Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O/[N:2]=[C:3](\[C:9](=O)[CH3:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[O:13]([C:15]#[N:16])[K]>CCO.O.[Pd]>[CH3:10][C:9]1[NH:16][C:15](=[O:13])[NH:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N/O)C(C)=O
Reactant: N#CO[K]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.7 %

Procedure:
A mixture of ethyl (2E)-2-(hydroxyimino)-3-oxobutanoate (8.50 g, 53.41 mmol) and 10% Pd/C (0.42 g) in EtOH (25 mL) and a 1.5 M solution of HCl (40 mL) were stirred under hydrogen (50 psig) for 4 h. The vessel was carefully vented then the mixture was filtered through Celite which was subsequently washed with EtOH. The filtrate was concentrated slightly to remove some of the EtOH but the water bath was kept below 40° C. A 5M solution of aqueous HCl (5 mL) was added to the yellow solution and this was added dropwise to a solution of KOCN (6.50 g, 80.12 mmol) in water (25 mL) at RT. The reaction mixture was stirred at RT for 3 days then cooled to 0° C. After 2 h, the precipitate was filtered and washed with a cold 1:1 mixture of MeOH/water (20 mL) and dried under vacuum to afford 1.70 g (19%) of the title compound as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br. s., 1H), 10.14 (br. s., 1H), 4.16 (d, 2H), 2.20 (br. s., 3H), 1.23 (t, 3H). LCMS m/z 171.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[Li+].[CH3:26]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:26])[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of compound 4A (898 mg, 2.50 mmol) in THF (10 mL) at −78° C. under nitrogen was added a 1.8 M solution of LDA (3.50 mL, 6.25 mmol) and the reaction was stirred at −78° C. for 1 h. Iodomethane (1.56 mL, 25.0 mmol) was added, and the mixture was stirred at −78° C. for 4 h. The reaction was quenched by adding EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. Purification via silica gel chromatography (0-15% EtOAc in hexane) provided compound 4B (276 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][C:14](OC(C)=O)=[O:15].O>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:12][C:14](=[O:15])[CH3:13])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) was dissolved in AcOH (140 ml) and Ac2O (5.9 ml, Aldrich) was added. The reaction was stirred at RT overnight. The mixture was added slowly to H2O (˜700 ml) forming a white precipitate. The solid was isolated by filtration, washed with H2O and dried under vacuum to yield N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[CH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:7][C:6]=2[CH:32]=1.CCCCCC.C([Li])CCC.[C:44](=[O:46])=[O:45]>C1COCC1>[C:44]([C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[CH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:7][C:6]=2[CH:32]=1)([OH:46])=[O:45]
Reactant: O=C=O
Reactant: Clc1ccc(C2CCN(CCC=C3Cc4cc(Br)ccc4Oc4ncccc43)CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine (Example 160) (130 mg) in THF (1.0 ml) was added 1.6M n-butyllithium hexane solution (0.17 ml) at −78° C. After stirring 10 minutes at the same temperature, CO2 (dry-ice) was added to the mixture. After being warmed to ambient temperature, the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluted with dichloromethane -methanol (5:1) to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][N:60]([CH2:63][CH2:64][O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])[C:59](=[O:73])[CH:58]=1>ClCCl>[C:69]([Si:66]([CH3:68])([CH3:67])[O:65][CH2:64][CH2:63][N:60]1[CH:61]=[CH:62][C:57]([NH:56][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])=[CH:58][C:59]1=[O:73])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.428 mmol) in dichloromethane (20 mL) was added iPr2NEt (138 mg, 1.07 mmol), followed by the addition of diphenylphosphinic chloride (Aldrich) (203 mg, 0.856 mmol). The mixture was stirred at room temperature for 30 min, then 4-amino-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2(1H)-one (115 mg, 428 μmol) was added. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 5% to 80% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-methoxy-5-methylsulfonylbenzoate (D14) (2.94 g) was dissolved in dioxan (18 ml) and lithium hydroxide monohydrate (0.762 g) in water (18 ml) was added. The mixture was stirred at room temperature for 2 h and then sufficient Amberlyst-15 H+ resin was added to adjust the pH to ˜4. The resin was removed by filtration and washed well with dioxan and the combined filtrates were evaporated. The residue was triturated with ether to give D15 as a pale buff solid (2 crops, 2.29 g).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[O:7])C>CO.O>[CH3:16][C:12]1[N:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nc2cccc(C)n2c1-c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc2nc(C(=O)O)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Potassium hydroxide (0.2 g, 0.003 mol) was added to a suspension of 5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (compound p, 0.35 g, 0.0010 mol) in methanol (0.4 mL) and water (4.7 mL). Stirred at 80° C. for 1 hour. The methanol was removed and 6N HCl added to the residue until pH approx. 5. The white solid that formed was filtered to give 290 mg of 5-methyl-3-(3-(trifluoromethyl)phenyl) imidazo[1,2-a]pyridine-2-carboxylic acid as a white solid. Rf 0.20, 100% ethyl acetate; MS m/z 319 (M−H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[CH3:16][CH:17]([S-:19])[CH3:18].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:19][CH:17]([CH3:18])[CH3:16]
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Reactant: CC(C)[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(C#N)ccc1C1OCCCO1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (5.51 g, 27 mmol) and sodium 2-propanethiolate (2.90 g, 26.6 mmol, purity 90%; 1 eq.) were initially charged in DMF (125 ml). Potassium carbonate (9.19 g, 66.5 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 4 h. TLC control then showed complete conversion. The reaction mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 4:1). The title compound was isolated as a solid (6.72 g, 96% of theory).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([S:47][CH2:48][C:49]3[N:50]=[C:51]([C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=4)[S:52][CH:53]=3)[N:42]=[C:41]([N:61]3[CH2:64][CH2:63][CH2:62]3)[C:40]=2[C:65]#[N:66])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70]>ClCCl>[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70].[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70].[NH2:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([S:47][CH2:48][C:49]3[N:50]=[C:51]([C:54]4[CH:55]=[CH:56][C:57]([Cl:60])=[CH:58][CH:59]=4)[S:52][CH:53]=3)[N:42]=[C:41]([N:61]3[CH2:62][CH2:63][CH2:64]3)[C:40]=2[C:65]#[N:66])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
180 mg (0.188 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate (Example 3A) were initially charged in 5 ml dichloromethane. 1.0 ml (12.98 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT for 30 min. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 153 mg (83% of theory) of the target compound.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([O:21][C:20]([F:19])([F:29])[F:30])[CH:23]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)(F)F)c1
Yield: 60.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 3-(trifluoromethoxy)aniline in place of the 2,4-difluoroaniline. 230 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(trifluoromethoxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([OH:14])=[O:13].N1C2C(=CC=CC=2)C(C(O[CH2:27][C:28]23[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]2)[CH2:30][CH2:29]3)=O)=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([O:14][CH2:27][C:28]12[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29]2)=[O:13]
Reactant: COc1ccc2[nH]cc(C(=O)O)c2c1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: COc1ccc2[nH]cc(C(=O)OCC34CCN(CC3)CC4)c2c1

Procedure:
Quinuclidin-4-ylmethyl 5-methoxy-1H-indole-3-carboxylate was prepared starting from 5-methoxyindole-3-carboxylic acid (synthesized as described in J. Med. Chem. 49, 1125 (2006)) following the procedure of (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate. MS (m/e): 314.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH:14]=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1ccc2[nH]c(C=O)cc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCc1ccc2c(c1)cc(C=O)n2C
Temperature: 150 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of 5-butyl-1H-indole-2-carbaldehyde (75 mg, 0.37 mmol) and methyl iodide (57 mg, 0.40 mmol) in 0.75 mL dimethylformamide was added potassium carbonate (57 mg, 0.41 mmol). The resulting suspension was stirred vigorously at 150° C. in a sealed vial under argon for 1 h. Solids were filtered and the liquor concentrated before being subjected to chromatography on silica gel (40% ethyl acetate in hexanes) to give 5-butyl-1-methyl-1H-indole-2-carbaldehyde (15 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:34]=[CH:33][C:8]2=[N:9][N:10]([C:12]3[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:31])([CH3:30])[C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:13]=3[OH:32])[N:11]=[C:7]2[CH:6]=1)=[O:4].[OH:35][C:36]([CH3:51])([CH3:50])[CH2:37][O:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43]C(O)[CH2:41][C:40]1([CH3:49])[CH3:48]>>[OH:35][C:36]([CH3:51])([CH3:50])[CH2:37][O:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH:1]([O:2][C:3]([C:5]2[CH:34]=[CH:33][C:8]3=[N:9][N:10]([C:12]4[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:31])([CH3:30])[C:23]5[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=5)[C:13]=4[OH:32])[N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:41][C:40]1([CH3:49])[CH3:48]
Reactant: COC(=O)c1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)c4ccc(Cl)cc4)c3O)nc2c1
Reactant: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccc3nn(-c4cc(C(C)(C)C)cc(C(C)(C)c5ccc(Cl)cc5)c4O)nc3c2)CC1(C)C

Procedure:
5-Methoxycarbonyl2-[2-hydroxy-3-(4-chloro-α,α-dimethylbenzyl)-5-tert-butylphenyl]-2H-benzotriazole (3.89 g, 0.0081 mol) and 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethyl-4-hydroxypiperidine (2.41 g, 0.0098 mol) are reacted together according to the procedure of Example 1. The title compound is obtained in a yield of 2.26 g (40.2%) as a yellow solid, melting at 80-90° C., whose structure is consistent with 1Hnmr and mass spectrometry. The compound has a molar absorptivity of 17,411 l/mole cm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1)=[O:7]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccnc(Br)c1
Product: CC(C)c1ccc(NC(=O)c2ccnc(Br)c2)cc1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and 4-isopropylaniline were converted to the title compound
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[C:25](OCC)=[O:26])=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:25](=[O:26])[N:9]2[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: CC(=O)NCCNc1cc(Br)ccc1N
Reactant: CCOC(=O)C(=O)c1ccc(OC)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(Br)cc3n(CCNC(C)=O)c2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of crude N-(2-(2-amino-5-bromophenylamino)ethyl)acetamide from Example 14 in ethanol (0.74 mL) 870 mg of ethyl 2-(4-methoxyphenyl)-2-oxoacetate was added. To that mixture acetic acid was added resulting in of 1% v/v AcOH in EtOH solution. The reaction mixture was stirred at 80° C. for 18 h and allowed to cool to room temperature. The yellow precipitate was collected by filtration and washed with two 5 mL portions of EtOH. The yellow solid was dried under vacuum to provide N-(2-(7-bromo-3-(4-methoxyphenyl)-2-oxoquinoxalin-1(2H)-yl)ethyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.CCOCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH3:7][N:5]1[CH:6]=[C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:3]=[N:4]1
Reactant: Cn1cc(Br)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-methylpyrazole (15 g, 38.5 mmol) in ether (150 mL) n-Butyllithium (2.5M in hexanes, 17 mL, 42.4 mmol) was added at −78° C. After the reaction solution was stirred at −78° C. for 30 minutes, tributyltin chloride (11.5 mL, 42.4 mmol) was added. It was stirred at −60° C. for 1 hour and warmed to room temperature, at which it was stirred for 1 more hour. Then, it was diluted with ethyl acetate (300 mL) and washed with water (200 mL) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel with hexanes/ethyl acetate=10/1 as eluant to get 1-methyl-4-tributylstannylpyrazole as a white wax. 1H NMR (CDCl3, 300 MHz): δ7.42 (s, 1H), 7.23 (s, 1H), 3.93 (s, 3 H). 1.28-1.55 (m, 18 H), 0.91 (t, J=15 Hz, 9 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[O-:21][S:22]([O-:24])=[O:23].[Na+:25].[Na+].CCO>O>[Na+:25].[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:22]([O-:24])(=[O:23])=[O:21])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCc1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure described for 11.1 using 10.4 (0.95 g, 2.85 mmol), Na2SO3 (0.50 g, 4.0 mmol) and EtOH (25 mL)/H2O (7 ml) mixture, the crude 11.4 was obtained and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:46]([S:48][CH2:49][CH2:50][O:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=3)[CH:23]=2)=[C:29]([CH3:36])[CH:30]=1)[CH3:47]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: CCSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCSCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.0 g, 3.15 mmol), 2-(ethylthio)ethanol (0.37 mL, 3.47 mmol) and tributylphosphine (1.18 mL, 4.73 mmol) in tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g, 4.73 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture were added reagents (2-(ethylthio)ethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) in a half amount as above, and the mixture was further stirred for 8 hr. The reaction mixture was diluted with diethyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.96 g, yield 86%) as a yellow oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36](C)(C)[O:37][SiH2]C(C)(C)C)[CH:30]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][OH:37])[CH:30]=1)[CH3:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(CCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
TBAF (1M in THF, 2.90 mL, 2.90 mmol) was added to a sol. of {2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (600 mg, 1.45 mmol) in THF (14.2 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (435 mg, quantitative yield). LC-MS: tR=0.93 min.