Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1.CO.[CH:29]1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH2:14][C:15]([O:17][CH3:29])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(O)Cn1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cn1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-indazol-1-ylacetic acid prepared as described in Example 3 (0.319 g) was suspended in dry dichloromethane (6 cm3) and methanol (0.04 cm3) and DMAP (10 mg) added. Dicyclohexylcarbodiimide (0.169 g) was added and the mixture stirred at room temperature for 2 hours and left to stand overnight. The mixture was filtered and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (hexane: TMBE,3:2) to yield methyl 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazol-1-yl]acetate (0.28 g) as an oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])=[O:6].[BH4-].[Na+]>C(O)C.O>[CH3:13][C:12]1[CH:11]=[C:10]([CH3:14])[CH:9]=[C:8]([CH3:15])[C:7]=1[CH:5]([C:4]1[CH:16]=[CH:17][C:18]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[C:2]([Cl:1])[CH:3]=1)[OH:6]
Reactant: Cc1cc(C)c(C(=O)c2ccc(-n3ccnc3)c(Cl)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(O)c2ccc(-n3ccnc3)c(Cl)c2)c(C)c1
Temperature: 50 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
In 100 ml of ethanol is dissolved 15.6 g of oily 3-chloro-4-(1-imidazolyl)-2',4',6'-trimethylbenzophenone obtained in the reference example 4. To the ethanol solution is added a solution of 1.8 g of sodium borohydride in 20 ml of water. After the whole solution is stirred at 50° C. for 17 hours, the reaction mixture is poured into ice-cold water and extracted with chloroform. The chloroform is distilled off and the residue is recrystallized from toluene to give 14 g of α-(2,4,6-trimethylphenyl)-3-chloro-4-(1-imidazolyl)benzenemethanol as white crystals, melting at 156°-157° C.
Reaction SMILES: ON=[C:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C.CN(C)C=[O:24]>Cl.CS(C)=O>[CH:16]1[N:14]2[C:15]3[C:3](=[O:24])[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]=3[NH:11][C:12](=[O:19])[C:13]2=[N:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2c(n3ccnc13)C(=NO)c1ccccc1-2
Agent: Cl
Solvent: CS(C)=O
Product: O=C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 7 h

Procedure:
A suspension of 1.5 g of 10-(hydroxyimino)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 90 ml of approximately 5N aqueous hydrochloric acid solution is stirred while boiling for 7 hours, cooled and then concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 70° C. The product obtained (2 g) is dissolved in 50 ml of dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered and the filter is then washed 3 times with 30 ml in total of dimethylformamide. The filtrate and the washings are combined, 600 ml of distilled water are added and they are centrifuged. The solid is suspended in 20 ml of distilled water, filtered, washed with 20 ml in total of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. The product obtained (1.13 g) is dissolved in 115 ml of dimethyl sulphoxide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered and the filter is then washed twice with 30 ml in total of dimethyl sulphoxide. The filtrate and the washings are combined, 115 ml of distilled water are added and they are centrifuged. The solid is suspended in 20 ml of distilled water, filtered, washed twice with 20 ml in total of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10-dione is thus obtained, in the form of a red-orange solid melting at 360° C. (decomposition) [N.M.R. spectrum: (200 MHz; DMSO d6 ; d in ppm): 7.42 and 7.55 (2t, J=7 Hz, 2H: --H7 and --H8); 7.52 and 7.72 (2d, J=7 Hz, 1H each: --H6 and --H9); 7.62 and 8.13 (2d, J=1 Hz, 1H each: --H of the imidazole); 13.60 (cplx, 1H: --NH--)].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH:12]1([C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[I-].[Na+]>CN(C)C=O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: c1c[nH]c(C2CCCCC2)n1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1-n1ccnc1C1CCCCC1
Temperature: 160 °C
Reaction time: 15.5 h
Yield: 33.9 %

Procedure:
2,5-Dichloro-3-nitropyridine 100 g, 2-cyclohexylimidazole 1.56 g, sodium iodide 500 mg and N,N-dimethylformamide 25 mL were mixed and stirred at 160° C. for 15.5 hours. The reaction liquid was poured in ice water and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was subjected to silica gel chromatography (hexane:ethyl acetate=2:1) to provide 1.08 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:7])[CH:5]=[CH2:6].[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11].[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:8][C:9]([CH3:14])([C:10](=[O:12])[CH2:11][CH2:2][CH:3]=[C:4]([CH3:7])[CH:5]=[CH2:6])[CH3:13]
Reactant: C=CC(C)=CCCl
Reactant: CC(=O)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(C)=CCCC(=O)C(C)(C)C
Yield: 78.6 %

Procedure:
According to the procedure described in Example 7, from 116 g of 1-chloro-3-methyl-2,4-pentadiene and 100 g of 3,3-dimethyl-butan-2-one in the presence of 200 g of powdered potassium hydroxide in 600 ml of toluene there are obtained 141 g of crude 2,2,7-trimethyl-6,8-nonadien-3-one which are subjected to a fractional distillation.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:32][CH3:33])=[CH:9][C:10]2[C:11]3[C:12]4[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:13]=4[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:15][C:16]=3[NH:17][C:18]=2[CH:19]=1)(=O)=O.C([Sn](CCCC)(CCCC)/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])CCC.[Cl-].[Li+].C(OCC)(=O)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[C:13]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:12]=2[C:11]2[C:10]3[CH:9]=[C:8]([O:32][CH3:33])[C:7](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:19][C:18]=3[NH:17][C:16]=2[CH:15]=1
Reactant: CCCC[Sn](/C=C/CCO)(CCCC)CCCC
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1/C=C/CCO)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 95.9 %

Procedure:
A solution of the triflate (169) (0.20 g, 0.35 mmol) prepared as described in example 308, (3E)-4-(tributylstannyl)-3-buten-1-ol (0.19 g, 0.53 mmol) and lithium chloride (29 mg, 0.70 mmol) in DMF (10 mL) was purged by bubbling nitrogen through the liquid for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) was added last and the solution was flushed with nitrogen for 2 min more, then warmed under an atmosphere of nitrogen for 3 h. The mixture was diluted with brine, extracted with ethyl acetate and worked up to give an oil which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:5) gave foreruns, while ethyl acetate/petroleum ether (1:1) increasing to pure ethyl acetate gave (170) as a yellow solid (0.15 g, 95%), mp 271–275° C. 1H NMR δ [(CD3)2SO] 11.86 (br s, 1H), 11.07 (br s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.58 (dd, J=8.1, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.41 (m, 3H), 6.87 (d, J=16.0 Hz, 1H), 6.44 (dt, J=16.0, 7.1 Hz, 1H), 4.62 (t, J=5.3 Hz, 1H), 3.94 (s, 3H), 3.58 (m, 2H), 2.42 (m, 2H). Found: C, 67.09; H, 4.36; N, 5.98. C25H19ClN2O4 requires C, 67.19; H, 4.28; N, 6.27.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](OC(C)(C)C)=[O:29])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:75]([O:79][C:80]([NH:82][C:83](C)([CH3:87])[C:84](O)=O)=[O:81])([CH3:78])([CH3:77])[CH3:76]>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](=[O:29])[C:83]([NH:82][C:80](=[O:81])[O:79][C:75]([CH3:76])([CH3:78])[CH3:77])([CH3:87])[CH3:84])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (17-2,276 mg, 0.683 mmol, 1 equiv), triethylamine (277 mg, 2.73 mmol, 4 equiv), PYBOP (711 mg, 1.37 mmol, 2 equiv) and 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (278 mg, 1.37 mmol, 2 equiv) in in DMF (10 mL) was warmed at 60° C. for 18 hours. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes gave tert-butyl 2-[2-(3{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrol-1-yl]-1,1-dimethyl-2-oxoethylcarbamate (17-3) as a pale yellow gum. LRMS m/z (M+H) 588.9 found, 589.0 required.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([C:35]#[N:36])=[C:30](Cl)[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:29]=[C:30]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:32]([NH2:34])[N:33]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 95 °C
Yield: 35.8 %

Procedure:
To a 25 mL pear flask were added tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (0.076 g, 0.21 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (0.054 g, 0.32 mmol) in DMSO (1 mL) to give a yellow suspension. Triethylamine (0.088 mL, 0.63 mmol) was added and the mixture was heated to 95° C. for 2 hours. The reaction appeared to stall so 1 equivalent of triethylamine was added. After a total of 4 hours of heating, the mixture was cooled and the reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acid mode, 20-25% ACN/water gradient). The product-containing fractions were combined, neutralized with a small amount of saturated NaHCO3, concentrated in vacuo to remove ACN, and then extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a pale beige solid (37 mg, 36%). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 11H), 1.87 (br s, 2H), 2.72 (br s, 2H), 2.97 (br s, 2H), 3.70 (s, 3H), 4.80-5.11 (m, 4H), 5.92 (br s, 1H), 6.59 (d, J=2.27 Hz, 1H), 6.76 (d, J=6.06 Hz, 1H), 7.16 (d, J=2.78 Hz, 2H), 7.32 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C24H32N10O2, 493. found 493.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[F:23][C:22]([F:24])([F:25])[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 1H-indole-7-carboxylate (47.8 g, 273 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (81 g, 341 mmol) were dissolved in DMF (1.3 L) at 0° C. 60% w/w NaH (12 g, 300 mmol) was added portion wise. The ice bath was removed and the mixture stirred at 0° C. for 3 hours, then overnight at RT. The reaction mixture was quenched with 3 L of NH4Cl(sat.) and the aqueous layer was extracted 3 times with 1 L of ether. The organic layers were combined, washed with water and brine. The compound was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 8.90 (d, 1H), 7.70 (s, 1H), 7.60 (d, 2H), 7.40 (d, 1H), 7.10 (t, 1H), 7.00 (d, 2H), 6.70 (d, 1H), 5.70 (s, 2H).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11](=O)[C:12]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][C:15]([C:21]2[C:26]([CH2:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:29][CH3:30])=[N:14][CH:13]=1)C.[Cl-].[NH4+]>CCOCC>[CH:1]1([CH:11]([C:12]2[CH:13]=[N:14][C:15]([C:21]3[C:26]([CH2:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:29][CH3:30])=[CH:16][C:17]=2[O:18][CH2:19][CH3:20])[OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCC1
Reactant: CCOC(=O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopentyl magnesium chloride solution (2 M in THF, 2 mL, 4 mmol) is slowly added to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-nicotinic acid ethyl ester (prepared by a route analogous to that given in Example 2) (163 mg, 0.5 mmol) in ether (5 mL) at 0° C. The mixture is stirred at room temperature for 30 minutes. Saturated ammonium chloride solution (2 mL) is added and the organic solution is separated. The organic layer is separated and dried over anhydrous Na2SO4. The solvents are removed in vacuo and the crude is purified with PTLC (hexanes/EtOAc 3:1) to give cyclopentyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol. 1H NMR: (CDCl3) 8.44 (s, 1H), 7.28 (t, 1H), 7.12 (d, 2H), 6.74 (S, 1H), 4.61 (t, 1H), 4.06 (q, 2H), 2.29 (m, 4H), 1.92 (m, 1H), 1.47 (m, 10H), 1.21 (m, 1H), 1.02 (m, 6H).
Reaction SMILES: [C:1](=[O:42])([O:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:19]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:20][NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=2)=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1](=[O:42])([O:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:19]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:20][NH:21][C:22]([CH3:32])([CH3:33])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[O:31])[CH:25]=2)=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2)[O:2][C:3]([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C)(Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(Cc1cccc(C=O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Manganese dioxide (0.6 g) was added to a solution of (R)-tert-butyl 5-(1-(tert-butyldimethylsilyloxy)-2-(1-(3-(hydroxymethyl)phenyl)-2-methylpropan-2-ylamino)ethyl)-2-oxo-1,2-dihydroquinolin-8-yl carbonate (Example 275, step f) (0.44 g) in dichloromethane (30 mL) and the mixture stirred vigorously at 20° C. for 3 hours. The reaction mixture was filtered through diatomaceous earth and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.42 g.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]([OH:39])=[O:38])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and pyrrolidine-2-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: C([O:8][C:9](=[O:62])[C@H:10]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH:11][C:12](=[O:54])[C@H:13]([CH2:43][C:44]([O:46]CC1C=CC=CC=1)=[O:45])[NH:14][C:15](=[O:42])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:41])[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:40])[NH:29]C(OCC2C=CC=CC=2)=O)=[CH:24][CH:23]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:62])=[O:8])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:54])[CH2:43][C:44](=[O:45])[OH:46])=[O:42])=[O:41])=[CH:23][CH:24]=1)(=[NH:29])[NH2:40]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(C(=O)NCCCCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(C(=O)NCCCCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Yield: 88.7 %

Procedure:
443 mg of N-[3-[(benzyloxy)carbonyl]-N-[5-[p-[N-[(benzyloxy)carbonyl]amidino]benzamido]valeryl]-L-alanyl]-3-phenyl-L-alanine benzyl ester and 111 mg of Pd/C in 9 ml of acetic acid were stirred under hydrogen gas for 31/2 hours. The solution was filtered and evaporated, the residue was dissolved in water and the solution was again evaporated. The residue was stirred in water, filtered off with suction and dried. 246 mg of N-[N-[5-(p-amidinobenzamido)valeryl]-L-α-aspartyl]-3-phenyl-L-alanine, m.p. 241° C., was obtained as the hydrate (1:2).
Reaction SMILES: ClC[C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:17]([OH:21])(=[O:20])[CH2:18][OH:19]>C(#N)C>[C:17]([O:21][C:3]1[C:16]2[C:11]([CH:10]=[C:9]3[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]3)=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:20])[CH2:18][OH:19]
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: O=C(O)CO
Solvent: CC#N
Product: O=C(CO)Oc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
A suspension of 9-chloromethyl anthracene (1.0 g, 4.4 mmol) in dry acetonitrile (50 ml) is added to a solution of glycolic acid (0.71 g 18.8 mmol) (dried by successive evaporation from dry acetonitrile) in acetonitrile (10 ml). The reaction is stirred for 18 hours at room temperature and refluxed for 2 hours. After evaporation of acetonitrile the residue is redissolved in methylene chloride and extracted with water and 0.5M sodium bicarbonate. The solution is dried and solvent evaporated. The residue is recrystallized from refluxing benzene at 40° C. to yield 0.73 g (2.6 mmol) of yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>C1(C)C=CC=CC=1.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>[OH:29][C:23]1([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:30]=[CH2:31])[CH:3]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)c1
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (see Example 135, step 2) (141 mg, 0.300 mmol), tributyl(vinyl)tin (114 mg, 0.360 mmol, 1.2 equivalents, and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol, 5 mol %) in toluene (3 mL) was heated at reflux under nitrogen until all starting material was consumed and precipitation of black palladium occurred (1-2 h). Filtration through Celite® and purification via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 10% ethyl acetate/hexane) yielded 111 mg (90%) tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(3-vinylphenyl)ethyl]piperazine-1-carboxylate as a viscous colorless oil. MS (ES) m/z 415.4 ([M+H]+); HRMS: calcd for C25H38N2O3, 414.2882; found (ESI), 415.2966.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38](O)=[O:39])=[N:35][CH:36]=1>>[Si:22]([O:21][CH2:20][CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cc1ccc(Cl)cn1
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cc3ccc(Cl)cn3)ccn2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 30) and (5-chloropyridin-2-yl)acetic acid (Preparation 80).