Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:14][C@H:13]([OH:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:15][C@H:13]2[CH2:12][C@H:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14]2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O[C@H]1C[C@@H](CCOCc2ccccc2)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@H](CCOCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 100 mL flask with cis-3-(benzyloxyethyl)cyclobutanol (1.84 g, 8.9 mmol), 4-nitrobenzoic acid (2.97 g, 17.8 mmol) and Ph3P (4.9 g, 18.7 mmol) inside, dry THF 25 mL was added under argon to give a colorless solution. This was cooled to 0° C. and DIAD (3.7 mL, 18.7 mmol) was added drop by drop. After 15 hr, the volatile materials were evaporated and the crude mixture was purified by silica gel flash chromatography (Hexane:EtOAc=9:1) to give off-white oil contaminated with some DIAD (3.74 g). 1H NMR (CDCl3, 400 MHz): δ 1.81-1.86 (m, 2H), 2.22-2.28 (m, 2H), 2.34-2.41 (m, 2H), 2.48-2.60 (m, 1H), 3.36-3.39 (t, J=6.4, 2H), 4.49 (s, 2H), 5.31-5.38 (m, 1H), 7.25-7.36 (m, 5H), 8.19-8.21 (dd, J=8.8, 2.0, 2H), 8.26-8.29 (dd, J=9.2, 2.0, 2H). 13C NMR (CDCl3, 100 MHz): δ 26.35, 34.84, 35.96, 68.82, 70.74, 73.17, 123.70, 127.76, 128.59, 130.88, 135.97, 138.65, 150.68, 164.42. MS (FAB): expected for C20H21NO5 (M−H)+ 354.38. Found 354.13378. IR (neat) νmax 2979, 2936, 2857, 1720, 1607, 1527, 1349, 1319, 1276, 1119, 1015, 874, 843, 738, 720, 698.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1C(C2C3NN=NC=3N=C(N)N=2)=CC=N1.[H-].[Na+].[Br:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:40]=[CH:41]C=1)[CH2:31]NC(=O)OC(C)(C)C>CN(C=O)C>[Br:26][CH2:27][C:28]1[CH:29]=[C:30]([CH3:31])[CH:40]=[CH:41][N:7]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2nn[nH]c12
Reactant: CC(C)(C)OC(=O)NCc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc(CBr)c1
Reaction time: 0.25 h
Yield: 138.7 %

Procedure:
A stirred solution of the 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (330 mg, 1 mmol) in dry DMF (5 mL) was treated with NaH (40 mg, 60% in oil, 1 mmol), stirred for 15 min, treated with tert-butyl N-(3-(bromomethyl)benzyl)carbamate (300 mg, 1 mmol) and stirred for 1 h. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL), the organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (1:1)]. The resulting yellow syrup was dissolved in MeOH (3 mL), treated with HCl (2 mL, 4-M in dioxane), stirred for 17 h and the resulting solid filtered to give the title compound (258 mg, 80%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@@H:10]([O:11]P(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@@H:6]1[OH:39])=[O:3]>C(N(C(CO)(CO)CO)CCO)CO>[OH:11][CH:10]1[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@H:6]([OH:39])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: OCCN(CCO)C(CO)(CO)CO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
10 mcg of FGF-21 polypeptide (1 mg/ml) were incubated in 20 mM BisTris pH 6.7, 50 mM NaCl, 10 mM MnCl2 containing 10 molar equivalents (0.4 mM) of UDP-GalNAc and MBP-hGalNAcT2 (40 mU/mg) for 6 hours at 30° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH2:6])=O.[CH2:21]([O:23]C(OCC)OCC)C>>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([CH:4]=[N:6][C:21](=[O:23])[NH:1]2)=[CH:7][C:8]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OCc1ccccc1
Reactant: CCOC(OCC)OCC
Product: COc1cc2[nH]c(=O)ncc2cc1OCc1ccccc1

Procedure:
2-Amino-4-methoxy-5-benzyloxybenzamide (JMC, 20, 146) (5 g) was mixed with triethylorthoformate (15 ml) and refluxed overnight. The reaction solution was cooled and triturated with EtOAc (40 ml) then filtered to give 7-methoxy-6-benzyloxyquinazolone (3.2 g). This product was mixed with DIPEA (15 ml) and to the solution was added POCl3 (3 ml) slowly. The reaction mixture was refluxed for 30 minutes and cooled, then poured into a stirred mixture of ice and CHCl3. The solution was further extracted with CHCl3 three times and washed with H2O followed by brine, dried over Na2SO4 and evaporated to give a light brown solid as the chloride for next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1-boc-4-(2-aminophenyl)-piperazine (5.55 g, 20 mmol) and triethyamine (5.6 mL, 40 mmol) in 200 mL of CH2Cl2 was added methanesulfonyl chloride (1.55 mL, 20 mmol). After stirring for about 4 hours, the solution was concentrated, and the residue dissolved in 200 mL of EtOAc. The solution was washed with 1 M HCl (2×), water and brine, and then dried (Na2SO4), filtered and concentrated to afford about 6.68 g (18.8 mmol, 94%) of the title compound as a brown solid. LRMS: 356.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[OH:30])(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N:32]1([CH2:41][C@H:42]([CH3:44])O)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CO.O1CCCC1>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[O:30][C@H:42]([CH3:44])[CH2:41][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Reactant: C[C@H](O)Cn1ncc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O[C@H](C)Cn1ncc2ccccc21
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A mixture of 0.25 g (0.54 mmol) (S)-3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 0.096 g (0.54 mmol) (S)-2-indazol-1-yl-1-methyl-ethanol, 0.285 g (1.08 mmol) triphenylphosphine, and 40 mL dry tetrahydrofuran was stirred at room temperature. Diethyl azodicarboxylate 0.2 mL (1.08 mmol) was added dropwise and the resulting yellow solution was stirred 18 h at room temperature. TLC analysis indicated complete reaction. The reaction mixture was concentrated in vacuo to give a deep yellow oil. The product ether was purified over silica eluting with ethyl acetate to 9:1 ethyl acetate:methanol to yield 0.298 g (0.48 mmol, 89%) of (S)-3-[4-acetylamino-2-((R)-2-indazol-1-yl-1-methyl-ethoxy)-benzenesulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester as a colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][CH3:30])[CH:9]([C:17]1[NH:18][C:19](=[O:28])[C:20]([OH:27])=[C:21]([C:23]([O:25]C)=O)[N:22]=1)[CH2:10][CH2:11][C@H:12]([O:15][CH3:16])[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:29]([N:8]([CH:9]([C:17]1[NH:18][C:19](=[O:28])[C:20]([OH:27])=[C:21]([C:23]([NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)=[O:25])[N:22]=1)[CH2:10][CH2:11][C@H:12]([O:15][CH3:16])[CH2:13][OH:14])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:30]
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Reactant: NCc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)[nH]1
Temperature: 80 °C

Procedure:
To a solution of methyl 2-{(4S)-1-[(tert-butoxycarbonyl)(ethyl)amino]-5-hydroxy-4-methoxypentyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (48 g, 112 mmol) in MeOH (1118 mL) was added 4-fluoro-benzylamine (28 g, 224 mmol) and triethylamine (31.2 mL, 224 mmol). The resulting mixture was sealed and heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with 10% citric acid (˜100 mL), and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was dissolved in acetonitrile and concentrated under reduced pressure (3×) to remove MeOH. The residue was dried under high vacuum for 2 days and used in the next reaction without purification. LC-MS: 523.5 (M+1).
Reaction SMILES: [CH2:1]([N:18]=[C:19]=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[N+:21]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[C:26]([O:30][C:19](=[O:20])[NH:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCNC(=O)Oc1cccc([N+](=O)[O-])c1

Procedure:
Using this procedure heptadecyl isocyanate was treated with 3-nitrophenol to give heptadecyl carbamic acid 3-nitrophenyl ester (mp 66°-73°, Anal. Calcd for C24H40N2O4 : C, 68.54; H, 9.59; N, 6.66. Found: C, 68.44; H, 9.88; N, 6.41) which was hydrogenated to give heptadecylcarbamic acid 3-aminophenyl ester (mp 69°-75°, Anal. Calcd for C24H42N2O4 : C, 73.80; H, 10.84; N, 7.17. Found: C, 73.79; H, 11.08; N, 6.84).
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH:24]([NH2:27])([CH3:26])[CH3:25].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[CH:24]([NH:27][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC(C)C)on1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) and isopropyl amine (22 mg, 0.37 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (26 mg, 0.19 mmol) and the reaction stirred under argon for 3 h at 50° C. Then the mixture was evaporated and the residue purified by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) to afford the title compound (95 mg, 83%) which was obtained as an off-white solid. MS: m/e=343.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-])=O)=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][N+]([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[NH:14][CH:7]=[CH:6]2
Reactant: COc1cccc(C=C[N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc2cc[nH]c12
Reaction time: 8 h

Procedure:
Compound 3 was synthesized according to the procedure of A. Kalir et al. [supra]. To a 250-mL Parr hydrogenation bottle, 4.893 g of 2 (21.84 mmol) was added. Compound 2 was dissolved in 90 mL of hot ethyl acetate and 9.0 mL of acetic acid. To this solution 0.260 g of 10% palladium on activated carbon (Aldrich) was added. This mixture was hydrogenated overnight at 4 atm. When the pressure stabilized, the reaction mixture was filtered and the solvent removed by rotary evaporation. The residue was dissolved in 60 mL of diethyl ether. The ether solution was washed with 35 mL of 5% aqueous ammonium hydroxide, 5% aqueous hydrochloric acid, and water, dried with MgSO4, and filtered. The ether was removed by rotary evaporation to yield 2.009 g of a green oil. This oil was chromatographed over 85 g of silica gel with 6:1 hexanes:ethyl acetate to yield 1.863 g (58%) of 3 as a very pale yellow oil: 1H NMR (CDCl3) δ 3.99 (s, 3H, OCH3), 6.61 (m, 2H), 7.18 (m, 3H), 8.43 (br s, 1H, NH).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([N:29]=[C:30]=[O:31])=[O:28])=[CH:25][CH:24]=1>[Na].C1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([NH:29][C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]3[O:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[O:13][CH2:12]3)[OH:10])[CH2:4][CH2:3]2)=[O:31])=[O:28])=[CH:25][CH:24]=1
Reactant: NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Reactant: COc1ccc(C(=O)N=C=O)cc1
Agent: [Na]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)NC(=O)NC2CCN(CC(O)C3COc4ccccc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxy-ethyl]piperidine (2.0 g 0.0072 m)) was dissolved in sodium dried benzene (100 mls). To the stirring solution was added p-methoxy benzoyl isocyanate (1.27 g 0.0072m) in benzene (20 mls) and the solution stirred at room temperature for 18 hours. The solvent was evaporated and the residue heated with isopropyl alcohol. The insoluble solid was filtered off and triturated with hot ethanol, filtered and dried to give the title compound (0.5 g 15%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[Cl:13][O-].[Na+]>O.Cl>[Cl:13][N:3]1[C:2]([CH3:12])([CH3:1])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]1([CH3:11])[CH3:10]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CS(=O)(=O)CC(C)(C)N1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.1 g (0.1 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane 4,4-dioxide is dissolved in 100 ml of water and 10 ml of 10N hydrochloric acid. The resulting solution is cooled to 0° C and within 90 minutes an addition made dropwise at between 0° and 5° C, with stirring, of 125 ml of a freshly prepared sodium hypochlorite solution (36 g of sodium hydroxide is dissolved in 300 ml of water, and at 0° C24 g of chlorine introduced). The reaction mixture is further stirred for 10 minutes at 0°-5° C; the precipitate is filtered off with suction, washed with water, dried, and crystallised from ligroin to yield 1-chloro-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide (13) as colourless crystals, M.P. 163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:5]2.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[C:25]1[C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[C:28]([CH:47]([CH3:49])[CH3:48])[O:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=1[C:25]1[C:29]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:5]4)=[CH:36][CH:37]=2)=[C:28]([CH:47]([CH3:49])[CH3:48])[O:27][N:26]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Ethyl 6-bromo-2-quinoxalinecarboxylate (0.108 g, 0.384 mmol), 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}methyl)isoxazole (0.27 g, 0.553 mmol), potassium phosphate (0.256 g, 1.21 mmol), palladium(II)acetate (0.0088 g, 0.039 mmol), triphenylphosphine (0.013 g, 0.050 mmol), 1,4-dioxane (8 mL) and water (0.035 mL) were combined and heated at 60° C. with stirring overnight. After 20 hours, the reaction mixture was allowed to stand at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was separated and extracted a second time with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil. The crude product was purified by flash chromatography over silica with hexanes:ethyl acetate (100:0 to 50:50) to give a yellow solid. The solid was dissolved in dichloromethane and the solution was concentrated to give 0.12 g (56%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoxalinecarboxylate as a yellow amorphous solid. 1H NMR (CDCl3, 400 MHz): δ 9.52 (s, 1H), 8.31 (d, J=9 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 8.06 (dd, J=9, 2 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.41 (m, 2H), 7.32 (dd, J=9, 7 Hz, 1H), 6.92 (d, J=9 Hz, 2H), 4.80 (s, 2H), 4.60 (quartet, J=7 Hz, 2H), 3.36 (septet, J=7 Hz, 1H), 1.51 (t, J=7 Hz, 3H), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 562 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33].CCN(CC)CC.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33])[C:46]([CH:43]1[CH2:45][CH2:44]1)=[O:47]
Reactant: O=C(Cl)C1CC1
Reactant: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N(Cc1ccccn1)Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 482.4 %

Procedure:
(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added Et3N (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min. After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with H2O and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]−); IR (thin film) 1645, 1115, 808 cm−1.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:15]=[C:14]([C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)C.[OH-].[Li+]>O1CCCC1.O>[CH3:26][N:24]([CH3:25])[S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:15]=2)=[O:29])=[CH:22][CH:21]=1)(=[O:27])=[O:28]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N(C)C)cc2)c2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(C(=O)c2cc(CC(=O)O)cc3ccccc23)cc1
Yield: 77878.5 %

Procedure:
To a stirred solution of [4-(4-dimethylsulfamoyl-benzoyl)-naphthalen-2-yl]-acetic acid ethyl ester (180 g, 0.42 mmol) in tetrahydrofuran:water (1:1; 4 mL) was added lithium hydroxide (40 mg, 0.97 mmol) at room temperature, and the resulting mixture was heated at reflux for 6 hours. The solvents were removed under reduced pressure, and the residue was washed with diethyl ether (5×5 mL), and then acidified with 50% aqueous hydrochloric acid solution (10 mL) and extracted with ethyl acetate (3×25 mL). The collected organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude solid, which was further washed with a hexane/ethyl acetate/ether mixture and freeze dried to give pure [4-(4-dimethylsulfamoyl-benzoyl)-naphthalen-2-yl]-acetic acid (130 g, 77%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.35 (br. s, 1 H), 7.96-8.11 (m, 5 H), 7.91 (d, J=8.2 Hz, 2 H), 7.52-7.68 (m, 3 H), 3.83 (s, 2 H), 2.66 (s, 6 H); HRMS cald. for C21H19NO5S (ESI+) [(M+H)+] 398.1057, obsd. 398.1056.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:14][OH:15])[CH2:8]1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O>[CH2:16]([O:23][C:24]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:14][OH:15])[CH2:8]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1CCCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCCC(CO)C1
Temperature: 0 °C
Yield: 94 %

Procedure:
Potassium carbonate was added to a mixture of azepan-3-yl-methanol (145) (0.032 g, 0.2485 mmol) in THF/H2O (2:1, 0.31 mL). The suspension was cooled to 0° C., and (benzyloxy)carbonyl chloride (0.071 mL, 0.497 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight, and was then concentrated in vacuo. CH2Cl2 and H2O were added. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by automated silica gel chromatography with 75:25 Hexanes:EtOAc to obtain 3-Hydroxymethyl-azepan-1-carboxylic acid benzyl ester (146) in approximately 94% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:26]([C:28]3[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:34]#[N:35])[CH2:25][C:24](=[O:36])[NH:23][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K97) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (82 mg).