Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH:17]=O)[O:15][CH:16]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN1CCCC1=O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH2:17][N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[O:15][CH:16]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1coc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1-c1coc(CN2CCN(C)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
A mixture of 4-(2-methoxy-5-nitrophenyl)-2-furaldehyde (230 mg, 0.93 mmol) and N-methylpiperazine (0.90 mL, 8.1 mmol) in 20 mL of dichloromethane and 2 mL of 1-methylpyrolidinone was cooled to 0° C. Sodium triacetoxyborohydride (1.21 g, 5.7 mmol) was added in portions followed by a few drops of acetic acid. The resulting mixture was stirred at 0° C. for 10 minutes then at room temperature for 1.5 hours. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 20% methanol in ethyl acetate to 1% ammonium hydroxide in 20% methanol in ethyl acetate. Trituration with diethyl ether and hexane provided 57 mg (18%) of 1-{[4-(2-methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazine as a light yellow solid, 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.25-2.36 (broad s, 4H), 2.38-2.46 (broad s, 4H), 3.52 (s, 2H), 4.04 (s, 3H), 6.96 (s, 1H), 7.31 (d, J=8 Hz, 1H), 8.14-8.20 (m, 2H), 8.38 (d, J=3 Hz, 1H); MS 332.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15](OCC)=[O:16])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C([Mg]Cl)(C)C>C1COCC1>[CH3:24][O:23][N:22]([CH3:21])[C:15]([C:10]12[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:14][CH2:13]1)[CH2:8][CH2:9]2)=[O:16]
Reactant: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C12CCC(c3ccccc3)(CC1)CC2
Temperature: -20 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a mixture of ethyl 1-phenylbicyclo[2.2.2]octane-4-carboxylate (Intermediate 4; 15 g, 58.06 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.87 g, 89.99 mmol) in anhydrous THF (130 mL) cooled to −20° C. was added isopropylmagnesium chloride (2M solution in THF; 87 mL) dropwise over 30 mins maintaining the internal temp at −10° C. The mixture was stirred at −10° C. for 1 hr and then quenched by adding 20% ammonium chloride solution. The mixture was extracted into EtOAc (2×200 mL), the organic phase was separated and dried and evaporated to leave a white solid. This was purified on a 330 g Crawford silica cartridge, loading in DCM and eluting with 20-40% EtOAc-isohexane, to provide the title compound as a white solid (8.66 g, 31.67 mmol, 55%); 1H NMR (CDCl3) δ 1.75-1.90 (6H, m), 2.01-2.06 (6H, m), 3.19 (3H, s), 3.70 (3H, s), 7.15-7.20 (1H, m), 7.28-7.36 (4H, m); GC-MS EI+ m/e 243 (M-CH2O), MH+ not seen
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:12][CH2:11]1
Reactant: Cc1cccc(C=O)n1
Reactant: NC1CC1
Product: Cc1cccc(CNC2CC2)n1

Procedure:
prepared by reaction of 6-methylpyridine-2-carbaldehyde with cyclopropylamine
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C>CN(C)C=O>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(O)cc1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
1.66 g (10 mmol) of 3-(4-hydroxyphenyl)-propionic acid in 80 ml of dimethylformamide are treated at room temperature and while stirring with 2.16 g (10 mmol) of 4-nitrobenzyl bromide and 1.4 ml (10 mmol) of triethylamine. After 12 hours, the mixture is evaporated in vacuo and the residue obtained partitioned between ethyl acetate and water. The organic phase is separated, washed with 10% potassium hydrogen carbonate solution and water, dried over sodium sulphate and then evaporated to dryness. The residue crystallizes from diisopropyl ether/petroleum ether. There is obtained 3-(4-hydroxyphenyl)-propionic acid 4-nitrobenzyl ester in the form of colourless needles of melting point 80°-82° C. The product is chromatographically pure in cyclohexane/chloroform/acetic acid (45:45:10). The yield amounts to 1.6 g (53% of theory).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36]3(O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O.C(Cl)Cl>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:28]2)(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Under N2, add triethylsilane (676 mg, 0.929 ml, 5.82 mmol, 2.6 eq) followed by trifluoroacetic acid (4.08 g, 2.7 ml, 35.79 mmol, 16.0 eq) to a CH2Cl2 solution (20 ml) of 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (9.25 mg, 2.24 mmol, 1 eq). Stir for 1.5 hours and then remove volatiles on rotovap. Add EtOAc to crude mix and workup with sat aqueous sodium bicarbonate. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as a pink oil. Purify by silica gel chromatography to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg, 87% yield) as a white solid. Mass Spectrum (m/e): 397.99 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([O:21]CC)=O)[N:8]=2)=[N:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:21])[N:8]=2)=[N:2]1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2cccc(OC)c2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1cccc2c(Nc3cc[nH]n3)nc(C(=O)c3ccc(F)cc3)nc12

Procedure:
To ethyl 4-(1H-pyrazol-3-ylamino)-8-methoxyquinazoline-2-carboxylate (200 mg, 0.64 mmol) in dry THF (8 mL) cooled to −40° C. was added dropwise over 2 min 1N 4-fluorophenylmagnesium bromide in THF (2.17 mL, 2.17 mmol). After 1.5 h the reaction mixture was quenched by addition of saturated aq ammonium chloride. The solution was concentrated and H2O was added. The precipitate was washed with water and diethyl ether to give (4-(1H-pyrazol-3-ylamino)-8-methoxyquinazolin-2-yl)(4-fluorophenyl)methanone as a yellow solid (74 mg, 87% purity by LC/MS) 1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3H) 6.75 (s, 1H) 7.35-7.41 (m, 3H) 7.58-7.65 (m, 2H) 8.07-8.12 (m, 2H) 8.2 (d, J=8.48 Hz, 1H) 10.64 (br. s., 1H) 12.51 (br. s., 1H) LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>>[Br:15][C:12]1[CH:13]=[N:14][C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16](=[O:18])[CH3:17])=[N:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Brc1cnc(NCc2ccccc2)nc1
Product: CC(=O)N(Cc1ccccc1)c1ncc(Br)cn1

Procedure:
The subtitle compound was prepared by the method of example 38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and acetylchloride, yield 0.21 g.
Reaction SMILES: C[C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.[CH2:27](Cl)Cl>>[CH2:9]([NH:8][C:7]1[CH:2]=[C:3]([OH:21])[CH:4]=[CH:5][C:6]=1[CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: ClCCl
Reactant: CCCCCCCCCCCCNc1cccc(OC)c1C
Agent: BrB(Br)Br
Product: CCCCCCCCCCCCNc1cc(O)ccc1C
Temperature: 0 °C
Yield: 70 %

Procedure:
As a general methyl group de-protection procedure, 4 methyl-3-dodecylamino-1-methoxy benzene 120 was suspended in dry CH2Cl2, cooled to 0° C. and 5 equivalents of a solution of BBr3 (1M CH2Cl2, Aldrich Chem. Co.) were added and the reaction maintained at 0° C. for 16 hours. The reaction was quenched at 0° C. by slow addition of MeOH and then careful addition of solid NaHCO3 (10 Equiv.) until foaming stops. The mixture was filtered, the filtrate was concentrated to an oil, and the product was isolated by normal phase chromatography eluting with methanol/CH2Cl2. The solvent was removed from the pure fractions to give 3-dodecylamino-1-hydroxy-4 methylbenzene 120 (R═H, R′═R′″═H, R″=Me) as a waxy solid in 70-80% yield (1HNMR (CDCl3) δ 6.91 (d, 1H), 6.17 (d, 1H), 6.14 (dd, 1H) 4.62 (bs, OH), 3.53 (bs, NH), 3.14 (t, 2 H), 2.09 (s, 3 H), 1.70 (p, 2 H), 1.46 (m, 18H), 0.93 (t, 3H))
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:33](=[O:34])[N:32]([CH2:35][CH3:36])[C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:16]=[CH:17][C:12]=3[CH:11]=2)=[C:6]([Cl:37])[CH:5]=1.[OH2:39].[NH2:40][NH2:41]>C(O)C>[Cl:37][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[C:10]1[C:33](=[O:34])[N:32]([CH2:35][CH3:36])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)[N:16]=[CH:17][C:12]=2[CH:11]=1)[C:3]([NH:40][NH2:41])=[O:39]
Reactant: NN
Reactant: O
Reactant: CCn1c(=O)c(-c2ccc(C(=O)OC)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Solvent: CCO
Product: CCn1c(=O)c(-c2ccc(C(=O)NN)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 57 %

Procedure:
3-Chloro-4-{8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl}benzoic acid methyl ester (6, 77 mg, 0.14 mmol) in the mixture of ethanol (4 mL) and hydrazine hydrate (1 mL) was heated at reflux for 2 h. The reaction mixture was cooled and the yellow precipitate was collected and washed with 2-propanol and diethyl ether to afford the title compound (40 mg, 0.08 mmol, 57%) as a yellow solid. ESMS m/z 533 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.94 (br. s., 2H) 8.77 (s, 1H) 7.95 (d, J=1.5 Hz, 1H) 7.87 (s, 1H) 7.83 (dd, J=7.8, 1.5 Hz, 1H) 7.66 (d, J=9.0 Hz, 2H) 7.51 (d, J=7.8 Hz, 1H) 6.94 (d, J=9.0 Hz, 2H) 4.56 (br. s., 2H) 4.36 (q, J=7.0 Hz, 2H) 3.05-3.15 (m, 4H) 2.42-2.48 (m, 4H) 2.22 (s, 3H) 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: O[CH:2]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9].[BrH:26].[C:27]([OH:30])(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>ClCCl>[C:27]([O:30][CH:23]([CH2:24][Br:26])[CH2:22][CH2:21][CH2:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9])(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: CCCCC(O)C(O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A mixture of 1-(5,6-dihydroxydecyl)-3,7-dimethylxanthine (2.11 g, 6 mmol) and a 30% solution of hydrogen bromide in acetic acid (3.58 mL, 18 mmol) was stirred for 90 minutes. The mixture was then added to a flask containing aqueous sodium bicarbonate solution (5 g in 40 mL ) and dichloromethane (50 mL). After 10 minutes of vigorous stirring, the layers were separated and the aqueous portion extracted with dichloromethane (2×50 mL). The combined organic phases were dried over sodium sulfate. The solvent was evaporated, yielding 2.72 g (100%) 1-(9-acetoxy-10-bromodecyl)-3,7-dimethylxanthine as a yellow oil. Without further purification, the oil was taken up in methanol (30 mL) and treated with a 1M solution of sodium methoxide (6 mL). After 30 minutes, the reaction mixture was added to water (30 mL) and extracted with dichloromethane (3×50 mL). The organic portions were combined and dried over sodium sulfate to give an off-white solid residue. Recrystalization in dichloromethane/petroleum ether yields 380 mg (91% yield) 1-(9,10-oxidodecyl)-3,7-dimethylxanthine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1F
Yield: 59.8 %

Procedure:
Ethyl 4-(2,4-difluorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.73 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.53 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([C:3]1(C=O)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1)=[CH2:2].[CH:11](=[O:13])[CH3:12].B(F)(F)F.C[CH2:19][O:20]CC>ClCCCl>[CH:19]([O:13][CH:11]([CH2:2][CH:1]=[C:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1)[CH3:12])=[O:20]
Reactant: CC=O
Reactant: CCOCC
Reactant: C=CC1(C=O)CC=CCC1
Agent: FB(F)F
Solvent: ClCCCl
Product: CC(CC=C1CC=CCC1)OC=O
Yield: 399.5 %

Procedure:
Following the general procedure as described in Example 1, 1-vinylcyclohex-3-enecarbaldehyde (1.50 g, 10 mmol), acetaldehyde (0.53 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (0.72 g, 40% yield). Mixture of E/Z isomers in a ratio 1:1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2([C:24]([O:26]C(C)(C)C)=O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([OH:3])=O.[OH:31][N:32]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:48][N:49]([CH3:57])[C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1.[ClH:58].CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:58].[CH3:48][N:49]([CH3:57])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3([C:24]([NH:32][OH:31])=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:52][CH:51]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)c2ccc(OCCCCC(=O)O)cc2)CCOCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)CCCCOc2ccc(S(=O)(=O)C3(C(=O)NO)CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Part A. To a solution of 4-[[4-(4-carboxybutoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid, 1,1-dimethylethyl ester (446 mg, 0.91 mmol, prepared as in Example 7) in anhydrous N,N-dimethylformamide (6 mL) was added 1-hydroxybenzotriazole (150 mg, 1.11 mmol), triethylamine (400 uL, 2.87 mmol), N,N-dimethyl-1,4-phenylenediamine (188 mg, 1.38 mmol), and finally 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.56 mmol). The reaction mixture was stirred at ambient temperature for 18 hr, and then concentrated in vacuo at 60° C. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amide. ESMS m/z=561 [M+H]+. This material was taken up in neat trifluoroacetic acid (5 mL). After 3 hr the trifluoroacetic acid was removed in vacuo at 60° C. to give the free acid. ESMS m/z=505 [M+H]+. To a solution of this material in anhydrous N,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (148 mg, 1.10 mmol), triethylamine (400 uL, 2.87 mmol), and tetrahydropyranhydroxylamine (320 mg, 2.73 mmol), followed by 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (262 mg, 1.37 mmol). The reaction mixture was stirred at ambient temperature overnight, and then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine (3×), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using 80% ethyl acetate/hexanes as eluant to afford the desired THP hydroxamate. ESMS m/z=604 [M+H]+. HRMS calculated for C30H41N3O8S: 604.2693 [M+H]+. found: 604.2709.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C1C(=O)N([Br:21])C(=O)C1>C1COCC1>[Br:21][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ccc2cc(Br)ccc2c1Br

Procedure:
6-Bromo-2-methoxynaphthalene (5.9 g, 24.81 mmol, 1 eq) and NBS (4.41, 24.81 mmol, 1 eq) are boiled in 50 ml of THF under reflux for 2 h. After washing with 1 N HCl, the organic phase is dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. The compound is obtained in quantitative yield (7.8 g).
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH3:35])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH3:35])(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C(=O)O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture of 4-(dihydroxyboranyl)benzoic acid (30 mg, 0.181 mmol), (cis)-1-acetyl-6-bromo-2-ethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 90) (40 mg, 0.107 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was treated with potassium carbonate (45 mg, 0.326 mmol) and the resulting mixture was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuo. Purification of the residue by MDAP (modifier: formic acid) gave 4-[(cis)-1-acetyl-2-ethyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (20 mg, 0.048 mmol, 45%)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH2:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[CH2:19][O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH2:24]1)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:31](=[O:32])[CH2:30][CH2:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][CH2:19][C:18]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:16]([Cl:15])[CH:17]=3)=[O:22])[CH2:28][CH2:27]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: NCc1cn(Cc2ccccc2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCc1cn(Cc2ccccc2)nn1

Procedure:
A reaction mixture comprising of (1-benzyl-1H-1,2,3-triazol-4-yl)methanamine (46.2 mg, 0.245 mmol), 3-(1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidin-4-yl)propanoic acid (88 mg, 0.245 mmol), HATU (187 mg, 0.491 mmol) and TEA (103 μl, 0.736 mmol) in DMF (0.8 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give aqueous solutions which were extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[NH:22][C:23]([CH3:27])=[C:24]([CH3:26])[N:25]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13].Cl[CH2:29][C:30]#[N:31].[C:32]([O-:35])([O-])=O.[K+].[K+].[Na+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:5][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:32]=2[O:35][CH2:29][C:30]#[N:31])[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]
Reactant: N#CCCl
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)N(CCC(C)C)Cc2nc(C)c(C)[nH]2)c(Cl)c1OC
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc(C)c(C)n2Cc2ccccc2OCC#N)c(Cl)c1OC
Temperature: 22 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
A mixture of 250 mg (0.50 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-(4,5-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide, 52 μL of chloroacetonitrile (0.75 mmol), 276 mg (2.0 mmol) of K2CO3, and 3 mL of anhydrous DMF is stirred under nitrogen at 22° C. for 24 h and poured into 10% NaCl. The mixture is extracted with 20 mL of ethyl acetate. The extract is concentrated under reduced pressure, diluted with 20 mL of xylenes, and the volatiles are thoroughly evaporated. The crude product is purified by chromatography on 30 g of silica gel using chloroform—methanol—28% ammonium hydroxide (98:1.8:0.2, v/v/v) for elution to afford 113 mg (42% yield) of the title compound. Mass Spec m/z (M++1) 539.