Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:23][CH2:24][C@H:25]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[C:29]([O:28][C:26](=[O:27])[C@@H:25]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:24][NH:23][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:21])=[CH:20][CH:19]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: C[C@@H](COc1ccc(C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H](COc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure for coupling 19-6 to 2-1, 22-4 (295 mg, 1.0 mmol) was coupled to 2-1 (336 mg, 1.0 mmol) to give 22-5 as a beige solid.
Reaction SMILES: [Br:1][C:2]1[C:12]([N:13]([CH2:17][CH2:18]Cl)[CH2:14][CH2:15]Cl)=[C:11]([CH3:20])[C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[Br:1][C:2]1[C:12]([N:13]2[CH2:17][CH2:18][N:28]([C:27]3[CH:29]=[CH:30][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[C:11]([CH3:20])[C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(N)cc1
Product: COc1ccc(N2CCN(c3c(C)c4c(c(C)c3Br)OC(C)(C)C4)CC2)cc1
Yield: 24.8 %

Procedure:
By using 6-bromo-N,N-bis(2-chloroethyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine (492 mg, 1.25 mmol) synthesized in Reference Example 152 and 4-methoxyaniline (185 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 117 to synthesize 138 mg of the title compound (yield 25%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH:14]([Mg]Br)=[CH2:15]>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH:14]=[CH2:15]
Reactant: CON(C)C(=O)c1ccccc1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(=O)c1ccccc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
A solution of 2-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4 mmol) in THF (150 mL) was cooled to −78° C. Vinylmagnesium bromide (120 mL, 120 mmol) was slowly added, and the mixture stirred at −78° C. for 10 min, slowly warmed to rt, and stirred for another 3 h. The reaction mixture was quenched with 1 N aq HCl (100 mL) at 0° C. The aqueous layer was extracted with EtOAc (100 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to afford 1-(2-fluorophenyl)-prop-2-en-1-one (7.6 g, yield: 58.4%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C(O[CH2:18][CH2:19][N+:20]([O-:22])=[O:21])(=O)C.C(C1C=C(O)C(=CC=1)O)(C)(C)C>C1(C)C(C)=CC=CC=1>[N+:20]([CH2:19][CH2:18][C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CC(=O)OCC[N+](=O)[O-]
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc2[nH]cc(CC[N+](=O)[O-])c12
Yield: 79 %

Procedure:
A solution of methyl 1H-indole-4-carboxylate (7.34 g, 41.9 mmol), 2-nitroethyl acetate (6.90 g, 51.9 mmol) and 4-tert-butylcatechol (0.026 g, 0.16 mmol) in xylene (50 mL) was refluxed for 6 hrs. The solvent was evaporated under reduced pressure to give a residual dark oily raw product that was purified by short column chromatography on silica using ethyl acetate-light petroleum as eluent. The product was obtained as yellowish solid material in 79% yield. Mp: 103° C. MS m/z 249 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][CH3:15]>C(O)(C)C>[CH2:13]([NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH2:14][CH3:15]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCN
Solvent: CC(C)O
Product: CCCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring suspension of 4-chloro-3-nitrobenzonitrile (7.30 g, 40 mmol) in isopropanol (30 mL) is added n-propylamine (9.87 mL, 120 mmol). The mixture is stirred at room temperature for 5 h, and the solid is then collected by filtration to give 4-n-propylamino-3-nitrobenzonitrile as a yellow solid. 1H NMR (CDCl3) δ 8.51 (1H, q), 8.42(1H, br s), 7.60(1H, m), 6.91(1H, d), 3.33(2H, q), 1.84-1.74(2H, m), 1.07(3H, t). LRMS 206.3 (MH+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([O:13][C:14](=[O:28])[CH:15](OC(=O)C)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11][CH3:12].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:9]([O:13][C:14](=[O:28])[CH:15]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: Oc1cccc(O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 11.0 g. (0.1 mol.) of resorcinol and 24.7 g. (0.085 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 250 ml. of methylene chloride at 0° was added 1 ml. of boron trifluoride etherate. The reaction mixture was allowed to warm to room temperature during a 30 minute period, then it was stirred for an additional 3 hours. The reaction mixture was washed five times with equal volumes of water, dried (Na2SO4) and concentrated in vacuo to give N-t-butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine n-butyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N+:13]([CH3:16])([O-:15])=[O:14].C[O-].[Na+]>CO>[OH:1][C:2]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a stirred and cooled mixture of 85.5 parts of ethyl 4-oxo-1-piperidinecarboxylate, 33.6 parts of nitromethane and 240 parts of methanol were added dropwise 10 parts of a sodium methoxide solution 30% at 10°~15° C. Upon completion, stirring was continued first for 2 hours at about 10° C. and further overnight at room temperature. The reaction mixture was evaporated at room temperature, crushed ice was added to the oily residue and the whole was acidified with acetic acid. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The oily residue was solidified on triturating in petroleum ether. The product was filtered off and dried, yielding 73 parts of ethyl 4-hydroxy-4-(nitromethyl)-1-piperidinecarboxylate (intermediate 3).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:35])/[C:9](=[N:23]\[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:36])[NH:4]1.[CH3:37][Si:38]([CH3:49])([CH3:48])[CH2:39][CH2:40][O:41][CH2:42][O:43][CH2:44][C@@H:45]1[CH2:47][O:46]1>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10](/[C:9](=[N:23]/[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:8]([NH:7][C@@H:6]2[C:5](=[O:36])[NH:4][C@@H:3]2[CH2:2][NH:1][CH2:47][C@H:45]([OH:46])[CH2:44][O:43][CH2:42][O:41][CH2:40][CH2:39][Si:38]([CH3:49])([CH3:48])[CH3:37])=[O:35])[N:11]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Reactant: C[Si](C)(C)CCOCOC[C@@H]1CO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@H](O)COCOCC[Si](C)(C)C)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.3 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(aminomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (500 mg, 0.95 mmol) in DCM (5 mL) was added (S)-trimethyl(2-((oxiran-2-ylmethoxy)methoxy)ethyl)silane (485 mg, 2.38 mmol). After stirring at rt for 12 h, another 2.5 equiv of (S)-trimethyl(2-((oxiran-2-ylmethoxy)methoxy)ethyl)silane was added. After stirring at rt for additional 12 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 2-10%) to afford the title compound (155 mg, 22%). LCMS: m/z=731.4 (M+1).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Br:18]C1(Br)C(=O)NC(=O)NC1=O>C(OCC)C>[Br:18][CH:3]([CH:2]=[O:1])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC(Br)C=O)CC1
Yield: 167 %

Procedure:
To a solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (Wityak J., et al., J. Med. Chem., 40, p. 50 (1997): 27.6 g) in diethyl ether was added dibromobarbituric acid (17.0 g), and the mixture was mixed for 12 hours. The insolubles were filtered off, and the filtrate was diluted with diethyl ether, sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (31.8 g) as a pale yellow viscous oily matter.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([O:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([O:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1nc2c(OCc3ccccc3)cccc2n1C
Agent: [Pd]
Solvent: CO
Product: COc1nc2c(O)cccc2n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.7 %

Procedure:
A mixture of 4-benzyloxy-2-methoxy-1-methyl-1H-benzimidazole (254.8 mg) and 10% palladium on carbon (25 mg) in methanol (2.5 ml) was stirred for 7 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=3:1, V/V) to give 4-hydroxy-2-methoxy-1-methyl-1H-benzimidazole (58.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8]COC.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)C=Cc1ccc(OCOC)c(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Yield: 70.9 %

Procedure:
In a manner similar to that of Example 2(g), by reaction of 10.1 g (20.3 mmol) of ethyl 3-(3-bromo-4-methoxymethoxyphenyl)acrylate obtained in Example 2(c) with 5.4 ml (102 mmol) of 98% sulfuric acid, 3.9 g of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate (49%) were obtained in the form of a white powder having a melting point of 112°-3° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[NH:48][C:47]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[N:46][CH:45]=3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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:57]([O:56][C:54]([N:50]1[CH2:51][CH2:52][CH2:53][C@H:49]1[C:47]1[NH:48][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:7]3[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C@@H:16]4[CH2:20][CH2:19][CH2:18][N:17]4[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])[CH2:9][CH:8]=3)=[CH:39][CH:40]=2)=[CH:45][N:46]=1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC=C(c2ccc(-c3cnc([C@@H]4CCCN4C(=O)OC(C)(C)C)[nH]3)cc2)CC1
Temperature: 80 °C
Yield: 92.9 %

Procedure:
To a solution of (25)-tert-butyl 2-(4-(trifluoromethylsulfonyloxy)cyclohex-3-enyl carbamoyl)pyrrolidine-1-carboxylate (2) (1.65 g, 3.73 mmol) and (5)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3) (1.95 g, 4.44 mmol) in THF (19 mL), Pd(PPh3)2Cl2 (130 mg, 0.185 mmol) and aqueous Na2CO3 (2M, 7.5 mL, 15 mmol) were added under N2 protection at rt. The reaction mixture was heated at 80° C. overnight, and cooled to rt. The mixture was then filtered through a CELITE™ pad and washed with ethyl acetate. The combined organic phases were concentrated to provide the crude product, which was purified by silica gel column chromatography (n-hexane/ethyl acetate, 1:2) to afford (2S)-tert-butyl 2-(4-(4-(2-((5)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)cyclohex-3-enylcarbamoyl)pyrrolidine-1-carboxylate (4) (2.1 g, 93% yield).
Reaction SMILES: Br[C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:12])=[CH:7][CH:6]=1)=[O:4].[O:15]1CCOCC1.[OH-:21].[Na+:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([OH:15])([CH3:14])[CH3:13])=[CH:6][CH:7]=1.[OH-:21].[Na+:22]
Reactant: C1COCCO1
Reactant: CC(C)(Br)C(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)C(=O)c1ccc(CBr)cc1

Procedure:
In a nitrogen atmosphere, 30.1 g (84 mmol t.q.) of 2-bromo-1-(4-bromomethyl-phenyl)-2-methyl-propan-1-one, 150 g of dioxane and 0.5 g of tetrabutylammonium bromide, dissolved in 15 g of water, are introduced into a 500 ml reaction flask. Then, at about 80° C., an initial amount of 34.7 g of 15% sodium hydroxide solution is added dropwise over about two hours. The reaction solution is alkaline, about pH 9-10. The reaction is checked using a 1H NMR spectrum. The intermediate formed in part, 1-(4-bromomethyl-phenyl)-2-hydroxy-2-methyl-propan-1-one, accumulates and, despite the addition of sodium hydroxide solution, the reaction stops before completion. The addition of sodium hydroxide solution is then interrupted and the salt-containing aqueous phase is separated off. Further 15% sodium hydroxide solution is slowly added dropwise at about 80° C. to the organic phase, totalling 44.8 g (0.164 mol) of 15% sodium hydroxide solution. The bromide, 1-(4-bromomethyl-phenyl)-2-hydroxy-2-methyl-propan-1-one, slowly disappears and the pH of the reaction solution remains at about 10. The salt-containing aqueous phase is again separated off and the organic phase is concentrated, resulting in 13.4 g of yellow oil which, in the 1H NMR spectrum, is a product mixture. The oil is separated on a silica gel column. A mixture of ethyl acetate: mixed hexanes 1:1 is used as eluant. Three liquid products are obtained and confirmed using a 1H NMR spectrum: 2-hydroxy-1-(4-hydroxymethyl-phenyl)-2-methyl-propan-1-one (Example 3a) as main product, the dimer 2-hydroxy-1-{4-[4-(2-hydroxy-2-methyl-propionyl)-benzyloxymethyl]-phenyl}-2-methyl-propan-1-one (Example 3b) as subsidiary product and, as components of a further small fraction which is separated by HPLC, 2-hydroxy-2-methyl-1-p-tolyl-propan-1-one and 1-(4-dibromomethyl-phenyl)-2-hydroxy-2-methyl-propan-1-one.
Reaction SMILES: [CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of crude dihydrobromide salt of (1R,3R,4S)-N1-isopropyl-3-(methoxymethyl)-N1-methylcyclohexane-1,4-diamine prepared according to the procedure of Example 4b, Step 2 (423 mg) in acetonitrile (5 mL) was treated with 2-(benzyloxycarbonylamino)acetic acid (259 mg), diisopropylethylamine (0.80 ml) and HATU (516 mg). The mixture was stirred overnight at rt, then was concentrated under vacuum. The residue was purified by reverse phase HPLC followed by lyopholization to provide benzyl 2-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexylamino)-2-oxoethylcarbamate (192 mg) as a white powder. MS found: (M+H)+=406.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][OH:17])([O-:3])=[O:2].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:22]([O:17][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of the product of Step A (2.4 g, 9.6 mmol) and TBSCl (1.73 g, 11.5 mmol) in DMF (15 mL) was added imidazole (1.3 g, 19.2 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (100 mL), and washed with brine (30 mL×3) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with PE) to obtain the title compound (3.5 g, 100%) as yellow solid. 1H NMR (600 MHz, CDCl3) δ 8.56 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 7.63 (dd, J=9.0, 2.2 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.52-3.48 (m, 2H), 0.94 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(Cl)c1
Reactant: O=C(Cl)CCc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc1-c1cccc(Cl)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropanoyl chloride, gave 3′-chloro-5-formyl-6-methoxy-N-(3-phenylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][O:28][CH3:29].O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH2:26][CH2:27][O:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: COCCBr
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCn1cc(C=O)c(-c2ccc(OC(C)C)cc2)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (655 mg, 4.6 mmol) in acetonitrile (6 ml) was stirred at 0-5° C. for 1 hr. 1-bromo-2-methoxyethane (195 mg, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL) and extracted with EtOAc (50 mL×3). The combined extracts was washed with brine (100 mL), dried and concentrated under vacuum (360 mg, yield 72%). The crude material was used in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([O:25][CH3:26])[C:22]3[C:17](=[CH:18][C:19]([O:29][CH3:30])=[C:20]([O:27][CH3:28])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(O)C.O1CCOCC1>[ClH:31].[ClH:31].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([O:25][CH3:26])[C:22]3[C:17](=[CH:18][C:19]([O:29][CH3:30])=[C:20]([O:27][CH3:28])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(OC)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc2nc(NC3CCNCC3)nc(OC)c2cc1OC

Procedure:
A solution of 4-(4,6,7-trimethoxy-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.48 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESI): 319.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CCO.Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Reaction time: 22 h
Yield: 66.8 %

Procedure:
To a suspension of Example 272A (0.13 g, 0.34 mmnol) in EtOH (3.5 mL), a solution of tin(II) chloride dihydrate (0.31 g, 1.36 mmol) in conc. HCl (0.68 mL) was slowly added. The reaction was stirred for 22 hours and partitioned between dichloromethane (75 mL) and 1 N NaOH (75 mL). The organic layer was washed with 1 N NaOH (1×50 mL), brine (1×50 mL), partially dried (Na2SO4), and concentrated to a colored solid (0.13 g). The desired product was crystallized from acetonitrile to yield colored crystals (0.08 g, 68%).