Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (120 mL) of 2-(4-bromo-benzyloxy)-pyridine (34 g, 128 mmol) described in Manufacturing Example 2-2-1 was added n-butyl lithium (50 mL, 2.6 M, hexane solution, 134 mmol) dropwise at −78° C. After 30 minutes of stirring, to the reaction solution was added N,N-dimethylformamide (10 mL, 134 mmol) dropwise at −78° C., which was stirred at room temperature. The reaction solution was partitioned into water and ethyl acetate, and the ethyl acetate layer was washed with water (2 times) and aqueous sodium chloride (once). The water layers were combined and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water (2 times) and aqueous sodium chloride (once). The ethyl acetate layer thus obtained was combined with the ethyl acetate layer obtained previously, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was then concentrated under a reduced pressure to obtain the title compound (26.8 g) as a crude product.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:38])[C:19]([C:35](=[O:37])[CH3:36])=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:17][C:18](=[O:38])[CH:19]([C:35](=[O:37])[CH3:36])[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Reactant: Br[Mg]Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)C(Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Cuprous iodide (1.15 g, 6.05 mmol) in dry THF (10 ml) was treated at 0° C. with benzylmagnesium bromide (2M in THF, 6.05 ml, 12.1 mmol) over a 3 minute period. The cuprate was stirred at 0° C. for 30 minutes and then cooled to -78° C. and then TMSCl (3.28 g, 30.2 mmol) in THF (5 ml) was added dropwise keeping the reaction temperature below -60° C. The mixture was stirred at below -60° C. for a further 10 minutes and then ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-prop-2-enoate (1 g, 3.01 mmol) in THF (5 ml) was added dropwise over 3 minutes. The mixture was stirred at below -60° C. for 45 minutes and then saturated NH4Cl (30 ml) and water (20 ml) were added. The mixture was allowed to warm to room temperature, the resultant precipitate was removed by filtration and the filtrate evaporated, the residue was dissolved in methylene chloride (200 ml), washed with water (30 ml), In HCl (50 ml) and water (30 ml), dried over Na2SO, and the volatiles removed in vacuo. Flash chromatography (SiO2 ; EtOAc:hexane (1.9)) afforded ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-4-phenyl-butanoate (1.19 g), 92%) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:31]([C:30]3[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=3)=[O:32])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccccc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 11-(2-ethylhexyl)-11H-benzo[a]carbazole (10.0 g, 30.6 mmol) in CH2Cl2 (150 mL) are added 4-fluorobenzoyl chloride (5.03 g, 31.7 mmol) and AlCl3 (4.58 g, 34.3 mmol) at 0° C. After stirring for 0.5 hour, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of n-hexane and CH2Cl2 (1:1) to obtain an off-white solid (8.14 g; 57%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.83 (t), 0.89 (t), 1.18-1.52 (m), 2.24-2.31 (m), 4.68-4.80 (m), 7.16 (t), 7.31 (t), 7.50 (t), 7.55-7.60 (m), 7.65 (t), 7.97 (dd), 8.06 (d), 8.31 (s), 8.50 (d), 8.65 (d); 19F-NMR spectrum (CDCl3). δ [ppm]−106.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[C:9]#[N:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]#[N:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2ccccc2Cl)cc1
Yield: 90.6 %

Procedure:
2-(2-chlorophenyl)-2-hydroxyacetonitrile (16.8 g, 0.1 mol) and 4-toluene sulfonyl chloride (21 g, 0.11 mol) was dissolved in toluene (100 mL) in a suitable reaction flask. Aqueous 5% NaOH (100 g, 0.125 mol) was added dropwise at 0-5° C. and the reaction continued at 10-15° C. until the reaction was completed by TLC monitoring. The organic layer was separated and the aqueous layer was extracted with toluene (50 ml×2). The combined organic layer was washed with water. After removal of toluene under reduced pressure, the target product was obtained (29 g, yield 90.6%).
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][C:12]=1[I:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(OCc2ccccc2)cc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
Iodine (71.96 g, 0.28 mol) in chloroform was added dropwise to a mixture of 2-benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.06 g, 0.27 mol) and silver trifluoroacetate (71.57 g, 0.32 mol) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate (5%, 2×2 l), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate, to give the title compound as a colorless oil (108.03 g), containing 11% unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. 1H NMR (360 MHz, CDCl3) d 7.67 (1H, d, J=2.8 Hz), 7.40 (5H, m), 7.16 (1H, dd, J=8.9, 2.8 Hz), 6.82 (1H, d, J=8.9 Hz), and 5.14 (2H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][O:9][CH2:10][C:11]=1[NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:7][CH2:8][O:9][CH2:10][C@H:11]1[NH:12][C@@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)COCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CCOC[C@H]1N[C@H](C)c1ccccc1
Reaction time: 17 h
Yield: 35.6 %

Procedure:
A solution of crude (R)-5-(1-Phenyl-ethylamino)-3,6-dihydro-2H-pyran-4-carboxylic acid ethyl ester (4.53 g, ca. 16.5 mmol) was dissolved in trifluoroacetic acid (45 mL) and treated with triethylsilane (7.9 mL, 49.4 mmol). The mixture was stirred for 17 h and then concentrated. The residue was dissolved in water and adjusted to pH 10 with 50% sodium hydroxide. The mixture was extracted with dichloromethane, and the combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (40% diethyl ether/petroleum ether) to provide the product as a colorless oil (1.63 g, 36%). 1H NMR (300 mHz, CDCl3) δ7.22 (m, 4H), 7.16 (m, 1H), 4.14 (q, J=7.3 Hz, 2H), 3.77 (m, 2H), 3.60 (q, J=7.3 Hz, 1H), 3.23 (m, 1H), 2.83 (m, 2H), 2.31 (m, 1H), 1.77 (m, 2H), 1.24 (m, 6H), ESI MS: (M+H)+=278.1 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.C(O)(C(F)(F)F)=O.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NNc1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 156.1 %

Procedure:
To a 0° C. solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0° C. for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96%). LC-ES/MS m/e 194.0 (M+1)
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([O:11]C)=O)(=[O:5])=[O:4])[CH3:2].[Cl:13][C:14]1[CH:32]=[CH:31][C:17]2[O:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH2:21][N:22]([C:23]([NH:25][NH2:26])=[O:24])[C:16]=2[CH:15]=1>>[CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([NH:26][NH:25][C:23]([N:22]1[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:11])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)NCCC(=O)OC
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CCS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(ethylsulfonyl)amino]-1-oxopropyl]hydrazide (22) was prepared from N-(ethylsulfonyl)-β-alanine, methyl ester (21), prepared as described above in Example 21, and 8-chlorodibenz[-b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in the manner described in Example 18 above on a 2.0 mmol scale to yield 0.25 g (28%) of product. Analysis calculated for C19H21NO5SCl 0.75 H2O (M.W. 466.43): C, 48.93; H, 4.86; N, 12.01; Cl, 7.60; S, 6.87. Found: C, 49.05; H, 4.61; N, 11.78; Cl, 8.34; S, 6.69.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:24][NH:25][CH3:26]>C(O)C.ClCCl>[CH3:24][N:25]([CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1)[CH3:26]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Br)c1cnoc1C1CC1
Reactant: CNC
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[bromo-(2-nitro-4-trifluoromethylphenyl)-methyl]-5-cyclopropylisoxazole (1.2 g) and dimethylamine (2.0 g of a 33% solution in ethanol) in dichloromethane was stirred at 0° C. for 2 hours and then at room temperature for a further 16 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with petroleum ether and ethyl acetate to give 4-[N,N-dimethylamino-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 300, 0.27 g) as a yellow oil: NMR (CDCl3); 1.02(4H, m), 2.08(1H,m), 2.12(6H,s), 4.9(1H, s), 7.8(1H, m), 7.9(1H, m), 8.0(1H,s), 8.1(1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[C:3]=1[Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccnc(Cl)c1
Solvent: CC(=O)O
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added NBS (75 g, 426 mmol) portionwise at RT (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)=[O:4].C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8][C:9]=1[Br:33])=[O:4]
Reactant: COC(=O)c1cnc([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1[nH]c([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 114 Part A (1.2 g of 83% pure, 0.28 mmol) was dissolved in CHCl3 (20 mL) and NBS (0.93 g, 0.41 mmol) was added. The mixture was stirred at RT under N2 for 1.5 h. It was diluted with CHCl3 and washed with water and brine. It was then dried over MgSO4 and concentrated to a white solid (0.79 g). MS: 424.4/426.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:28][C:29]3[CH:36]=[CH:35][C:32]([CH3:33])=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(C)cc2)CC1
Yield: 42.4 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound and 4-methylbenzaldehyde (0.66 g) were reacted and treated in the same manner as in Example 121 to give 1.07 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-methylbenzylamino)hexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:21]>C(OCC)(=O)C>[OH:21][CH:2]([CH2:18][OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:13])=[O:14])[S:11][C:7]=2[CH:6]=1
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1nc2ccc(OCC(O)CO)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Epoxypropoxy)benzothiazole-2-sulfonamide (1.21 gm, 4.25 mmol) was dissolved in ethyl acetate (35 mL) and added to water (25 mL) containing concentrated sulfuric acid (2.5 mL). This two phase mixture was stirred at room temperature overnight and then was poured into water and repeatedly extracted with 5% methanol/ethyl acetate (V/V). The extracts were dried (Na2SO4) and evaporated. The residue (1.2 gm) was dissolved in methanol and allowed to sit overnight to give 1.0 gm of impure product. This material was purified by chromatography on silica gel, eluting with 1% methanol/ethyl acetate (V/V). The combined fractions containing product were evaporated and the residue was triturated with methanol to give material which was recrystallized from methanol/ethyl acetate (0.3 gm), m.p. 183°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[NH2:30][C:31]1[C:36]([CH:37]=O)=[CH:35][CH:34]=[CH:33][N:32]=1.ClCCCl>>[NH2:30][C:31]1[C:36]([CH2:37][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[O:16][C:15]([CH2:14][N:13]([CH3:28])[S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:29])(=[O:11])=[O:12])=[N:19][N:18]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Nc1ncccc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4cccnc4N)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (42 mg, 0.10 mmol), 2-aminopyridine-3-carbaldehyde (15 mg, 0.12 mmol), STAB (42 mg, 0.2 mmol) DCE (0.8 mL) and a few 4 Å molecular sieves. The crude product was purified using prep method D.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=O)[N:7](C)[C:6]=2[CH:12]=1.O.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:9])=[C:6]([NH:7][CH3:8])[CH:12]=1
Reactant: Cn1c(=O)sc2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1cc(Cl)ccc1S
Reaction time: 3 h
Yield: 98.1 %

Procedure:
5-Chloro-3-methyl-2-benzothiazolinone (70.0 g) was added to a mixture of water (118 ml), ethanol (350 ml) and potassium hydroxide (78.6 g). The solution was refluxed with stirring for three hours. After the solvent was evaporated under reduced pressure, the residual oil was dissolved in water. After removal of insoluble yellow crystals by filtration, the filtrate was neutralized with 2N-acetic acid, then resulting oily substance was extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4), and evaporated to give oily 4-chloro-2-methylaminothiophenol (59.7 g). To a solution of sodium hydroxide (14.0 g) in water (100 ml) was added 4-chloro-2-methylaminothiophenol (59.6 g) with stirring, and then was added dropwise a solution of chloroacetic acid (34.0 g) in water (50 ml) at 20-25° C., followed by heating almost to boiling for three hours.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:15]1([CH:14]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2ccc(Br)cc2)C2CCCCC2)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C2CCCCC2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 524.3 [M−H]−.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C[O-].[Na+].Cl[CH:13](Cl)[C:14]([O:16][CH3:17])=[O:15].Cl>CO.O>[CH3:17][O:16][C:14]([CH:13]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)=[O:15]
Reactant: Oc1ccccc1O
Reactant: COC(=O)C(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1Oc2ccccc2O1
Temperature: 25 °C

Procedure:
Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight in methanol, 40.3 g, 186 mmol), and methyl dichloroacetate (13.3 g, 93.2 mmol) were combined in dry methanol (100 mL). The solution was heated to reflux overnight. The reaction was cooled to room temperature, acidified by addition of concentrated hydrochloric acid and then reduced in volume under vacuum to about 50 mL. Water was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic solution was dried with MgSO4, concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexane) to yield benzo[1,3]dioxole-2-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(C(C)=O)C>[CH2:20]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
A mixture of 8.7 g (43.4 mmoles) of methyl 3-chloro-4-hydroxyphenylacetate, 6.2 g (44.8 mmoles) of powdered anhydrous potassium carbonate, 7.6 g (44.6 mmoles) of benzyl bromide, and 25 ml of methyl ethyl ketone was refluxed for six hours.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:45])[CH:13]([N:20]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([OH:31])=[CH:30][C:22]=4[CH:21]3[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:47][CH:48]([F:50])[F:49]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:45])[CH:13]([N:20]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:31][CH2:47][CH:48]([F:50])[F:49])=[CH:30][C:22]=4[CH:21]3[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: FC(F)CBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(C(C(=O)NCc1ccc3c(c1)OCO3)c1ccccc1)CCC2
Product: COc1ccc(CC2c3cc(OCC(F)F)c(OC)cc3CCCN2C(C(=O)NCc2ccc3c(c2)OCO3)c2ccccc2)cc1OC

Procedure:
prepared by reaction of N-benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide with 2-bromo-1,1-difluoroethane.