Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Yield: 70.4 %

Procedure:
Using 4-bromobenzoic acid (0.50 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.54 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (0.70 g) was obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:16]=1)[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[CH2:27].N1C=CC=CC=1>CCOCC>[C:25]([O:13][CH2:12][C:11]1[CH:10]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:14]=1)(=[O:29])[C:26]([CH3:28])=[CH2:27]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(CO)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCc1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
3,5-Di-tert-butyldimethylsilyloxybenzyl alcohol (13.0 g, 35.2 mmole) and freshly distilled methacryloyl chloride (4.06 g, 38.8 mmole) were dissolved in 75 ml of ether and cooled to 0° C. Pyridine (3.21 g, 40.6 mmole) in ether (10 ml) was added dropwise and the reaction mixture was stirred overnight at room temperature. The pyridinium hydrochloride was filtered off and the filtrate was passed over a silica bed to remove the traces of methacrylic acid. Through the silica bed were passed another 75 ml of ether, and after combination of the fractions, the ether was removed under reduced pressure to obtain an oily product (14.2 g, 32.7 mmole, 93%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]=[C:10]2[NH2:20])=[CH:6][CH:5]=1.[CH3:23]I>CC(N(C)C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]([CH3:23])[C:10]2=[NH:20])=[CH:21][CH:22]=1
Reactant: CI
Reactant: Nc1nc(=O)c2ccccc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c2ccccc2n(Cc2ccc(F)cc2)c1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 570 mg. of sodium hydride in 50.0 ml. of dimethylacetamide is added 2.7 g. of 1-(4'-fluorobenzyl)-2-amino-quinazolin-4(1H)-one followed by stirring for one hour at room temperature. There is then added 3.0 g. of methyl iodide and the resulting solution is stirred for 18 hours at room temperature. The resulting mixture is then evaporated in vacuo to remove the solvent and the residue stripped twice with benzene. The resulting residue is poured over ice-water and the precipitate which forms (about 0.5 hour) is washed with water, dried by suction, dissolved in methylene chloride, treated with sodium sulfate, alumina and charcoal and then filtered through Celite. The solvent is exchanged for ether and concentration results in a precipitate which is recovered by filtering, washed with pentane and dried under reduced pressure to obtain 1-(4'-fluorobenzyl)-2-imino-3-methyl-2,3-dihydro-quinazolin-4(1H)-one, m.p. 135°-137°C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([OH:23])=[CH:10][CH:9]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:23][C:11]1[C:12]2[S:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([F:7])=[CH:9][CH:10]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccccc2sc2c(O)ccc(F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1c2ccccc2sc2c(OCc3ccccc3)ccc(F)c12
Temperature: 25 °C
Yield: 66.2 %

Procedure:
K2CO3 (21.0 g, 150 mmol) was added to a stirred suspension of 1-Fluoro-4-hydroxy-thioxanthen-9-one (18.47 g, 75.0 mmol) in methanol (100 mL) followed by benzylbromide (16 mL, 75.0 mmol) which was added in slow stream via syringe. The resulting mixture was then heated to reflux for 90 minutes and then cooled to room temperature before it was poured onto crushed ice (0.5 L). The resulting precipitate was filtered off and dried (P2O5) to give the title compound as a yellow solid (16.7 g, 66.1%) m/z (LC-MS, ESP): 337 [M+H]+, R/T=5.22 mins
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][CH3:14])(=[O:12])[CH2:10][CH3:11].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:14][O:13][C:9](=[O:12])[CH:10]([CH3:11])[CH:27]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[OH:28]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
LDA (1.3 mL, 2.6 mmol) was added to a solution of methyl propionate (0.22 g, 2.6 mmol) in THF (5 mL) cooled to −78° C. under nitrogen atmosphere. The reaction was stirred for 30 min, and then 4-benzyloxy-benzaldehyde (0.50 g, 2.4 mmol) in THF (5 mL) was added. The reaction was stirred at −78° C. for 5 min, and then allowed to warm to room temperature and stirred overnight. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl acetate:hexane (15:85 to 25:75) gradient to give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-propionic acid methyl ester (0.12 g, 16%) as an oil. MS found: (M+H)+=301.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)=O)(C)(C)C.Cl>CCOC(C)=O>[Br:23][C:21]1[CH:22]=[C:17]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cncc(Br)c2)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: Brc1cncc(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
2-(5-Bromo-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester (320 mg, 0.86 mmol) is added into 4.0 M HCl in EtOAc (10 mL) and the solution is stirred at room temperature for 16 hrs. The solvent is evaporated and the residue is dissolved in water and saturated aqueous NaHCO3 solution is used to adjusted the pH to 9-10. Then the mixture is extracted with DCM for three times. The organic layers are combined, dried over Na2SO4, filtered and concentrated to give 192 mg of the crude 2-(5-bromo-pyridin-3-yl)-1H-indole which is used in the next step directly.
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:22][C:23]([CH3:30])([C:27](O)=[O:28])[C:24]([OH:26])=[O:25].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:59]([N:78]1[CH:82]=[C:81]([CH2:83][CH2:84][CH2:85][NH2:86])[N:80]=[CH:79]1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CN(C=O)C>[CH3:22][C:23]([CH3:30])([C:27]([NH:86][CH2:85][CH2:84][CH2:83][C:81]1[N:80]=[CH:79][N:78]([C:59]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:82]=1)=[O:28])[C:24]([OH:26])=[O:25]
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)N=C=NC(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)O)C(=O)NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[C:13]1[CH:22]=[C:21]([CH3:23])[C:20]2[CH2:19][NH:18][CH2:17][CH2:16][C:15]=2[N:14]=1)[CH3:4].[CH3:24][N:25]1[C:29](S(C)(=O)=O)=[N:28][N:27]=[N:26]1>C1COCC1.[Li]CCCC.[Cl-].[Na+].O.CCOC(C)=O>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[C:13]1[CH:22]=[C:21]([CH3:23])[C:20]2[CH2:19][N:18]([C:29]3[N:25]([CH3:24])[N:26]=[N:27][N:28]=3)[CH2:17][CH2:16][C:15]=2[N:14]=1)[CH3:4]
Reactant: CCc1cccc(CC)c1-c1cc(C)c2c(n1)CCNC2
Reactant: Cn1nnnc1S(C)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cccc(CC)c1-c1cc(C)c2c(n1)CCN(c1nnnn1C)C2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 2-(2,6-diethylphenyl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (21.7 mg, 0.061 mmol) in THF (0.5 mL), 1.6 M n-BuLi in hexanes (0.119 mL, 0.190 mmol) was added at −78° C. under nitrogen. After stirring for 10 min. at the same temperature, 1-methyl-5-(methylsulfonyl)-1H-tetrazole (24.90 mg, 0.154 mmol) was added. The mixture was warmed up to rt and stirred for 19 h. The mixture was diluted with brine and EtOAc. The products were extracted with EtOAc, and the organic layer was concentrated. The crude was purified by RP-HPLC (X-Bridge Phenyl®, H2O (0.1% NH4OH)/CH3CN), then the fractions including the desired product were lyophilized to give the desired product. 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.30 (m, 2 H), 7.14 (d, J=7.58 Hz, 1 H), 6.98 (s, 1 H), 4.58 (s, 2 H), 4.01 (s, 3 H), 3.68 (t, J=5.94 Hz, 2 H), 3.25 (br t, J=5.94 Hz, 2 H), 2.30-2.37 (m, 7 H), 1.06 (t, J=7.58 Hz, 6 H); MS (ESI+) m/z 363.27 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[CH3:39][NH:40][C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1

Procedure:
N-Methyl-3-(1-methyl-1H-indol-6-yl)-3-phenyl-acrylamide CXLIV was prepared from 3-(1-methyl-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].O[N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>C1COCC1>[O:15]=[C:10]1[CH2:11][CH2:12][C:13](=[O:14])[N:9]1[O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: O=C1CCC(=O)N1O
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CCCC(=O)ON1C(=O)CCC1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
4-pentynoic acid (5.0 g, 51 mmol) and N-hydroxy succinimide (5.87 g, 51 mmol) were added to a solution of DCC (12.6 g, 61.2 mmol) in THF (125 ml) at −10° C. The mixture was then stirred for 1 h at −10° C. then left to stir at room temperature overnight. (A white precipitate was observed after 15 min). Acetic acid (0.63 ml) was then added. The resulting DCU was removed by filtration. The filtrate was then evaporated to give 10a (10 g, 100% crude yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][C:24]([O:27]C)=[CH:25][CH:26]=1.B(Br)(Br)Br.ClCCl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:18])[F:19])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[N:23][CH:22]=1
Reactant: COc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)cn1
Agent: BrB(Br)Br
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)cn1
Yield: 31 %

Procedure:
A solution of 3-[4-fluoro-3-(6-methoxypyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (30 mg, 0.077 mmol) in 1,4-dioxane (2 ml) was treated with a 1M solution of boron tribromide in dichloromethane (0.77 ml, 0.77 mmol) and heated at reflux for 72 h. The mixture was partitioned between dichloromethane and water and the aqueous layer adjusted to pH 7. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. 5-[2-Fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]pyridin-2-ol was obtained in 31% yield after purification on silica gel: δH (400 MHz, DMSO) 6.46 (1H, d, J 9), 7.48-7.55 (2H, m), 7.72 (1H, ddd, J 8, 5 and 2), 7.76-7.82 (1H, m), 7.90 (1H, dd, J 8 and 2), 8.30 (1H, s), 9.35 (1H, d, J 7), 11.97 (1H, br); m/z (ES+) 375 (M++H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.Cl.[CH3:11][NH:12][O:13][CH3:14].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of 3-methylglutaric anhydride (5.0 g) and N,O-dimethylhydroxylamine hydrochloride (4.19 g) in dichloromethane (100 mL) was stirred at 0° C. and treated dropwise with pyridine (6.9 mL). The resulting solution was warmed to rt over 45 min and then stirred overnight. After this time, the mixture was concentrated under vacuum, and the resulting residue was taken up in saturated aqueous sodium chloride and 1:1 ether/dichloromethane. The aqueous and organic layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to provide 5-(methoxy(methyl)amino)-3-methyl-5-oxopentanoic acid as a yellow oil (7.27 g). Mass spectrum m/z 188.10 (M−H−).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12](C(O)=O)=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.SC1C=C(C=CC=1)[C:25]([OH:27])=[O:26]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:16][CH:17]=2)[C:25]([OH:27])=[O:26])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cccc(S)c1
Product: Cc1ccc(Sc2cccc(C(=O)O)c2)c([N+](=O)[O-])c1
Yield: 80.9 %

Procedure:
The product from Example 84a (0.94 g, 3.29 mmol) was reacted with 3-mercapto-benzoic acid (0.51 g, 3.31 mmol) as described in Example 84b to give the title compound (0.77 g, 80%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[N:19]2[NH:22][CH3:23])=[CH:11][CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[N:19]2[N:22]([C:24](=[O:26])[CH3:25])[CH3:23])=[CH:11][CH:10]=1
Reactant: CNn1c2cnccc2c2ccc(Cl)cc21
Reactant: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)N(C)n1c2cnccc2c2ccc(Cl)cc21
Yield: 28.3 %

Procedure:
A solution of the product of example 43 (19 mg, 0.082 mmol) in pyridine (0.40 ml) was treated with acetic anhydride (0.037 ml, 0.36 mmol) in two portions over 48 h. The reaction was subsequently concentrated to dryness and the residue coevaporated with AcOH under reduced pressure. The crude product was purified as described in example 46. The pure fractions with product were combined and lyophilized to provide 9 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]/[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[C:37]1(/[CH:43]=[CH:44]/C2C=CC(B(O)O)=CC=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15]/[N:14]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2](/[CH:44]=[CH:43]/[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)\[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A mixture of ethyl Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (830 mg), 4-(E-2-phenylethenyl)phenylboronic acid (268 mg), potassium carbonate (626 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine)palladium (0) (105 mg) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residues were subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at 40° C. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[4-(E-2-phenylethenyl)phenyl]acetic acid (634 mg, yield: 77%) as pale-yellow crystals. m.p. 194-195° C. (decomposition)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:49])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:38][C:39]([CH3:48])([CH3:47])[CH2:40][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[C:25](=[O:37])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)(C)(C)C.Cl>CO>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:49])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:38][C:39]([CH3:47])([CH3:48])[CH2:40][N:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)[C:25](=[O:37])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(CN1CCCCC1)NC(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(CN1CCCCC1)NC(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(/C=C/C(=O)Nc2ccccc2N)cc1
Yield: 12 %

Procedure:
(E)-[2-(3-{4-[(1,1-Dimethyl-2-piperidin-1-yl-ethylamino)-(4-trifluoromethyl-phenylcarbamoyl)-methyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (crude material from Example 15) was treated with 1.25M HCl in methanol (2 mL) at room temperature for 2 hours. The reaction was quenched slowly with solid sodium bicarbonate until the pH was 6-7. The mixture was diluted in acetonitrile with a small amount of dimethylsulfoxide, passed through a 40 μm pipette filter, and then purified by preparative HPLC to obtain 8 mg desired product (12% over two steps). MS: calc'd 594 (MH+) exp 594 (MH+). 1H NMR (CD3OD, 400 MHz) δ 7.81 (d, 2H, J=10.6 Hz), 7.78 (d, 1H, J=15.6 Hz), 7.71 (d, 2H, J=8.2 Hz), 7.64 (d, 2H, J=10.6 Hz), 7.62 (d, 2H, J=8.2 Hz), 7.32 (m, 4H), 6.90 (d, 1H, J=16 Hz), 4.90 (s, 1H), 3.55 (broad m, 2H), 3.17 (broad m, 2H), 3.16 (d, 1H, J=13.6 Hz), 3.01 (d, 1H, J=13.6 Hz), 2.2-1.8 (m, 6H), 1.33 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:13]([C:27]#[N:28])=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=2)[C:11]=1[C:39]#[N:40].[ClH:41]>C(#N)C.[Cu](Cl)Cl>[Cl:41][C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:13]([C:27]#[N:28])=[C:12]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:33][CH:34]=2)[C:11]=1[C:39]#[N:40]
Reactant: N#Cc1c(N)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
262 mg (2.24 mmol) of isopentyl nitrite and 301 mg (2.24 mmol) of copper(II) chloride were initially charged in 10.4 ml of acetonitrile. 500 mg (1.12 mmol) of the compound from Example 5A were added, and the mixture was then stirred at 60° C. for 4 h. After cooling to RT, 2.2 ml of 1N hydrochloric acid were added. The aqueous phase was extracted three times with in each case 30 ml of ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium bicarbonate solution, twice with water and once with saturated aqueous sodium chloride solution and dried over sodium sulfate. After removal of the solvent, the product was used without further purification for the subsequent reaction.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[C:19]4[NH:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13](=[O:20])[N:12](COC)[C:11]=3[CH:24]=2)=[N:4][N:3]=[N:2]1.[ClH:25]>C(O)C>[ClH:25].[NH:4]1[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[C:19]4[NH:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13](=[O:20])[NH:12][C:11]=3[CH:24]=2)=[N:1][N:2]=[N:3]1
Reactant: COCn1c(=O)c2c(c3ccc(Cc4nnn[nH]4)cc31)NCCC2
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2cc(Cc3nnn[nH]3)ccc2c2c1CCCN2
Temperature: 80 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
The compound (34 mg, 0.10 mmol) prepared in step 2 was dissolved in ethanol (5 ml), added with conc. hydrochloric acid (1.0 ml). The resulting mixture was stirred at 80° C. for 10 hours. Once the reaction was completed, the mixture concentrated under reduced pressure and filtered to obtain the title compound (28 mg, yield: 84%, yellow solid).