Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[NH:6][N:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC(C)C)(C)C.O.ClCCl>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[N:6]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:5]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: C[Si](C)(C)CCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-Iodo-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: 30 g of potassium hydroxide pellets are added to 30 ml of water at a temperature in the region of 0° C. After complete dissolution, 7 g of 3-iodo-5-nitro-1H-indazole, 50 ml of dichloromethane and then 82 mg of tetrabutylammonium bromide are added. The reaction mixture is stirred at a temperature in the region of 0° C. and 5 ml of 2-(trimethylsilyl)ethoxymethyl chloride are added over 15 minutes. The reaction mixture is stirred at a temperature in the region of 0° C. for 1.5 hours, and then 150 ml of water are added and the mixture is reheated to a temperature in the region of 20° C. After settling out, the aqueous phase is extracted with 2 times 70 ml of dichloromethane. The organic extracts are pooled, washed with 2 times 70 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. The residue thus obtained is dissolved in 40 ml of hot diisopropyl ether, filtered under hot conditions through paper and then recrystallized. The crystals are filtered through sintered glass, washed with 2 times 10 ml of diisopropyl ether and then dried under reduced pressure (2 kPa) at a temperature in the region of 20° C. 4.6 g of 3-iodo-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole are thus obtained in the form of a yellow solid (Rf=0.4, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (80/20 by volume)).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:17]=[CH:16][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH3:5][O:4][C:2]([N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([Br:6])[CH:17]=[CH:16][C:10]=2[CH2:11][CH2:12]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: Brc1ccc2c(c1)CCNCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccc(Br)cc2CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Methyl chloroformate (444 mg, 4.70 mmol) was added to a 0° C. mixture of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine (950 mg, 3.82 mmol) and triethylamine (915 mg, 9.04 mmol) in 19 mL of dichloromethane. The resulting solution was stirred at 0° C. for 2 h. Water was added, the layers were separated and the aqueous phase was washed with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to leave 1.07 g of an oil. This material was combined with 52 mg from an earlier experiment and purified by column chromatography on silica gel (24 g SiO2, Analogix column) eluting @ 30 mL/min with 1:1 ethyl acetate/heptane. 763 mg of product was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[N:13]([S:28]([O-:31])(=[O:30])=[O:29])[C:12]2=[O:32])=[O:9])[N:6]=1.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([OH:17])=[O:16])[N:13]([S:28]([OH:31])(=[O:29])=[O:30])[C:12]2=[O:32])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(=O)O)c1csc(N)n1

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 10 ml of water is dissolved 155 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-nitrobenzyloxycarbonyl)-2-oxoazetidine-1-sulfonate (syn-isomer). To the solution is added 145 mg of 10% palladium-on-carbon, and the mixture is subjected to catalytic reduction at ambient temperature under normal pressure with stirring. Three hours later, 10 ml of an aqueous solution of 25 mg of sodium hydrogen carbonate is added to the reaction mixture. The catalyst is removed by filtration, and the filtrate is washed with ethyl acetate, and concentrated under reduced pressure. The concentrate is purified by column chromatograhy on Amberlite XAD-II, followed by lyophilization to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-carboxy-1-sulfo-2-oxoazetidine.disodium salt (syn-isomer).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:33][N:32]=[C:31]2[C:7]=1[CH2:8][CH:9]1[CH:22]3[CH:13]([C:14]4[CH:15]=[CH:16][C:17]([O:23]CC5C=CC=CC=5)=[CH:18][C:19]=4[CH2:20][CH2:21]3)[CH2:12][CH2:11][C:10]12[CH3:34])=[O:5])C>[Pd].C1COCC1.C(O)C>[OH:23][C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH:22]([CH2:21][CH2:20][C:19]=2[CH:18]=1)[CH:9]1[CH2:8][C:7]2[C:31]([C:10]1([CH3:34])[CH2:11][CH2:12]3)=[N:32][NH:33][C:6]=2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]nc2c1CC1C3CCc4cc(OCc5ccccc5)ccc4C3CCC21C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1Cc1c2n[nH]c1C(=O)O
Reaction time: 24 h

Procedure:
Palladium on charcoal (50 mg, 5% Pd) was added to a solution 2-Benzyloxy-6a-methyl-4b,5,6,6a,8,10,10a,10b,11,12-decahydro-7,8-diaza-pentaleno[2,1-a]phenanthrene-9-carboxylic acid ethyl ester(214 mg, 0.5 mmol, CAB03051) in THF (15 mL) and ethanol (15 mL). The resulting mixture was stirred under a hydrogen-atmosphere (balloon) for 24 hours, filtered through a 3 cm layer of celite and concentrated under reduced pressure. The residue was dried under high vacuum. Yield: 165 mg (98%) light grey solid. 1H-NMR (DMSO-d6, 400 MHz), δ: 0.92 (s, 3H, —CH3), 1.30-2.86 (m, 13H), 6.44 (d, J=2.3 Hz, 1H), 6.52 (dd, J=8.6, 2.3 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 9.02 (s, 1H, —OH), 12.90 (bs, 2H, —COOH and NH). LRMS (FAB+): 176.0 (100), 329.1 (45, [M+H]+). HRMS (FAB+): 339.171135 C20H23N2O3requires 339.170868
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14]C)=O)[CH:3]=1.[NH2:16][OH:17].Cl>CO>[OH:17][NH:16][C:12]([C:4]1[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)=[O:14]
Reactant: COC(=O)c1cc(S)n2nc(C)nc2n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1nc2nc(C(=O)NO)cc(S)n2n1
Yield: 107.5 %

Procedure:
Methyl 7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate (500 mg) (2.23 mmol) are suspended in 10 ml of absolute methanol. 2.95 mg (8.9 mmol) of hydroxylamine are added within 4 days while stirring. The reaction mixture is acidified (pH 6) with 3N aqueous hydrochloric acid. The product is filtered off under suction and washed in sequence with water, methanol and diethyl ether. There are obtained 540 mg of N-hydroxy-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxamide as yellow crystals of melting point 178°-179° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:36])[N:4]2[C:29](=[CH:30][C:31]=1[C:32](=[O:35])[CH2:33][CH3:34])[C:7]1=[N:8][C:9]3[C:14]([C:15]([CH2:16][O:17][C:18](=[O:28])[CH2:19][NH:20]C(OC(C)(C)C)=O)=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(C(O)=O)(F)(F)F.O>>[NH2:20][CH2:19][C:18]([O:17][CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[C:29]3[N:4]([CH2:5][C:6]=12)[C:3](=[O:36])[C:2]([CH3:1])=[C:31]([C:32](=[O:35])[CH2:33][CH3:34])[CH:30]=3)=[O:28]
Reactant: CCC(=O)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1COC(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1COC(=O)CN

Procedure:
The title compound was prepared according to the procedure in Example 5B except using 8-methyl-12-[[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (D2O/DSS) d 7.6-7.3 (m, 4H), 6.64 (s, 1H), 5.58 (s, 2H), 4.58 (s, 2H), 4.20 (s, 2H), 2.92 (q, J=7.2 Hz, 2H), 1.94 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Anal. Calcd for C22H21N3O4.CF3CO2H.H2O: C, 55.07; H, 4.62; N, 8.03. Found: C, 55.32; H, 4.69; N, 7.98.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([OH:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1>>[CH:42]1[N:43]=[C:44]([NH2:45])[C:39]2[N:38]=[CH:37][N:36]([C@@H:34]3[O:35][C@H:31]([CH2:30][O:29][P:26]([O:25][P:22]([O:21][CH2:20][C@H:18]4[O:19][C@@H:15]([N:13]5[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH2:10][CH:9]=[CH:14]5)[C@H:16]([OH:49])[C@@H:17]4[OH:48])([OH:24])=[O:23])([OH:28])=[O:27])[C@@H:32]([OH:47])[C@H:33]3[OH:46])[C:40]=2[N:41]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
The effluent was equilibrated with 50 millimolar sodium phosphate and 1.2 millimolar NAD+, pH 7.5 at 25° C. to form the binary complex of alcohol dehydrogenase and NAD. The binary complex was then applied to the 4-[3-(N-6-aminocaproyl)aminopropyl]pyrazole dextran resin prepared as described above using 2 ml. resin per g liver and applying the solution at the rate of 10 ml./min. The affinity resin was then washed with the same buffer, 50 millimolar phosphate and 1.2 millimolar NAD pH 7.5.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:26][C:20]3[N:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O.C(O)(=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:20]3[N:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]=3[CH:18]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
After adding 0.381 g (1.3 equivalents) of sodium hydride (60% dispersion, Aldrich) to a solution of 2.46 g of the 6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 153-3 in dimethylformamide (30 ml), the mixture was stirred at room temperature for 40 minutes, 1.68 ml (1.3 equivalents) of 2-(chloromethoxy)ethyltrimethylsilane was added, the mixture was stirred at room temperature overnight, and then 20 ml of water and 1 ml of acetic acid were added and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (ethyl acetate) to obtain 2.83 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17](O)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(C#N)(=O)(OCC)OCC.[NH2:30][C:31]1[CH:45]=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:35][P:36]([O:37][CH2:38][CH3:39])([O:40][CH2:41][CH3:42])=[O:43])=[CH:44][CH:45]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)C1=Cc2cc(C3CCCCC3)ccc2CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)C2=Cc3cc(C4CCCCC4)ccc3CC2)cc1)OCC
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
To a solution off 7-cyclohexyl-3,4-dihydronaphthalene-2-carboxylic acid (0.51 g) in N,N-dimethylformamide (DMF) (15 ml), diethyl phosphorocyanidate (DEPC) (0.36 g) was added under ice-cooling conditions, followed by stirring for 30 minutes. Diethyl 4-aminobenzylphosphonate (0.54 g) and triethylamine (0.22 g) were then added in this order, followed by stirring under ice-cooling conditions for 2 hours, after which the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to yield 7-cyclohexyl-N-(4-diethoxyphosphorylmethylphenyl)-3,4-dihydronaphthalene-2-carboxamide (0.43 g, 45%) as colorless prisms having a melting point of 137°-138° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:29])[CH:11]([OH:28])[CH:12]([CH3:27])[C:13](=[O:26])[C:14]([CH3:25])([CH3:24])[CH:15]([O:20][CH:21]([CH3:23])[CH3:22])[O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][C:41]([Cl:44])([Cl:43])[Cl:42])=[O:38]>C(Cl)Cl>[Cl:42][C:41]([Cl:44])([Cl:43])[CH2:40][O:39][C:37](=[O:38])[O:28][CH:11]([CH:10]([CH3:29])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:12]([CH3:27])[C:13](=[O:26])[C:14]([CH3:24])([CH3:25])[CH:15]([O:20][CH:21]([CH3:22])[CH3:23])[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-Benzyloxy-5-hydroxy-1,1-diisopropoxy-2,2,4,6-tetramethyl-heptan-3-one 32 (1.0 g, 2.4 mmol) and pyridine (0.8 mL, 7.3 mmol) in CH2Cl2 (10.0 mL) at 0° C. was added 2,2,2-trichloroethyl chloroformate (668.0 μL, 4.9 mmol) and the mixture was then allowed to warm to rt. After 1 h, the reaction mixture was quenched with brine and then extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 93:7) to give 32a (1.285 g, 92%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 1.03-1.09 (m, 12H), 1.15 (d, J=1.8 Hz, 3H), 1.17 (d, J=1.9 Hz, 3H), 1.19-1.21 (m, 6H), 1.97-2.11 (m, 1H), 3.2 (dd, J=6.2 and 9.0 Hz, 1H), 3.54 (dd, J=4.8 and 9.1 Hz, 1H), 3.57-3.60 (m, 1H), 3.82 (qd, J=3.6 and 5.9 Hz, 2H), 4.47 (s, 2H), 4.57 (s, 1H), 4.72 (d, J=11.9 Hz, 1H), 4.81 (d, J=11.9 Hz, 1H), 5.08 (t, J=6.0 Hz, 1H), 7.29-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 11.9, 15.0, 18.8, 21.4, 21.7, 22.3, 23.2, 23.4, 35.7, 42.5, 53.4, 53.9, 69.4, 70.9, 71.4, 73.3, 81.3, 94.7, 103.4, 127.5, 127.6, 128.2, 138.2, 154.0, 215.6; IR (film, NaCl, cm−1) 2966, 1760, 1698, 1247; LRMS (ESI) calcd for C27H41O7Cl3Na [M+Na+] 605.2, found 605.2; [α]23D=−20.4 (c=1.0, CHCl3.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)#[CH:24].C(N(CC)CC)C.[Na+].[Cl-]>CN(C)C=O.[Cu](I)I.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]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]#[C:24][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1OCc1nc2ccccn2c1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
In a flask placed under an argon flow, 2 g (3.82 mmol) of methyl 2-((3-iodoimidazo[1,2-a]pyridin-2-yl)methoxy)benzoate were dissolved in 8 ml of dimethylformamide with magnetic stirring. To this solution were added: 0.074 g (0.382 mmol) of copper iodide, 0.551 g (4.59 mmol) of 1-ethynyl-4-fluorobenzene and 8 ml (57.3 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.35 g (0.382 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being treated with 100 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate, 1/1, v/v). 1.36 g (yield=84%) of methyl 2-((3-((4-fluorophenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methoxy)benzoate were obtained as a pale brown solid. LC-MS: m/z=401 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.63 (d, J=6.7 Hz, 1H), 7.75-7.59 (m, 4H), 7.48 (ddd, J=15.9, 11.5, 4.8 Hz, 2H), 7.40-7.26 (m, 3H), 7.13 (t, J=6.8 Hz, 1H), 7.01 (t, J=7.4 Hz, 1H), 5.40 (s, 2H), 3.68 (s, 3H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([NH:33][C:34](=[O:48])[C@@H:35]2[CH2:39][C@@H:38]([NH2:40])[CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:24]=1.[OH:49][C@H:50]([CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51](O)=[O:52]>ClCCl.C(Cl)(Cl)Cl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([NH:33][C:34](=[O:48])[C@@H:35]2[CH2:39][C@@H:38]([NH:40][C:51](=[O:52])[C@H:50]([OH:49])[CH2:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH:24]=1
Reactant: O=C(O)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1-Hydroxybenzotriazole (147 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (766 mg) were added to a stirred solution of trans-4-amino-N-tert-butoxycarbonyl-L-proline 3-quinolylamide(E, 1.30 g) and (R)-2-hydroxy-4-phenylbutanoic acid (F, 720 mg) in dichloromethane (40 mL) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1, v/v) to give the title compound (1.85 g) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.45 (m, 9H), 1.70 (m, 2H), 1.94 (m, 1H), 2.15 (m, 1H), 2.75 (m, 2H), 3.29 (m, 1H), 3.80 (m, 1H), 4.11 (m, 1H), 4.53 (m, 1H), 4.60 (m, 1H), 6.76 (m, 1H), 7.15-7.26 (m, 5H), 7.48 (m, 1H), 7.57 (m, 1H), 7.73 (m, 1H), 7.95 (d, J=16.8 Hz, 1H), 8.68 (s, 1H), and 8.69 (s,1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]#[N:8])=[O:5].[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>C(O)(=O)C.O.N1CCCCC1>[C:7]([C:6](=[CH:9][CH:10]([CH3:12])[CH3:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])#[N:8]
Reactant: CC(C)C=O
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=CC(C)C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
A solution of piperidine (0.3 mL, 3.04 mmol) in acetic acid (3 mL) was added to a solution of ethyl cyano acetate (10 g, 88.50 mmol) and isobutyraldehyde (9.35 g, 0.13 mol) in acetic acid at room temperature. The reaction mixture was allowed to stand for 24 h at room temperature, then diluted with water (50 mL) and extracted with ether (3×50 mL). The combined ether layers were washed with saturated bicarbonate solution, water, and brine and the organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. Purification by vacuum distillation (95° C. at 0.1 mm Hg) afforded ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g, 30%) as a liquid.
Reaction SMILES: C(B(CC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)C.Br[C:13]1[C:22]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[OH-].[K+].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.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>[O:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:4]3[CH:5]=[CH:6][N:7]=[CH:8][CH:9]=3)[C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: CCB(CC)c1ccncc1
Reactant: Brc1cccc2c1OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cc2c(c(-c3ccncc3)c1)OCCO2

Procedure:
14.7 mmol of diethyl(pyrid-4-yl)borane, 22 mmol of 5-bromo-2,3-dihydro[1,4]benzodioxine, 44.1 mol of KOH in powder form, 7.4 mmol of tetrabutylammonium bromide and 0.74 mmol of tetrakis(triphenylphosphine)palladium in 75 ml of tetrahydrofuran are mixed at room temperature, and the mixture is then refluxed for 24 hours. 225 ml of ethyl acetate are added and the mixture is washed with a saturated sodium chloride solution. Drying is carried out over MgSO4, followed by evaporation and purification over a silica column (eluant CH2Cl2,then CH2Cl2 /CH3COOC2H5 80/20).
Reaction SMILES: BrCC([O:5][CH2:6][CH3:7])=O.[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[NH:14]1[C:9]2[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:15][CH2:7][C:6]1=[O:5]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CNc2ccccc2N1

Procedure:
A solution of ethyl bromoacetate (III, 13.3 ml) in THF (50 ml) is added over 2 hr to a stirred solution of 1,2-phenylenediamine (II, 10.0 g) and triethylamine (16.8 ml) in THF (22 ml) and methylene chloride (22 ml). The mixture is heated at 60° for 3 hr, and is concentrated. The resulting solids are suspended and shaken vigorously in hexane (250 ml) and water (150 ml). The hexane layer is decanted, and the process is repealed with two additional 250 ml portions of hexane. The solids are filtered, dried and recrystallized from methylene chloride/hexane to give the desired product as a solid. The concentrated filtrate is purified by flash chromatography eluting with ethyl acetate/methylene chloride (25/75) to give additional title compound, mp 135°-136°: NMR (CDCl3) 8.30, 6.85-6.95, 6.65-6.80, 4.00 and 3.86 δ.