][S:21]([C:24]1[N:25]([CH3:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([F:33])=[CH:28][CH:27]=2)(=[O:22])=[O:23])(=[O:37])=[O:36]
Reactant: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCNCC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[4-(5-fluoro-1-methyl-1H-indole-2-sulfonylamino)-3-methanesulfonyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.019 g) was treated with 2.5 N HCl/ethyl acetate (2.5 ml). The reaction mixture was stirred at rt for 3 h, then ether (20 ml) was added. The precipitate was collected, washed with ether and dried under high vacuum over P2O5 to produce the title compound (0.014 g) as an off-white amorphous powder. MS (ISN): 464.0 (M−H)−
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38])([O-:33])=[O:32]>ClCCl.CN(C=O)C>[C:1]([C:3]1[C:4]([F:14])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)=[O:10])#[N:2]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(F)c(C#N)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirring slurry of 5-cyano-4-fluoro-2-methoxy-benzoic acid (1.92 g, 9.8 mmol) in dichloromethane (20 mL, 0.5 M) was added oxalyl chloride (2.57 mL, 29.5 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1–2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (20 mL, 0.5 M). To the stirring mixture at 0° C. was added diisopropylethyl amine (4.3 mL, 24.6 mmol) followed by 3-nitrobenzylamine hydrochloride salt (2.78 g, 14.8 mmol). The stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (3×25 mL) and saturated aq NaCl (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided [5-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamide (2.0 g, 63%) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (d, J=7.5 Hz, 1 H), 8.19 (9, 1 H), 8.15 (d, J=8.4 Hz, 1 H), 7.96 (bd s, 1 H), 7.70 (d, J=6.3 Hz, 1H), 7.54 (t, J=8.0 Hz, 5 H), 6.86 (d, J=10.5 Hz, 1 H), 4.76 (d, J=5.4 Hz, 1H), 4.07 (d, J=1.2 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:15]1[C:14]([Cl:13])=[CH:32][C:18]3[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]([C:23]([F:25])([F:26])[F:24])[O:22][C:17]=3[CH:16]=1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc4cc(Br)ccc4c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 6-bromo-2-napthol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 252.6-254.8° C. 1H NMR (acetone-d/300 MHz) 8.19 (s, 1H), 8.04 (d, 1H, J=9.1 Hz), 7.93 (s, 1H), 7.87 (d, 1H, J=8.9 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.55 (s, 1H), 7.43 (d, 1H, J=9.1 Hz), 6.72 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=6.5 Hz). FABLRMS m/z 497 (M-H). ESHRMS m/z 496.9421 (M-H, Calc'd 496.9403). Anal. Calc'd for C21H11BrClF3O4 with 1.75 wt % H2O: C, 49.60; H, 2.38; Br, 15.71; Cl, 6.97. Found: C, 49.55; H, 2.03; Br, 15.56; Cl, 7.22.
Reaction SMILES: O1CCOCC1.[F:7][CH:8]([F:32])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=[C:18]([CH3:31])[CH:17]=2)[N:10]=1.[Cl:33][C:34]1[CH:35]=[N:36][N:37]([CH2:39][CH2:40][NH:41]C(=O)OC(C)(C)C)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[ClH:33].[NH2:41][CH2:40][CH2:39][N:37]1[CH:38]=[C:34]([C:20]2[CH:21]=[C:16]([NH:15][C:11]3[N:10]=[C:9]([CH:8]([F:7])[F:32])[CH:14]=[CH:13][N:12]=3)[CH:17]=[C:18]([CH3:31])[CH:19]=2)[CH:35]=[N:36]1
Reactant: CC(C)(C)OC(=O)NCCn1cc(Cl)cn1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCN)c2)c1
Product: Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
1,4-Dioxane (40 mL) and water (9 mL) were added to a flask containing 4-(difluoromethyl)-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (3.00 g, 8.31 mmol), tert-butyl (2-(4-chloro-1H-pyrazol-1-yl)ethyl)carbamate (3.06 g, 12.5 mmol), SiliaCat Si-DPP-Pd (9.58 g, 2.49 mmol, 0.26 mmol/g), and sodium carbonate (4.40 g, 41.5 mmol). The reaction was heated at 110° C. overnight. The reaction mixture was filtered, washed with 1,4-dioxane, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate/hexanes) and dissolved in a small amount of 1,4-dioxane. Hydrochloric acid (4N in 1,4-dioxane, 10 mL) in was added and the mixture was allowed to stir for 3 hours. The mixture was diluted with diethyl ether, filtered, washed with diethyl ether, and dried over anhydrous sodium sulfate to afford N-(3-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine hydrochloride. MS ESI calc'd. for C17H19F2N6 [M+H]+ 345. found 345. 1H NMR (500 MHz, DMSO-d6): δ 9.92 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 8.29 (s, 3H), 8.15 (s, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.34 (s, 1H), 7.04 (t, J=5.3 Hz, 2H), 6.89 (t, J=54.5 Hz, 1H), 4.42 (t, J=6.3 Hz, 2H), 3.27-3.25 (m, 2H), 2.28 (s, 3H).
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:25]I.[C:27]1([S:33]([CH2:36][CH2:37][CH2:38][CH2:39]O)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.O>[I:25][CH2:39][CH2:38][CH2:37][CH2:36][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(CCCCO)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(CCCCI)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of imidazole (1.4 g, 20.5 mmol) in CH2Cl2 (20 mL) is added PPh3 (5.4 g, 20.5 mmol). The solution is cooled to 0° C. and iodine (5.2 g, 20.5 mmol) is added in 2 portions. The mixture is allowed to warm to RT then 4-benzenesulfonylbutan-1-ol is added and the mixture is stirred at RT for 24 h. The mixture is diluted with water and extracted with EtOAc (3×). The organic layer is washed with a 20% solution of Na2S2O3 and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using hexane/EtOAc (1:1) as eluent to give the title compound as a white solid.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1.OC1(C2C=C(C)C=CC=2)CC(=O)C=C1C1C=CN=CC=1.CN(C1C=CC=CN=1)C.[C:50]([O:53]C(=O)C)(=[O:52])[CH3:51]>C(Cl)Cl>[C:50]([O:53][C:3]1([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][C:5](=[O:7])[CH:6]=[C:2]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=[O:52])[CH3:51]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C2=CC(=O)CC2(O)c2ccncc2)c1
Agent: CN(C)c1ccccn1
Agent: Cc1cccc(C2(O)CC(=O)C=C2c2ccncc2)c1
Solvent: ClCCl
Product: CC(=O)OC1(c2cccc(C)c2)CC(=O)C=C1c1ccncc1
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-4-pyridine-4-yl-3-m-tolyl-cyclopent-2-en-1-one, and it's regioisomer 4-hydroxy-3-pyridine-4-y1-4-m-toly1-cyclopent-2-en-1-one prepared as described in Example 8, Step E (265 mg, 1.0 mmole) in methylene chloride (5 mL) was added dimethylamino pyridine (183 mg, 1.5 mmole) and acetic anhydride (0.12 mL, 1.2 mmole) at r.t. The reaction mixture was stirred at that temperature for 1 hr before quenching the reaction with 1 mL of methanol. Concentration and purification (silica, hexane/ethyl acetate) gave the title compound as the slower eluting isomer. MS (m/z): Calcd. C19H17NO3(M+): 307, found (M+H) +: 308.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]1[C:20]2[CH:19]([CH2:21]O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:8]1[C:20]2[CH:19]([CH2:21][O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCCBr
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCBr)OCC1c2ccccc2-c2ccccc21
Reaction time: 18 h
Yield: 86.9 %

Procedure:
DDC (6.00 g, 29 mmol) was added in one portion to a cooled solution (0° C.) of 4-bromobutyric acid (5.00 g, 29.9 mmol), 4-(dimethylamino)pyridine (353 mg, 2.9 mmol) and 9-fluorenemethanol (5.63 g, 25 mmol) in CH2Cl2 (150 mL). The mixture was allowed to stand at 4° C. for 18 h, and then filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in EtOAc and the solution washed sequentially with 1N NaHCO3, 1N HCl and H2O. The solution was dried (Na2 -SO4) and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel (200 g) using hexane-EtOAc (15:1) as the eluant to give the pure title compound as an oil (7.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[S:26]([C:23]2[CH:24]=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)CNc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of (4-fluoro-phenyl)-isobutyl-amine (250 mg, 1.5 mmol) in DCM (5 mL) was added pyridine (242 μL, 3.0 mmol) followed by 6-chloropyridine-3-sulfonyl chloride (379 mg, 1.8 mmol) and the reaction was stirred at room temperature for 2 hours. Water and saturated aqueous NaHCO3 were added and then extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-20% EtOAc in cyclohexane) to give 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (411 mg, 67%). LCMS (m/z, Method A) ES+ 343 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:14][C:15]1[C:16](=[O:22])[NH:17][N:18]=[CH:19][C:20]=1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[N:14]=[C:15]2[C:16](=[O:22])[NH:17][NH:18][CH:19]=[C:20]2[N:21]=1
Reactant: COc1cc(SC)ccc1C(=O)O
Reactant: Nc1cn[nH]c(=O)c1N
Product: COc1cc(SC)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Temperature: 50 °C

Procedure:
Two grams of 2-methoxy-4-methylmercapto-benzoic acid are suspended in 20 ml of polyphosphoric acid, and 1.2 gm of 4,5-diamino-2H-pyridazin-3-one are added thereto with stirring at 50° C. The mixture is heated for 90 minutes to 100°-110° C. and then poured onto ice water, and the product which is precipitated on stirring is subjected to suction filtration. The mother liquor is extracted with ethyl acetate, after which the aqueous phase is made ammoniacal and extracted again with ethyl acetate. The last ethyl acetate phase is evaporated. The residue is combined with the above solid product and purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:0 to 100:3)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[O-]S([C:38]([F:41])(F)[F:39])(=O)=O.ClC1C=[N+]([F:50])C=C(Cl)C=1>CC#N>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([F:39])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[C:27]([F:50])[CH:26]=[C:38]([F:41])[C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: F[n+]1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)c(F)cc(F)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(F)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (232 mg) was dissolved in anhydrous MeCN (10 mL) under N2 and 3,5-dichloro-1-fluoropyridinium triflate (85%, 353 mg) was added and the mixture was refluxed for 1 day. More 3,5-dichloro-1-fluoropyridinium triflate (175 mg ) was added and the mixture was refluxed for another day. The mixture was then concentrated, and the residue was taken up with water and extracted with CH2Cl2. The extract was washed with sat. NaHCO3, water, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 5:1 to 2:1) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-fluorophenyl)-L-phenylalanine methyl ester(109 mg ) and N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3,5-difluorophenyl)-L-phenylalanine methyl ester (37 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[F:42][C:43]1([F:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.O>CN1CCCC1=O>[F:42][C:43]1([F:49])[CH2:48][CH2:47][N:46]([C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:9]=3)[N:12]=2)[CH2:45][CH2:44]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c21
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(N3CCC(F)(F)CC3)c21
Temperature: 150 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
100 mg (0.18 mmol) of 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 16A) was dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction vessel suitable for a microwave, and 0.19 ml (1.07 mmol) of N,N-diisopropyl ethylamine and 140 mg (0.89 mmol) of 4,4-difluoropiperidine hydrochloride were added. Then the reaction vessel was sealed with a septum and was heated in the microwave for 5 h at 150° C. Then the same amounts of N,N-diisopropyl ethylamine and 4,4-difluoropiperidine hydrochloride were added again to the reaction solution and the reaction mixture was stirred for 6 h at 150° C. in the microwave. Water was added to the reaction mixture, the precipitated solid was stirred for 30 min at room temperature and then filtered off. The precipitated solid was stirred with 1 ml acetonitrile, the solid was filtered off and was washed with 0.5 ml acetonitrile. 63 mg of the target compound (64% of theor.) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[C:21]([F:23])[C:7]([CH2:8][N:9]2[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)=[C:6]([F:24])[CH:5]=1)[CH3:2].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:24])[C:7]([CH2:8][N:9]2[C:13]([O:14][CH3:27])=[C:12]([CH3:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)=[C:21]([F:23])[CH:22]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(O)c1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(OC)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.95 g of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1H-pyrazole-3-carboxylate 1-1-1 (11.6 mmol, 1.0 eq.) were dissolved in 50 mL of acetone. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) and 5.78 g (41.8 mmol, 3.6 eq.) of potassium carbonate were added and stirred over for 24 hours at rt. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) were added and the mixture was stirred for further 24 hours at rt. The suspension was filtered off over sea sand and the filtrate was concentrated in vacuo. The residue was extracted by DCM and water. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to give 2.29 g (6.46 mmol, 55.7%) of analytically pure target compound.