Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed by triethylamine (1.39 mL, 10 mmol). After removing the ice bath, the reaction was stirred for 4 h. The mixture was poured into ice water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using EtOAc in hexanes (0-40%) gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H), 2.10-1.79 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: CO[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])(=[O:13])[CH3:12]
Reactant: COCCC1CCOC1=O
Reactant: CC(=O)O
Product: CC(=O)OCCC1CCOC1=O
Temperature: 120 °C
Reaction time: 69 h
Yield: 65 %

Procedure:
In a stirred vessel there is heated to 120° C. a mixture of 20 g of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone, 100 g of glacial acetic acid, and 10 g of Nafion. Following a period of 69 h, the reaction is terminated (conversion: 89%) and the catalyst is separated by filtration. Following purification by distillation, there is obtained 65% of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone (based on the 3-(2'-methoxyethyl)-dihydro-2(3H)furanone used).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:22])=[N:11][C:12]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]([CH3:37])[C:18](=[O:20])[CH:17]([O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:22])[N:11]=2)[CH3:21])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(OC(C)C(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 12 and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:12]3[CH:7]4[C:8]5([C:13]([O:15]C)=[O:14])[CH:11]3[CH:10]1[CH:9]5[CH:6]24)=[O:4].[OH-].[Na+]>CO.O>[C:13]([C:8]12[CH:7]3[CH:6]4[C:5]5([C:3]([O:2][CH3:1])=[O:4])[CH:12]3[CH:11]1[CH:10]5[CH:9]24)([OH:15])=[O:14]
Reactant: COC(=O)C12C3C4C1C1C2C3C41C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C12C3C4C1C1C2C3C41C(=O)O
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Cubane-1,4-dicarboxylic acid dimethyl ester (3.10 g, 14.1 mmol) purchased from Enichem Sintesi SpA, was dissolved in 75 ml of hot methanol in a 250 ml, round-bottomed flask equipped with a condenser. Solid NaOH (ACS grade 0.560 g, 14.1 mmol) was added, and the reaction mixture was refluxed under N2 for 13-15 h, then cooled to room temperature. The reaction mixture was diluted with 120 ml of water and extracted with ether (1×75 ml, 3×25 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated, leaving 373 mg (12%) of recovered starting material. The aqueous layer was acidified to pH 3 with 6N HCl and then extracted with chloroform (4×50 ml). The combined organic phase was dried over sodium sulfate, filtered, and concentrated furnishing 2.25 g (77%) of 1-carboxy-4-carbomethoxycubane as a white powder having a melting point of 178°-179° C. An NMR spectrum of the product at 500 MHz, dissolved in deuterated chloroform, had peaks assigned the following sigma values: 4.27 ppm (multiplet, 6 hydrogens) and 3.71 ppm (singlet, 3 hydrogens).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CC(F)(F)F)CC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of 49 (200 mg, 0.39 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (134 mg, 0.58 mmol) and DIPEA (0.2 mL, 1.16 mmol) and in THF (15 mL) was stirred and heated at 85° C. for 4 h in a sealed flask, then at RT (scheme 22). The reaction mixture was concentrated, diluted with a minimum of methanol in water. The pH was adjusted to 10-11 with a saturated aqueous solution of sodium bicarbonate and a few drops of 1N NaOH at the end. The suspension was shaken for 15 min and the solid was collected by filtration, rinsed with water and dried under high vacuum. The crude product was purified by Biotage (SiliaFlash 25 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 10/90 over 20 CV), to afford the title compound 84 (26 mg, 0.043 mmol, 11% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.54 (bd, J=1.4 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (dd, J=9.0, 1.4 Hz, 1H), 6.64 (dd, J=5.5, 0.8 Hz, 1H), 6.58 (bd, J=2.5 Hz, 1H), 3.55 (s, 2H), 3.15 (q, J=10.2 Hz, 2H), 2.69-2.51 (m, 5H), 2.48-2.35 (m, 4H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS 601.6 (m/z): (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][CH:9]=2)[N:4]([C:24]2[CH:25]=[C:20]([Cl:19])[N:21]=[CH:22][N:23]=2)[CH:3]=1
Reactant: COc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1
Reactant: Clc1cc(Cl)ncn1
Product: COc1ccc(-c2ccc3c(Br)cn(-c4cc(Cl)ncn4)c3c2)cc1

Procedure:
The target compound was prepared as in Example 9 using 3-bromo-6-(4-methoxyphenyl)-1H-indole (500 mg, 1.65 mmol) and 4,6-dichloropyrimidine (247 mg, 1.65 mmol).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1)([CH3:17])([CH3:16])C.[N+:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)CC(=O)C2)([O-:31])=[O:30]>C1COCC1>[Cl:27][C:23]1[CH:24]=[CH:25][C:26]2[C:14]3([CH2:16][C:34]4[C:38](=[CH:39][CH:40]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=4)[CH2:17]3)[O:18][C:19](=[O:28])[NH:20][C:21]=2[N:22]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2nc(Cl)ccc2C2(Cc3ccc([N+](=O)[O-])cc3C2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of N,N,N′,N′-tetramethylethylenediamine (3.3 mL, 22 mmol) in THF (8 mL) is cooled to −20° C. and treated with n-butyllithium (2.5 Min hexanes, 8.8 mL, 22 mmol) over 10 min. After stirring for 30 min, the mixture is cooled to −78° C. and treated with a solution of tert-butyl(6-chloropyridin-2-yl)carbamate (2.29 g, 10 mmol) [Williams US2006/028835] in THF (6 mL) over 15 min. After 1 h, the mixture is warmed to −50° C. and treated with a solution of 5-nitro-1,3-dihydro-2H-inden-2-one (2.66 g, 15 mmol) in THF (8 mL) over 10 min. The mixture is then allowed to warm to rt and stirred for 24 h. The reaction is quenched by addition of saturated aqueous NaHCO3 and the mixture is then extracted with EtOAc (×3). The combined organic extracts are washed successively with water and brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:8].Br[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:19]=O>CN(C)C=O>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][C:7]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC(Br)c1ccccc1
Reactant: CN(C)CCCNC(=S)Nc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(-c2ccccc2)sc1=Nc1ccccc1
Yield: 53.8 %

Procedure:
Using N-[3-(dimethylamino)propyl]-N′-phenylthiourea (650 mg) obtained in Reference Example 3 as described below, 2-bromo-2-phenylacetoaldehyde (600 mg) and N,N-dimethylformamide (11 ml), the title compound (497 mg) was obtained in a similar manner to in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.C([O:19][N:20]=O)CC(C)C>CCOCC.C1COCC1.Cl.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])/[C:10](=[N:20]/[OH:19])/[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCCCc2cc(Br)ccc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1/C(=N/O)CCCc2cc(Br)ccc21
Temperature: 24 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
Example 3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved in 2:1 Et2O/THF (120 mL) and 1N HCl in Et2O (9 mL) was added. The solution was cooled to 0° C. before addition of iso-amylnitrite (1.2 mL, 9 mmol) and the reaction was stirred 18 hours at 24° C., concentrated, and applied to 25 (M) Biotage® silica gel column. Gradient elution from 15-100% B (A=Hexanes; B=EtOAc) over 1 L and gave Example 6, (E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1 g (64%). RT=1.9 minutes (condition 1). LCMS: Anal. Calcd. For C11H10NBrO2: 268. found: 268 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)=[O:14])=[C:11]([CH3:31])[N:10]=1>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:29]=[CH:30][C:9]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:10][C:11]=2[CH3:31])=[CH:17][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2cncn2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 41 mg of 1,2,4-triazol and 14 mg of sodium hydride in 2 mL of DMF was stirred for 10 min. 70 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140° C. for 6 h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-1,2,4-triazol-1-yl)nicotinamide. MS (Q1) 391.4 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:21]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:20][C:19]([O:30][CH3:31])=[CH:18][C:4]=1[C:5](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:6].[OH:32][C@@H:33]([C:45]([O:47][CH3:48])=[O:46])[CH2:34][C:35]([NH:37][C@@H:38]([CH2:43][SH:44])[C:39]([O:41][CH3:42])=[O:40])=[O:36]>>[Si:23]([O:22][C:21]1[C:3]2[CH2:2][S:44][CH2:43][C@@H:38]([C:39]([O:41][CH3:42])=[O:40])[NH:37][C:35](=[O:36])[CH2:34][C@@H:33]([C:45]([O:47][CH3:48])=[O:46])[O:32][C:5](=[O:6])[C:4]=2[CH:18]=[C:19]([O:30][CH3:31])[CH:20]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H](O)CC(=O)N[C@@H](CS)C(=O)OC
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c(CBr)c(C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Product: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)cc2C(=O)O[C@H](C(=O)OC)CC(=O)N1

Procedure:
p-Nitrobenzyl 2-bromomethyl-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate was reacted with methyl (R)-2-[(R)-3-hydroxy-3-methoxycarbonyl-propionylamino]-3-mercapto-propionate in an analogous manner to the procedure described in Example 1(f), and the product was subjected in an analogous manner to a sequence of procedures described in Example 13(f) and in Example 21 to yield dimethyl (4R, 8S)-14-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-12-methoxy-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4,8-dicarboxylate as a white solid. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/hexane, dimethyl (4R, 8S)-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-12-methoxy-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4,8-dicarboxylate as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=2[N:14]=1)[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>[Fe].C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=2[N:14]=1
Reactant: CN(CCN1CCCC1)c1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN(CCN1CCCC1)c1nc2cc(N)ccc2o1

Procedure:
The title compound is prepared according to the procedure outlined in Example 61, Step 3 using methyl(5-nitro-benzooxazol-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine (160 mg, 0.55 mmol), iron powder (154 mg, 2.75 mmol), and acetic acid (5 mL) to yield 60 mg (42%) of product: mass spectrum (ion-spray): (m/z)=261.2 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].I[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:37]=[N:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: CC(=O)Nc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)cn1
Temperature: 90 °C

Procedure:
To a mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (41.5 mg) and N-(5-iodo-pyridin-2-yl)-acetamide (39.3 mg) in N,N-dimethylformamide (2 mL) a 2 M aqueous Na2CO3 solution (0.125 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (8 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, the mixture is filtered over basic alumina and eluted with N,N-dimethyl-formamide/MeOH (9:1; 2 mL). The solvent is evaporated and the residue is purified by preparative HPLC (eluent water (+0.1% NH3)/MeOH) to yield the desired product. HPLC (method 13): tR=0.25 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14](O)([CH3:16])[CH3:15])[N:13]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([CH3:16])=[CH2:15])[N:13]=1
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C(C)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Yield: 78 %

Procedure:
To a 25 mL round bottom flask attached with Vigreux column was added 2-[2-(2,6-Dichloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazol-4-yl]-propan-2-ol (383 mg, 764 μmol), anhydrous toluene (8 mL) and acetic acid (3.5 mL). The reaction solution was allowed to stir at reflux for 1.5 hr. The cooled reaction solution was concentrated in vacuo, and the residue was taken into EtOAc (200 mL) and washed with aq NaHCO3 (100 mL×2) and aq. NaCl (100 mL). The organic phase was partitioned, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed through a 25 g SiO2 column using a mobile gradient of 100% Hx to 80% EtOAc to provide 288 mg (78% yield) of title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (br s, 1H), 8.08-7.97 (m, 2H), 7.92 (d, 1H), 7.89 (d, 2H), 7.75 (t, 1H), 7.64-7.57 (m, 3H), 7.43 (d, 2H), 5.77 (br s, 1H), 5.10 (br s, 1H), 3.29 (s, 3H), 2.11 (s, 3H); MS (ES): 483.1, 485.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.[OH-].[Na+].[NH2:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:2][C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[NH:27][CH:26]=[N:25][CH:24]=1)=[O:9])=[O:3]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(=O)NCCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O

Procedure:
5.24 Grams of 3-acetylaminopropionic acid was dissolved in a mixed solvent of 25 ml of chloroform and 4.04 g of triethylamine. To the solution which was stirred keeping the temperature below -5° C., was added 6.83 g of isobutyl chloroformate. After stirring for additional 20 minutes at room temperature, the resultant solution and 20 ml of 2 N aqueous sodium hydroxide solution were simultaneously added dropwise to 45 ml of aqueous solution containing 3.10 g of histidine which has been adjusted to a pH of 10.50 while the reaction system was stirred and maintained to a temperature below 10° C. and a pH between 10.30 and 10.50. After stirring for additional 30 minutes at room temperature, the reaction solution was settled and the lower layer (chloroform layer) was separated out. The aqueous layer was treated by a similar manner as in Example 4 to obtain 3.65 g of N-acetyl-L-carnosine crystals. The specific rotation power [α]D20 was 26.5 (C=3, H2O). Also, the infrared spectrum (IR) and high resolution nuclear magnetic resonance (NMR) were identical with those of an authentic sample.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH:54]=[CH2:55]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:58]([O:57][C:53]([CH:54]=[CH:55][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:56])[CH3:59]
Reactant: Brc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1

Procedure:
A degazed solution of 1-{3-[(4′-bromobiphenyl-4-yl)oxy]propyl}piperidine (2.8 g), triethylamine (2.8 mL), tri(o-tolyl)phosphine (365 mg), palladium acetate (170 mg) and ethyl acrylate (2.9 mL) in acetonitrile (5 mL) is stirred at a temperature close to 60° C. for one hour, then at room temperature overnight and finally 6 h at a temperature close to 90° C. The solution is concentrated under reduced pressure, redissolved in dichloromethane, filtered and chromatographied over silica gel to give 1.3 g of 1-(3-{[4′-(2-ethoxycarbonylethen-1-yl)biphenyl-4-yl]oxy}propyl)piperidine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[C:5]=1[NH:12][C:13](=[O:27])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[C:6]([Br:11])[CH:7]=1)[NH:12][C:13](=[O:27])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)([CH3:15])[C:3]2=[O:2]
Reactant: COC(=O)c1cc(Br)cc(Br)c1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)C(=O)Nc3c(Br)cc(Br)cc3C2=O)cc1[N+](=O)[O-]
Yield: 26.2 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 3,5-dibromo-2-[2-(4-methoxy-3-nitro-phenyl)-propionylamino]-benzoic acid methyl ester (0.65 g, 1.26 mmol) and LiHMDS (3.78 mmol, 1M solution in THF). After normal workup, the objective compound (160 mg, 27%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, DMSO-d6) δ 1.68 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 7.32 (d, J=9.0 Hz, 1H, ArH), 7.43 (dd, J=8.8, 2.4 Hz, 1H, ArH), 7.69 (d, J=2.4 Hz, 1H, ArH), 7.84 (d, J=2.6 Hz, 1H, ArH), 8.12 (d, J=2.6 Hz, 1H, ArH); MS(EI) m/e 482 [M+], 277, 207, 102 ; HRMS m/e cacld. for C17H12N2O5Br2 481.9113, found 481.9122.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][CH2:18]Br>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:16][O:17][CH3:18])=[CH:7][N:8]=1
Reactant: COc1ccc(O)cn1
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(OC)nc1
Yield: 49257.8 %

Procedure:
To a mixture of 6-methoxypyridin-3-ol (25 g, 0.2 mol) and K2CO3 (82.8 g, 0.6 mol) in DMF (250 mL) was added bromomethyl methyl ether (30 g, 0.24 mmol) slowly at rt for a period of 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 59%) as a colorless oil. LRMS (M+H+) m/z 170.1