Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:11][C:12](=[O:14])[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:17]([Si](C)(C)C)([F:20])([F:19])[F:18]>C(#N)C.C(OCC)C>[F:18][C:17]([F:20])([F:19])[C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:13][C:12]([OH:11])=[O:14]
Reactant: O=C1C=C(c2ccc(F)cc2)C(=O)O1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccc(F)cc1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-fluorophenylmaleic anhydride (1.42 g, 7.39 mmol) (prepared by procedures similar to those described in Dean, W. D.; Bum, D. M. J. Org. Chem. 1993, 58, 7916-7917), in acetonitrile (15 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (1.1 g, 7.39 mmol), followed by the drop-wise addition of CF3SiMe3 (1 ml, 7.39 mmol), under nitrogen. The reaction mixture was stirred for 1 h, and then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The organic layer was removed and the aqueous layer acidified to pH=1 by the addition of conc. hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer removed, dried (Na2SO4), and the solvent evaporated in vacuo to yield D5 (1.4 g, 72%) as a mixture of isomers. C11H6F4O3 requires 262 Found 261 (M-H−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:21](=O)([O-])[O-].[K+].[K+].CBr>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccnc1S(=O)(=O)Nc1ccccc1
Agent: CBr
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccnc1S(=O)(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.8 g), acetonitrile (100 mL) and potassium carbonate (1.9 g) was treated with a mixture of methyl bromide (1.5 mL) and acetonitrile (6.0 mL), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure, triturated with dichloromethane and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a tan oil (1.5 g).
Reaction SMILES: [CH3:1][CH:2]1CC2C(=CC=C(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)C=2)N1.C(C1C=C(C2OC(C)=C(CCl)N=2)C=CC=1)C.C([C:46]1[CH:47]=[C:48]([C:52]2[O:53][C:54]([CH3:78])=[C:55]([CH2:57][N:58]3[C:66]4[C:61](=[CH:62][C:63]([C:67]([OH:76])([C:72]([F:75])([F:74])[F:73])[C:68]([F:71])([F:70])[F:69])=[CH:64][CH:65]=4)[CH2:60][CH:59]3[CH3:77])[N:56]=2)[CH:49]=[CH:50][CH:51]=1)C>>[CH2:1]([C:51]1[CH:46]=[CH:47][C:48]([C:52]2[O:53][C:54]([CH3:78])=[C:55]([CH2:57][N:58]3[C:66]4[C:61](=[CH:62][C:63]([C:67]([OH:76])([C:68]([F:69])([F:71])[F:70])[C:72]([F:74])([F:75])[F:73])=[CH:64][CH:65]=4)[CH2:60][CH:59]3[CH3:77])[N:56]=2)=[CH:49][CH:50]=1)[CH3:2]
Reactant: CCc1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Agent: CCc1cccc(-c2nc(CCl)c(C)o2)c1
Product: CCc1ccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)cc1

Procedure:
In analogy to example 51.3, from 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole (example 51.2) and 2-(3-ethyl-phenyl)-4-chloromethyl-5-methyl-oxazole was prepared 2-{1-[2-(3-ethyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, orange gum, MS: 499 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[S:14])[CH2:4][CH2:3]1.C(O)C.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:18]([NH:20][C:13]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:14])[CH3:19]
Reactant: O=C1CCC(N=C=S)c2ccccc21
Reactant: CCN
Solvent: ClCCl
Solvent: CCO
Product: CCNC(=S)NC1CCC(=O)c2ccccc21
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-oxo-1-naphthyl isothiocyanate (5.0 g.) in methylene chloride (100 ml.), ethylamine is added via ethanol )15 ml.) saturated with ethylamine. After stirring for 18 hours, the mixture is heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water and the title compound collected and dried; m.p. 134° C. to 138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[Cu][C:14]#[N:15].O.C(O)C>CC(O)COC(C(C)=C)=O>[C:14]([C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([F:1])[CH:7]=1)#[N:15]
Reactant: N#C[Cu]
Reactant: CC(=O)Nc1ccc(I)cc1F
Agent: C=C(C)C(=O)OCC(C)O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C#N)cc1F
Temperature: 153 °C
Yield: 75 %

Procedure:
N-(2-Fluoro-4-iodo-phenyl)-acetamide (63 g, 226 mmol) was dissolved in HPMA (100 mL). Copper(1) cyanide (20.6 g, 230 mmol) was added and the mixture heated to an external temperature of 153° C. for 5 h. The hot reaction mixture was poured into water (1 L) with stirring. A large amount of solid formed. The solid was filtered and washed with water (200 mL). The solid was extracted by heating in a flask with methylene chloride (500 mL) for 15 min. The solid was filtered off, washed with methylene chloride (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown-orange solid. Ethanol (100 mL) was added and the mixture heated to reflux. The solid did not all dissolve. The cooled mixture was filtered to give a light brown solid. The filtrate was concentrated to ½ volume and cooled overnight to give a further crop of solid. The combined solids were washed with cold ethanol (30 mL) and dried under vacuum to give 30 g (168 mmol). Yield: 75%; mp 173° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.3 (br s, 1H, NH), 8.3 (t, J=8.2 Hz, 1H), 7.9 (d, J=10.7 Hz, 1H), 7.67 (d, J=10.7 Hz, 1H), 2.16 (s, 3H, Me).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:28]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
A solution of 1-(t-butyloxycarbonyl)-1,4-diazepane (92.0 g, 0.46 mol) and triethylamine (96.0 ml, 69.7 g, 0.69 mol) in dichloromethane (500 ml) at 0° C. was treated dropwise with a solution of 4-morpholinecarbonyl chloride (64.0 ml, 82.0 g, 0.55 mol) in dichloromethane (100 ml) and the reaction was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with dichloromethane (400 ml) and washed with 2N citric acid (3×400 ml), saturated brine (1×500 ml), dried over MgSO4 and evaporated to give the subtitle compound as an off-white solid (141.7 g, 98%). Rf 0.80 (0.880 aqueous ammonia:methanol:dichloromethane 1:10:90, v/v). MS m/z 314 (MH)+. Found: C,57.50; H,8.69; N,13.41; C15H27N3O4 requires C, 57.50; H, 8.69; N,13.41%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:22][S:23](=[O:29])(=[O:28])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[N:22]([CH3:37])[S:23](=[O:28])(=[O:29])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2OCS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
In a 15 mL reaction tube was added tert-butyl(1-(4-(2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.099 mmol), potassium carbonate (41 mg, 0.296 mmol) and iodomethane (7.5 μL, 0.118 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at room temperature for 2 hours, then diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a colourless oil (50 mg, 97% yield). 1H-NMR (500 MHz, CDCl3) δ 7.24-7.47 (8H, m), 7.16-7.23 (2H, m), 5.23 (2H, s), 5.05 (1H, br s), 3.36 (3H, s), 2.20-2.65 (4H, m), 2.01-2.15 (1H, m), 1.77-1.90 (1H, m), 1.10-1.50 (9H, br m). LCMS (Method A) RT=7.16 min, M+H+=522.01.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-].Cl>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([NH2:26])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(OCc2ccccc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-methoxybenzoic acid (8, 1.16 g. 4.5 mmol) in CH2Cl2 (25 mL) at room temperature was added oxalyl chloride (1.5 mL, 17.9 mmol). The reaction mixture was stirred at room temperature for 2 h. It was concentrated to dryness to provide the crude acid chloride as a brown-yellow waxy solid. The crude acid chloride was dissolved in THF (10 mL) and was added dropwise to a stirred mixture of concentrated NH4OH (20 mL) and THF (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h and was adjusted to pH 8 with 2 N HCl. The precipitate was collected, washed with water, and dried in vacuo to afford the title compound (0.73 g, 63%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=3.3 Hz, 1H), 7.82 (br s, 1H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.30 (m, 1H), 7.10 (dd, J=9.0, 3.3 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 5.75 (br s, 1H), 5.08 (s, 2H), 3.94 (s, 3H); ESI MS m/z 258 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:1][CH:2]2[NH:6][C:5](=[O:7])[CH:4]=[CH:3]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1C=CC(O)N1
Reactant: C1CCCCC1
Product: O=C1C=CC(OC2CCCCC2)N1
Temperature: 90 °C

Procedure:
A mixture of 5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 150 cm3 of cyclohexane with 2.5 g of Amberlite IR 120 H is heated to 90° C. for 3 hours. After filtering, evaporating the solvent under reduced pressure and chromatographing the residue on silica (eluent: ethyl acetate-n-hexane, 1--1), 4.98 g of the expected product is obtained. m.p. 65°-66° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(CC(=O)O)cc1

Procedure:
4-(Bromomethyl)phenylacetic acid (4.85 g, 21.17 mmole), sodium methoxide (30% in methanol, ˜12 ml, ˜65 mmole)) and methanol (30 ml) were mixed and refluxed over night. The reaction mixture was allowed to cool down and was then acidified with HCL (1M). Methanol was evaporated. Water was added and the reaction mixture was extracted three times with dichloromethane. The combined organic phases was washed with brine and dried with NA2SO4. Evaporation gave 3.6 g, 94.4%, of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13](=[O:15])[CH3:14])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:16][C:17](=[O:19])[CH3:18])[CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:19])[CH3:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([O:12][C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: COC(=O)c1c(OC(C)=O)cc(C)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(OC(C)=O)cc(CBr)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.6 %

Procedure:
Methyl 4-methyl-2,6-diacetoxybenzoate (14.9 grams, 56.0 mmoles) was dissolved in carbon tetrachloride (200 mL), and N-bromosuccinimide (11.1 grams, 62.2 mmoles) and benzoyl peroxide (0.2 grams, 0.8 mmoles) were added. The mixture was refluxed under nitrogen. After 3.5 hours, an additional portion (0.2 grams) of N-bromosuccinimide was added. Reflux was continued for an additional hour. The reaction mixture was cooled to room temperature and then in ice for 1 hour, and the solid removed by filtration. The filtrate was evaporated to dryness. Hexanes (250 mL) was added to the residue, and the mixture was boiled until dissolution was obtained. The hexanes solution was concentrated to about 75 mL when a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. White crystals formed slowly, and the mixture was chilled in ice for 2 hours to complete crystallization. The solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 11.9 grams (62% yield) of methyl 4-bromomethyl-2,6-diacetoxy-benzoate (m.p. 93-95° C., open capillary, uncorrected). The product was contaminated with a small amount of methyl 2,6-diacetoxy-4-dibromomethylbenzoate, which did not interfere with subsequent reactions.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.I[C:17]1[C:18]([C:26]([F:29])([F:28])[F:27])=[N:19][NH:20][C:21]=1[NH:22][C:23](=[O:25])[CH3:24]>CN(C=O)C.[Cu]I.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>[C:1]1([C:7]#[C:8][C:17]2[C:18]([C:26]([F:28])([F:29])[F:27])=[N:19][NH:20][C:21]=2[NH:22][C:23](=[O:25])[CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1[nH]nc(C(F)(F)F)c1I
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1
Temperature: 85 °C
Yield: 73.1 %

Procedure:
A degassed solution of phenylacetylene (3.9 ml, 35 mmol) and Et3N (36 mL) in DMF (13.5 mL) was added to N-[4-iodo-3-(trifluoromethyl)-1H-pyrazol-5-yl]acetamide (4.5 g, 14 mmol), CuI (530 mg, 2.8 mmol) and PdCl2(PPh3)2 (980 mg, 1.4 mmol) under an atmosphere of N2. The reaction was then heated to 85° C. for 3.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 1:9 to 1:0) yielding the title compound as a brown oil (3 g) which was used in the subsequent step.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cccc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 47.7 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (431 mg, 1.3 mmol), 3-chlorobenzylamine (187 mg, 1.3 mmol), N,N-diisopropylethylamine (342 mg, 1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (277 mg, 48% yield). 1H NMR (400 MHz, CD3OD): δ 7.96 (d, 1H), 7.37-7.26 (m, 4H), 6.29 (d, 1H), 6.18 (s, 1H), 4.42 (s, 2H), 3.55 (m, 4H), 2.92 (m, 4H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4: 446.17; Observed: 469.2 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[N:19][OH:20]
Reactant: O=Cc1ccc(-c2ccc(O)c(F)c2)cc1Cl
Reactant: NO
Agent: Cl
Product: ON=Cc1ccc(-c2ccc(O)c(F)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 3-chloro-3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (1.52 mmol) with hydroxylamine hydrochloride (233 mg, 3.34 mmol) according to Method C to yield 260 mg (66%) of yellowish solid: mp 198-200° C.; 1H NMR (DMSO-d6): δ 7.03 (1H, t, J=8.79 Hz), 7.41-7.43 (1H, m), 7.60 (1H, dd, J=12.91 Hz, J=2.20 Hz), 7.64-7.66 (1H, m), 7.77 (1H, d, J=1.92 Hz), 7.84 (1H, d, J=8.24 Hz), 8.36 (1H, s),10.16 (1H, bs), 11.68 (1H, bs); MS (ESI) m/z 264/266 (M−H)−, 266/268 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[S:23]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[CH:22][C:13]=2[CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:18]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (0.234 g, 0.420 mmol), N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.126 g, 0.504 mmol), and THF (4.20 ml) to give a clear solution. The flask was cooled in an dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.924 ml, 0.924 mmol) was added dropwise over 30 seconds. The reaction was stirred for 30 minutes, then the cooling bath was removed and the reaction was stirred for 30 minutes. The mixture was diluted with saturated aq. ammonium chloride solution, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g, 0 to 10% MeOH/DCM) to give N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as a white foam. (ESI) 510.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CCN(CC)CC>C1COCC1>[C:14]([O:11][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(O)C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
4-Methoxymandelic acid (5.00 g, 27.44 mmol) was dissolved in 100 mL of THF. To this solution was added acetic anhydride (2.85 mL, 30.18 mmol), followed by Et3N (10 mL). The resulting mixture was stirred at room temperature overnight, concentrated, re-suspended in water, and extracted with EtOAc. The combined organic phase was dried over Na2SO4, and concentrated to give 5.95 g yellow syrup as the intermediate 79a. 1H NMR (300 MHz, CDCl3) δ 7.38 (d, 2H, J=8.67 Hz), 6.90 (d, 2H, J=8.67 Hz), 5.87 (s, 1H), 3.80 (s, 3H), 2.16 (s, 3H). LCMS (ESI−) [M−H]/z Calc'd 223, found 223.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Cl.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:28][C:27]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:26]=2[Cl:25])[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[[N-(2-amino-5-(trifluoromethoxyl)benzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 2,4-dichlorobenzyl chloride (0.066 mL), a piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 hours. The resulting reaction mixture was cooled to room temperature, loaded onto a Varian™ SCX column and washed with a 50% chloroform/methanol (10 mL) and methanol (10 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (5 mL) and concentrated. A 1,4-dioxane (2 mL) solution of 4 M HCl was added to the resulting residue, and the obtained mixture was stirred at room temperature overnight, concentrated and then purified by preparative TLC to afford (R)-3-[[N-(2-amino-5-(trifluoromethoxy)benzoyl]glycyl]amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compd. No. 1905) (17.6 mg, 70%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 505 (M++H, C21H21Cl2F3N4O3).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:32])[N:14]([CH:16]([CH2:30][OH:31])[CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:15])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O>[C:8]([O:12][C:13](=[O:32])[N:14]([CH:16]([CH:30]=[O:31])[CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:15])([CH3:9])([CH3:11])[CH3:10]
Reactant: CN(C(=O)OC(C)(C)C)C(CO)C(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C(C=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
17.8 ml (127 mmol) of triethylamine and a solution of 22.8 g (127 mmol) of sulfur trioxide pyridine complex in 100 ml of dimethyl sulfoxide are added in succession to a solution of 14.5 g (42.5 mmol) of (1-hydroxymethyl-2,2-diphenyl-ethyl)-methyl-carbamic acid tert-butyl ester in 80 ml of dimethyl sulfoxide. After 45 minutes the reaction mixture is poured into ice-water and exhaustively extracted with ether. The combined organic phases are washed twice with 1M potassium hydrogen sulfate, twice with water and once with 1M sodium hydrogen carbonate, dried over sodium sulfate and concentrated by evaporation, yielding the title compound in the form of a yellow oil. TLC: methylene chloride/methanol (95:5) Rf=0.88.