Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([I:31])[CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:26])=[C:23]([I:31])[CH:22]=1
Reactant: O=C(O)c1cc(F)c(F)cc1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
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
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (1.89 g, 3.38 mmol), 4,5-difluoro-2-iodobenzoic acid (0.8 g, 2.817 mmol), DIPEA (1.5 mL, 8.45 mmol) and HATU (1.07, 2.817 mmol) in DMF (15 ml) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. MS (ESI) 525 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][NH2:29])[CH3:27])=[CH:22][CH:21]=1>CO>[CH3:7][O:6][CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[CH:1]=[N:29][N:28]=[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:31])[F:30])=[CH:21][CH:22]=1)[CH3:27]
Reactant: COC(c1cc(C)no1)c1ccccc1C=O
Reactant: CC(=NN)c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COC(c1cc(C)no1)c1ccccc1C=NN=C(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To 0.23 g (1 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylisoxazole in 2 ml of methanol was added 0.22 g (1.1 mmol) of 4'-(trifluoromethyl)acetophenone hydrazone and stirred at room temperature for 3 hours. After completion of the reaction, methanol was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-{4-(4-trifluoromethylphenyl)-2,3-diaza-1,3-pentadienyl}benzyl]-3-methylisoxazole (0.23 g, 55.4%) as oil.
Reaction SMILES: N#N.[C:3]([CH2:5][CH2:6][O:7][P:8](Cl)[N:9]([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])#[N:4].[CH2:17]([O:24][C@@H:25]1[C@H:29]([OH:30])[C@@H:28]([CH2:31][O:32][C:33]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:27][C@H:26]1[N:56]1[C:65]2[N:64]=[CH:63][N:62]=[C:60]([OH:61])[C:59]=2[N:58]=[CH:57]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.CN1C=CN=C1>CO.C(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[CH2:17]([O:24][C@@H:25]1[C@H:29]([O:30][P:8]([O:7][CH2:6][CH2:5][C:3]#[N:4])[N:9]([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C@@H:28]([CH2:31][O:32][C:33]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:27][C@H:26]1[N:56]1[C:65]2[N:64]=[CH:63][N:62]=[C:60]([OH:61])[C:59]=2[N:58]=[CH:57]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(O)ncnc43)[C@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Agent: Cn1ccnc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(O)ncnc43)[C@H](OCc3ccccc3)[C@@H]2OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Under the protection of N2, 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (1.21 mL, 5.45 mmol) was added drop-wise to a 0° C. anhydrous tetrahydrofuran (12 mL) solution of 2′-O-benzyl-5′-O-[bis(4-methoxyphenyl)(phenyl)methyl]inosine (1.80 g, 2.72 mmol), N,N-diisopropylethylamine (1.42 mL, 8.17 mmol)), and 1-methylimidazole (0.11 mL, 1.36 mmol). The reaction was gradually warmed to room temperature and stirred for 60 min. The reaction was then quenched with methanol (5 mL) and stirred for 5 min. After the solvent was removed under the reduced pressure, the residue was purified by flash chromatography (gradient: methylene chloride with methanol 0-4%, with 1% triethylamine in both methylene chloride and methanol) to produce 1.83 g (78%, 2.13 mmol) final product. LCMS: for C47H53N6O8P calculated 860.4. found 861.3 [M+H]+ and 884.4 [M+Na]+. 31P NMR (600 MHz, CD3CN) δ: 150.82, 150.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (93 mg, 0.33 mmol), 3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (73 mg, 0.33 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 110.3 mg (69%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.43 (br s, 1H, NH), 11.74 (br s, 1H, NH), 9.23 (br s, 1H), 8.33 (s, 1H), 7.73 (dd, J=2.5 & 6.7 Hz, 1H), 7.44 (m, 1H), 7.32-7.37 (m, 2H), 6.61 (d, J=2.28 Hz, 1H), 3.69 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2), 2.22 (s, 3H, CH3). MS 483 [M+].
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][OH:20])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[N:1]1([CH2:10][C:11]2[CH:26]=[CH:25][C:14]([C:15]3[O:20][CH:19]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[N:17]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A stirred solution of methyl N-{4-[(1H-benzimidazol-1-yl)methyl]benzoyl}-serinate (2.8 g, 7.93 mmol) in THF is treated with Burgess Reagent (2.26 g, 9.45 mmol) and activated 4 Å molecular sieves (1 g), stirred at 60° C. for 2 h, cooled to room temperature and concentrated under reduced pressure. A solution of the resultant residue (0.1 g, 0.29 mmol) in CH2Cl2 is cooled to 0° C., treated with bromo trichloromethane (0.06 g, 0.33 mmol) and DBU (0.05 g, 0.33 mmol), stirred at room temperature overnight and concentrated under reduced pressure. The resultant residue is purified by column chromatography (silica, CH3OH/CHCl3 0→5%) to give the title product in 52% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.28 (s, 1H); 8.08 (d, J=8 Hz, 2H); 8.00 (m, 1H); 7.85 (d, J=8 Hz, 2H); 7.30 (m, 5H); 5.43 (s, 2H); 3.95 (s, 3H). LCMS (ESI+) 334 (MH+).
Reaction SMILES: [C:1]1([C:11]2([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26].C(OCC)(=O)C>ClCCl.CCCCCC>[C:1]1([C:11]2([CH2:16][O:17][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2cccc3ccccc23)CCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2cccc3ccccc23)CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of (1-naphthalen-1-yl-cyclopentyl)-methanol (340) (9.0 g, 39.8 mmol) in dichloromethane (180 mL) was added triethylamine (11.0 mL, 79.5 mL) and the reaction mixture was cooled to 0° C. To this reaction mixture was added mesylchloride and stirring was continued at room temperature for 18 h (silica TLC, 10% ethyl acetate in hexane; Rf=0.2). The reaction mass was diluted with dichloromethane (100 mL), washed with water (2×100 mL) and brine (100 mL) and dried and concentrated in vacuum to get a crude mass which was purified by Combi-Flash using gradient eluent mixture of ethyl acetate and hexane to get pure methanesulfonic acid 1-naphthalen-1-yl-cyclopentylmethyl ester (341) (4.25 g, 35%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].C(=O)([O-])O.[Na+].O>CO>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:14][CH2:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCC(F)(F)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a solution of 2-chloro-1,3-dinitrobenzene (2.94 g, 14.54 mmol) in methanol (30.0 mL) were added 3-amino-2,2-difluoropropanoic acid (2.0 g, 15.99 mmol), sodium hydrogen carbonate (2.69 g, 31.98 mmol) and water (15 mL). The reaction mixture was stirred at 80° C. for 1 day. The starting material wasn't consumed completely. To the mixture was added sodium hydrogen carbonate (5.88 g, 63.96 mmol) and the mixture was stirred at 80° C. for 0.5 day. After cooling, the solvent was removed. The residue was neutralized with 1N hydrochloric acid (100 mL) and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (3.52 g, 12.09 mmol, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([NH2:38])[N:32]=2)[C:27](F)=[N:28][CH:29]=1>C1COCC1>[NH2:38][C:33]1[N:34]=[C:35]([CH3:37])[N:36]=[C:31]([C:26]2[C:27]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=3)=[N:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)[N:32]=1
Reactant: CC(=O)Nc1ccc(N)cc1F
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.7 %

Procedure:
A mixture of N-(4-amino-2-fluorophenyl)acetamide (0.084 g, 0.501 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.487 mL, 2.504 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.417 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min and then removed from the ice bath and stirred for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by prep HPLC. Fractions containing the product were combined and the solvent was removed in vacuo. The residue was basified using sat. NaHCO3 (10 mL). The aqueous layer was extracted with CHCl3 (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated to give the product as a brown solid (40 mg). m/z (ESI, +ve ion) 388.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.08 (s, 1H); 9.63 (s, 1H); 8.75 (d, J=2.74 Hz, 1H); 8.43 (d, J=2.74 Hz, 1H); 7.93-8.06 (m, 2H); 7.88 (br. s., 1H); 7.71 (t, J=8.80 Hz, 1H); 7.45 (dd, J=8.80, 1.76 Hz, 1H); 2.45 (s, 3H); 2.06 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([C:20]([OH:22])=O)[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCCC1>[CH2:48]([NH:55][C:20]([C@@:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:22])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)[C@]1(C(=O)O)CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: CCOC(=O)[C@]1(C(=O)NCc2ccccc2)CC(=O)N([C@@H](C)c2ccccc2)C1
Reaction time: 48 h

Procedure:
(R)-3-Ethoxycarbonyl-1-((S)-α-methylbenzyl)-5-oxopyrrolidine-3-carboxylic acid (10 g) was dissolved in tetrahydrofuran (100 ml). Hydroxybenztriazole (0.89 g) was added and the mixture was stirred. Dicyclohexylcarbodiimide (6.76 g) and benzylamine (3.86 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was allowed to stand for 2 days and filtered through Celite. The filtrate was concentrated under reduced pressure. Ethyl acetate was added, and the mixture was washed with an aqueous solution of potassium carbonate, water, dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The obtained oil was purified by silica gel column chromatography (developing solvent, n-hexane:ethyl acetate=4:1) to give the object compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1Br.[CH3:12][C:13]1([CH3:22])[CH2:18][CH2:17][C:16](B(O)O)=[CH:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13]([CH3:22])([CH3:12])[CH2:14][CH:15]=1
Reactant: N#CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1(C)CC=C(c2cc(CC#N)ccc2N)CC1

Procedure:
The title compound was prepared from (4-amino-3-bromo-phenyl)-acetonitrile (as prepared in the previous step, 805 mg, 3.81 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (705 mg, 4.57 mmol), Pd(PPh3)4 (440 mg, 0.380 mmol), and 2M Na2CO3 (15.2 mL, 30.5 mmol) according to the procedure in Example 34, step (b) (417 mg, 46%). 1H—NMR (CDCl3; 400 MHz): δ 6.89 (1H, dd, J=8.1, 2.0 Hz), 6.84 (1H, d, J=2.0 Hz), 6.59 (d, 1H, J=8.1 Hz), 5.60 (m, 1H), 3.71 (br s, 2H), 2.19-2.15 (m, 2H), 1.90-1.88 (m, 2H), 1.45-1.42 (m, 2H), 0.92 (s, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:11]=[C:12](/[CH:19]=[CH:20]/[C:21]([OH:23])=O)[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12.[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[N:10]1[CH:11]=[C:12](/[CH:19]=[CH:20]/[C:21]([NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][C:29](=[O:38])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:23])[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: O=C(O)/C=C/c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Diisopropylethylamine (DIPEA, 0.34 g, 2.63 mmol) was added to a solution of (E)-3-(imidazo[1,2-a]pyridin-3-yl)acrylic acid (0.17 g, 0.88 mmol) in 20 mL of dichloromethane (DCM). After addition of tert-butyl-2-aminophenylcarbamate (0.22 g, 1.65 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.43 g, 1.14 mmol) the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the reaction mixture was washed with saturated sodium bicarbonate (NaHCO3) and brine. It was dried over Na2SO4, filtered and evaporated to give crude (E)-tert-butyl (2-(3-(imidazo[1,2-a]pyridin-3-yl)acrylamido)phenyl)carbamate. The solid was washed with ethyl acetate (50 mL) and saturated NaHCO3 gave pure product as a light colored solid (0.11 g). ES+(M+H)+379.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]1[N:13]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]1[N:13]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:15][N:16]=1
Reactant: Oc1cccc(F)c1F
Reactant: ClCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(OCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of 2,3-difluorophenol (109 mg) at room temperature in dimethylformamide DMF (5 ml) under an argon atmosphere were added 2-chloromethyl-1-trityl-1H-imidazole (200 mg) and potassium carbonate (193 mg). The mixture was heated to 80° C. and stirring was continued overnight. The brown suspension was cooled to room temperature, diluted with EtOAc and washed with 1 N NaOH. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane→cyclohexane/EtOAc 55:45) to give 2-(2,3-difluoro-phenoxymethyl)-1-trityl-1H-imidazole (240 mg) as a light yellow gum. MS (ISP): 453.0 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:31](=[O:35])[C:32]([NH2:34])=[O:33])=[C:9]([CH2:28][CH2:29][CH3:30])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:34][C:32](=[O:33])[C:31]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]=1[CH2:28][CH2:29][CH3:30])=[O:35]
Reactant: CCCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
A mixture of 440 mg (0.9 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 5 mL of 1N NaOH and 15 mL of MeOH was stirred for 0.75 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl to pH 2-3 and extracted with EtOAc. The EtOAc solution was dried (MgSO4) and evaporated to give 374 mg (88% yield) of [[3-(2-amino-1,2-dioxoethyl)-1([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22](O)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:32]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]([Cl:32])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(Cl)c2ccncc2)cc1
Temperature: 80 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide (1.1 g, 2.5 mmol) was dissolved in SOCl2 and heated at 80° C. overnight. Excess SOCl2 was removed by rotary evaporation. The residue suspended in 50 mL DCM was washed with saturated sodium bicarbonate solution (50 mL) and dried over MgSO4. Evaporation of solvent gave white crystalline solid. MS: (M+H)=450.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[S:29][C:28]([C:30](Cl)=[O:31])=[CH:27][CH:26]=1>C(Cl)Cl>[C:11]([O:10][C:8]([NH:7][C@@H:3]([CH2:2][NH:1][C:30]([C:28]1[S:29][C:25]([Cl:24])=[CH:26][CH:27]=1)=[O:31])[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Commercially available (S)-3-Amino-2-tert-butoxycarbonylamino-propionic acid (BOO-Dap-OH) (408 mg, 2 mmol) was suspended in 4 ml DCM and DIPEA (1.75 ml, 10 mmol). 5-Chloro-thiophene-2-carbonyl chloride (362 mg, 2 mmol) (described in WO 2005068456) in 4 ml DCM was added slowly and the mixture was stirred at RT for 2 h. The reaction was filtered and the solvent evaporated. The resulting solid (895 mg) was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[I:22]N1C(=O)CCC1=O.P(O)([O-])([O-])=O.[Na+].[Na+]>ClCCl>[I:22][C:13]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(C)C)cc1C
Reactant: O=C1CCC(=O)N1I
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(I)c(C(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To methyl 4-isopropyl-2-methylbenzoate (compound 198.1, 2.31 g, 12.0 mmol, 1.0 equiv) in a 100 mL round bottom flask was carefully added TFA (24 mL) and the mixture was cooled to 0° C. N-Iodosuccinimide (2.70 g, 12.0 mmol, 1.0 equi) was added portionwise over 2 minutes and the resulting mixture was added under nitrogen and stirred at 0° C. for 20 min then at room temperature for 15 hours. The mixture was carefully diluted. To a mixture of dichloromethane (50 mL) and added to saturated aqueous disodium phosphate to maintain a pH above 3 (total disodium phosphate about 500 mL). The mixture was shaken well, separated and the aqueous was extracted with additional DCM (5×25 mL). The combined organics was washed with a mix of saturated sodium sulfite (10 mL) plus water (40 mL) followed by brine (50 mL), dried (Na2SO4), filtered and removed in vacuo. The crude product was purified by silica column chromatography (hexanes to 3% ethyl acetate) to obtain the title compound as a light tan oil (3.59 g, 94%). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.17 (septet, J=6.8 Hz, 1H), 2.59 (s, 3H), 1.23 (d, J=6.8 Hz, 6H).