Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O=O.C[O:10][C:11](=O)[CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH:14]=1.[H-]>C(OCC)C.O>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([CH2:12][CH2:11][OH:10])=[CH:14]1
Reactant: COC(=O)Cc1coc2ccccc12
Agent: O=O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: OCCc1coc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiAlH4 (1.025 g, 37.95 mmol) was suspended in diethyl ether with exclusion of oxygen. A solution of the benzofuran-3-ylacetic acid methyl ester just prepared (2.546 g, 13.4 mmol) in diethyl ether (15 ml) was then slowly added to the mixture and the mixture was stirred at room temperature for 30 min. The course of the reaction was monitored by TLC. For complete hydrolysis of the excess hydride, a mixture of water (2 ml) and diethyl ether (5 ml) was cautiously added dropwise to the mixture. The ethereal solution obtained was filtered over kieselguhr and the filter cake was rinsed with diethyl ether. After removal of the solvent, the desired alcohol was obtained in a yield of 1.93 g (89%) as a pale yellow oil and was employed for the further synthesis without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Br:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Reactant: CC(Br)c1ncnc(Cl)c1I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g) then, 4-chloro-6-(1-bromoethyl)-5-iodopyrimidine (1.8 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].Cl[CH2:8][C:9]1[CH:39]=[CH:38][C:12]([C:13]([NH:15][C:16]2[S:17][C:18]3[C:24]([C:25]4[N:26]=[C:27]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[S:28][CH:29]=4)=[CH:23][CH:22]=[C:21]([O:36][CH3:37])[C:19]=3[N:20]=2)=[O:14])=[CH:11][CH:10]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[S:17][C:18]3[C:24]([C:25]4[N:26]=[C:27]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[S:28][CH:29]=4)=[CH:23][CH:22]=[C:21]([O:36][CH3:37])[C:19]=3[N:20]=2)=[O:14])=[CH:38][CH:39]=1)[CH3:6]
Reactant: CNCCOC
Reactant: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(-c4csc(N5CCOCC5)n4)c3s2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
0.035 g N-(2-methoxyethyl)-methylamine (0.00039 Mol) and 0.064 g (4-chloromethyl-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl]-benzamide (0.00013 Mol) dissolved in THF (2 ml) were heated to reflux for 4 hrs. After cooling to room temperature and evaporation of the solvent the residue was triturated with water (7 ml). A precipitation formed, which was filtered, washed with water and dried yielding the title product as an off-white solid (79%); F.p.: 100-110° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=2[N+:27]([O-:29])=[O:28])=[N:22]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc(F)cc2[N+](=O)[O-])n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.32 g, 3.2 mmol) and ethyl isocyanate (0.23 g, 3.2 mmol) were added to a solution of 3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole (0.69 g, 2.9 mmol) in ethyl acetate (10 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow solid of N-ethyl-3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (0.72 g, yield: 79.7%). mp: 81-84° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.34 (dq, J=1.4 and 7.2 Hz, 2H), 5.78 (q, J=0.8 Hz, 1H), 6.71 (br s, 1H), 7.34-7.37 (m, 2H), 7.73 (ddd, J=1.2, 2.2 and 7.7 Hz, 1H).
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13](N2C=C[N+](C)=C2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([N:28]([CH3:37])[C:29]([C@@H:31]1[CH2:35][C@@H:34]([OH:36])[CH2:33][NH:32]1)=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].C(OC([C@@]1(NC(N2C[C@H](O)C[C@H]2C(=O)N(CCCCC=C)C)=O)C[C@@H]1C=C)=O)C>>[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([N:32]2[CH2:33][C@H:34]([OH:36])[CH2:35][C@H:31]2[C:29](=[O:30])[N:28]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH3:27])[CH3:37])=[O:14])[CH2:9][C@@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3]
Reactant: C=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Agent: [I-]
Product: C=C[C@H]1C[C@]1(NC(=O)N1C[C@H](O)C[C@H]1C(=O)N(C)CCCCC=CC)C(=O)OCC
Yield: 38 %

Procedure:
Compound 72a was synthesized from compounds 34 and 71a as a beige solid in 38% yield, following the procedure as described for compound 50.
Reaction SMILES: C([O:3][C:4]([CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][N:8]([CH2:19][CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([N:31]4[CH:35]=[N:34][N:33]=[CH:32]4)[CH:29]=3)[NH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO>[C:15]([O:14][C:12]([N:11]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([N:31]4[CH:32]=[N:33][N:34]=[CH:35]4)[CH:29]=3)[NH:24][CH:23]=2)[CH2:7][CH:6]1[C:4]([OH:5])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1CN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of 4-tert-butyloxycarbonyl-1-[3-(5-(1,2,4-triazol-4-yl) -1H-indol-3-yl)propyl]piperazine-3-carboxylic acid ethyl ester contaminated with a small amount of the 2-isomer (524 mg, 1.1 mmol; see Example 3, Step 2) in EtOH (10 mL) was added NaOH (0.54 mL of a 4M aqueous solution, 2.2 mmol). The mixture was heated at 50° C. for 2 h, then cooled to room temperature and evaporated lit vacuo. The residue was dissolved in water (10 mL) and neutralized using 1M hydrochloric acid. The solvent was evaporated and the residue chromatographed on silica gel, eluting with CH2Cl2 :MeOH:AcOH (90:10:1→80:20:2), to afford 4-tert-butyloxycarbonyl -1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperazine-3-carboxylic acid, as a cream-coloured foam, contaminated with a small amount of the 2-isomer.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[OH:16][C:17]1[C:18]([SH:23])=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:23][C:18]2[C:17]([OH:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: Oc1cccnc1S
Product: CCCc1c(CSc2ncccc2O)ccc(C(C)=O)c1O
Yield: 78.6 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.25 g of 3-hydroxy-2-mercaptopyridine, 0.33 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-3-hydroxypyridine was obtained in a manner similar to Example 14.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl.CC(O)=O>[CH:1]1([CH2:7][S:8]([C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Nc1nc2cc(SCC3CCCCC3)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)CC3CCCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3.2 g of [5-[(cyclohexylmethyl)thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 120 ml CHCl3 and 120 ml HOAc at -20° C there is added a solution of 2.1 g of m-chloroperbenzoic acid. The resulting mixture is stirred and allowed to warm to room temperature. Stirring is continued for 5 hours and then CHCl3 is removed in vacuo. Water is added and the solution is neutralized with NaHCO3. The resulting solid is filtered off and crystallized from acetonitrile (1.5 g) to give the title compound, m.p. 272°-274° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH3:13].[C:15]([Cu])#[N:16].[Li+].[Cl-].Cl>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:15]#[N:16])[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1cc(Br)c(F)cc1OC
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)c(F)cc1OC
Temperature: 150 °C
Yield: 142.5 %

Procedure:
A stirring solution of 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (5.0 g, 10.0 mmol) in DMF (38 mL, 0.5 M) was treated with CuCN (3.92 g, 43.7 mmol). Equipped with a reflux condenser, the mixture was heated at 150° C. for 24 hours. After cooling, the reaction was poured into a 2 L erlenmeyer flask. Ethyl acetate (400 mL), saturated aq LiCl (100 mL), 1N HCl (100 mL), 11 g of iron (III) chloride hexahydrate, and 15 mL of concd HCl was added to the solution. This green mixture was heated at 70° C. for 2 h (or until emulsion dissapated). After cooling to room temperature, the mixture was poured into a seperatory funnel and extracted with ethyl acetate (600 mL total). The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL) and saturated aq NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 5-cyano-4-fluoro-2-methoxy-benzoic acid methyl ester (2.98 g, 0.75%) as a white crystalline solid: 1H NMR (CDCl3, 300 MHz) δ 8.15 (d, J=7.5 Hz, 1 H), 6.80 (d, J=11.1 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H).
Reaction SMILES: C(O)C.[CH2:4]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1CCCCC1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>C(OCC)C>[CH2:4]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[C:32]3[S:28][C:29](=[O:34])[NH:30][C:31]3=[O:33])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc2c1ccn2Cc1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc3c2ccn3Cc2ccccc2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To 60 ml of ethanol, there were dissolved 3.00 g of 1-benzylindole-4-carbaldehyde prepared in Example 1 and 0.22 g of piperidine, followed by addition of 2.99 g of 2,4-thiazolidinedione to the resulting solution and heating the mixture under reflux for 24 hours. To the reaction solution, there was added 120 ml of diethyl ether and the mixture was stirred at 0° C. for one hour. The crystals precipitated were filtered off and washed with a diethyl ether/ethanol (2:1) mixed solvent. The crystals were dried under reduced pressure to give 3.24 g of 5-(1-benzylindol-4-yl)methylene-2,4-thiazolidinedione as yellow crystals. The yield thereof was found to be 76%.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[N:10]=1.Br[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:24]([CH3:37])[CH:23]=1>C1(C)C=CC=CC=1>[CH3:28][C:26]1[CH:27]=[C:22]([N:14]2[CH2:13][CH2:12][C:11]3[N:10]=[C:9]([C:8]([F:7])([F:19])[F:20])[CH:18]=[CH:17][C:16]=3[CH2:15]2)[CH:23]=[C:24]([CH3:37])[C:25]=1[NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3nc(C(F)(F)F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(dibenzylidineacetone)palladium (15 mg, 0.026 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (40 mg, 0.1 mmol) were added to dry toluene (5 mL purged with argon for 30 min), and the mixture was stirred for an additional 30 minutes at room temperature under argon. Potassium tert-butoxide (188 g, 71 mmol), compound 7 (191 mg, 0.8 mmol), aid compound 8 (200 mg, 0.67 mmol) were then added; the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature, filtered through a pad of silica gel, and purified by preparative TLC (DCM/MeOH 5%) to afford compound 11.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:12]=[C:8]1[CH:7]=[C:6]([C:13]([F:16])([F:14])[F:15])[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:3][CH:4]=2)[O:9]1
Reactant: O=c1cc(C(F)(F)F)c2ccc(O)cc2o1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
To a solution of 7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one (213 mg, 0.925 mmol) in DMF (1.5 mL) was added tert-butyl (2-bromoethyl)carbamate (416 mg, 1.851 mmol) and K2CO3 (384 mg, 2.776 mmol) at r.t. After stirred at 85° C. for 12 hours, the reaction mixture treated with 10.0 mL of saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with Ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v Hexane:Ethyl acetate as solvent to afford title compound (300 mg, 87% yield) as a white solid. 1H NMR 300 MHz (CDCl3) δ 7.64 (d, J=6.0 Hz, 1H), 6.91 (m, 2H), 6.61 (s, 1H), 4.95 (s, 1H), 4.11 (m, 2H), 3.58 (m, 2H), 1.56 (s, 9H), HRMS (m/z): [M+H]+ calculated for C17H18F3NO5. found, 374.1207.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2.[CH2:29]([OH:34])/[CH:30]=[CH:31]\[CH2:32][OH:33].C([O-])(O)=O.[Na+]>CN1CCCC1=O.Cl[Pd]Cl>[OH:33][CH2:32][CH2:31][CH:30]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2)[CH2:29][OH:34]
Reactant: CC(C)C1=NCCc2ccc(C=Cc3cc(Br)c4cc(C#N)ccc4c3)cc21
Reactant: OC/C=C\CO
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)C1=NCCc2ccc(C=Cc3cc(C(CO)CCO)c4cc(C#N)ccc4c3)cc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A solution of Example 1K (3.09 g, 10 mmol) in N-methylpyrrolidinone (10 mL) was treated with PdCl2 (120 mg, 1 mmol), cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and NaHCO3 (1.01 g, 12 mmol), heated to 130° C., stirred for 1 hour, cooled to room temperature, and purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]3[CH3:21])=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), 151b (1.0 g, 3.4 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.7 g, 10.2 mmol), and cesium carbonate (2.2 g, 6.8 mmol). After bubbling nitrogen through the resulting mixture for 10 minutes, XantPhos (198 mg, 0.34 mmol) and tris(dibenzylideneacetone)dipalladium(0) (313 mg, 0.34 mmol) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 151c as yellow solid (1.1 g, 63%). MS-ESI: [M+H]+ 478.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@@:13]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C@H:17](OS(C)(=O)=O)[C@@H:16]2[C@H:14]1[C@H:15]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1OCCOCCOCCOCCOC1.CN(C)C=O>O>[N:1]([C@H:17]1[C@@H:16]2[C@@H:14]([C@H:15]2[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@:13]([NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:11])([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@@H:18]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](OS(C)(=O)=O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](N=[N+]=[N-])[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 71.8 %

Procedure:
Sodium azide (8.29 g, 127.45 mmol) is added to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-[(methylsulfonyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (16.99 g, 25.49 mmol) and 15-crown-5 (508.57 μL, 561.46 mg, 2.55 mmol) in dimethylformamide (254.90 mL, 240.96 g, 3.30 moles) at 85° C. and stirred. After 7 days, the reaction is cooled to room temperature then diluted with water and extracted with ethyl acetate (3×). The combined organics are washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography eluting 2-60% ethyl acetate in hexanes to yield the title compound (11.2 g, 18.3 mmol, 72%). MS (m/z): 635/637 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.[CH3:25][Mg]Br>C1COCC1>[OH:1][C:2]1([CH3:25])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: C[Mg]Br
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CCC(=O)C3)cc2)cc1
Solvent: C1CCOC1
Product: CC1(O)CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
The product from Example 154 (130 mg, 0.41 mmol) in dry THF (6 mL) under an atmosphere of nitrogen at 0° C. was treated with a 3.0M solution of methylmagnesium bromide (0.82 mmol). After warming to ambient temperature and stirring for 2 hours, the mixture was quenched with 3 mL of cold saturated ammonium chloride solution and then the solution was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (55% yield).
Reaction SMILES: [NH2:1][CH:2]([C:16](=[O:34])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][N:27]=1)[CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[CH3:15].[CH2:35]=[O:36]>C(O)(=O)C>[CH:35]([NH:1][CH:2]([C:16](=[O:34])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][N:27]=1)[CH2:3][C:4]1[C:5]([CH3:15])=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:36]
Reactant: CC(=O)Oc1cc(C)c(CC(N)C(=O)N2CCCCC2c2ncc(-c3ccccc3)[nH]2)c(C)c1
Reactant: C=O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(C)c(CC(NC=O)C(=O)N2CCCCC2c2ncc(-c3ccccc3)[nH]2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 0.7 mmol of acetic acid 4-{2-amino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenyl ester and 0.8 mL of formaldehyde, cooled in an ice bath under argon, was added 0.5 mL of acetic acid. The resulting mixture was allowed to slowly return to room temperature and stir overnight. The mixture was then extracted with ethyl acetate. The ethyl acetate was washed with water, dried over magnesium sulfate and concentrated to 0.39 g of an orange-yellow oil which was taken to the next step without further purification.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Product: COC(=O)c1ccc2occ(-c3ccc(OC(F)(F)F)cc3)c2c1
Yield: 74 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(trifluoromethoxy)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 74%) was obtained as colorless crystals.