Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:33]([O:35][P:36]([CH2:41][CH2:42][NH2:43])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:38]([O:37][P:36]([CH2:41][CH2:42][NH:43][CH2:26][C:23]([CH3:24])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[CH2:1][CH3:2])[CH2:9][O:8][C:7]2=[O:13])(=[O:40])[O:35][CH2:33][CH3:34])[CH3:39]
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Reactant: CCOP(=O)(CCN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCNCC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reaction time: 4 h
Yield: 98.7 %

Procedure:
4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalate salt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid (15.7 mg, 0.263 mmol) was added, followed by sodium triacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hrs, the crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide 27.7 mg (97%) of the desired product after lyophilization. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.14 (t, J=7.5 Hz, 3H), 1.26 (m, 2H), 1.30 (t, J=7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q, J=7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H), 5.15 (s, 2H), 5.51 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.39 ppm; MS=540 [M++1].
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[CH2:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:25]#[CH:26]>C(Cl)(Cl)Cl>[CH2:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:29][CH2:28]1)[C:25]#[CH:26]
Reactant: C#CCN1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (323 mg, 1.407 mmol) and diisopropylethylamine (0.26 ml, 1.477 mmol, 1.05 eq) in 6 ml CHCl3 at 0° C., N-propargylpiperazine obtained in step 2(iii) above was added (173 mg, 1.407 mmol, 1 eq). The mixture was stirred for 24 h at room temperature. 10 ml of CHCl3 was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The crude product was purified by FC to give the title compound (HLA20) as a white solid. (337 mg, 86% yield). H1 NMR (250 MHz,CDCl3), 2.23 (m, 1H), 2.54 (s, 8H), 3.28 (d, J=2.44 Hz, 2H), 3.80 (s, 2H), 7.08 (m, 1H), 7.36 (d, J=10.59, 1H), 7.46 (dd, J=8.55, 4.18 Hz, 1H), 8.67 (dd, J=8.56, 1.55 Hz, 1H), 8.78 (dd, J=4.18. 1.51 Hz, 1H); 13C NMR (100 MHz, CDCl3) 46.77, 51.98, 52.87, 60.55, 73.05, 78.92, 108.60, 121.40, 124.58, 127.87, 128.87, 134.10, 138.68, 147.50, 151.78.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH2:16])=[C:10]3[CH:9]=[N:8]2)[CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH2:26][C:27](O)=[O:28])[CH:21]=[C:22]([Cl:24])[CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:16][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:7]([CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:27](=[O:28])[CH2:26][NH:25][C:20]4[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=4)[CH2:2]3)[N:8]=[CH:9][C:10]=12
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Nc1ncnc2c1cnn2C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncnc2c1cnn2C1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 50 °C
Yield: 6.8 %

Procedure:
A mixture of 1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (620 mg, 2.2 mmol), 2-((3,5-dichlorophenyl)amino)acetic acid (475 mg, 2.2 mmol, 1 eq), HBTU (822 mg, 2.2 mmol, 1 eq) and DIPEA (560 mg, 4.4 mmol, 2.0 eq) in THF (10 mL) was heated to 50° C. for 16 h. The mixture was concentrated in vacuo and purified by silica gel column with EA in PE (20% to 100%, v/v) to give the title product (63 mg, yield: 7%). 1H NMR (400 MHz, DMSO-d6) δ: 8.21 (d, 1H), 8.11 (d, 1H), 7.85-7.65 (m, 2H), 6.76 (s, 1H), 6.73 (s, 1H), 6.60 (d, 1H), 6.32 (t, 1H), 4.76-4.71 (m 0.5H), 4.61-4.54 (m, 1H), 4.48 (d, 0.5H), 4.19 (d, 0.5H), 4.11-4.08 (m, 1H), 4.02-3.94 (m, 1.5H), 3.86-3.81 (m, 0.5H), 3.17-3.09 (m, 1H), 2.95-2.90 (m, 0.5H), 2.20-2.12 (m, 1H), 2.08-2.05 (m, 1H), 1.89-1.82 (m, 1H), 1.72-1.51 (m, 1H). ESI-MS: 420.1 (M+H)+.
Reaction SMILES: [CH3:1][OH:2].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4]1>>[CH3:1][O:2][CH2:4][CH:5]([OH:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCC1CO1
Reactant: CO
Product: CCCCCCCCCCCCC(O)COC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The same reactor that was used in Production Example 5 was charged with 64 g (2 mol) of methanol and 2 g of boron trifluoride diethyl ether complex and then the mixture was raised to 60° C. Then, 212.3 g (1 mol) of 1,2-epoxytetradecane was added dropwise to the mixture over one hour and the resulting mixture was kept as it was for 3 hours. The reaction was terminated just after confirming that 1,2-epoxytetradecane left unreacted was less than 1% by gas chromatography and then the reaction mixture was cooled. Thereafter, methanol was removed in the same manner as in Production Example 5 to obtain 2-hydroxytetradecyl methyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH-:8].[O:9]=[C:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:23](O)=O)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:23]1[C:18]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:9])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: [NH-]c1ccccc1N
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
In a 50-ml three-necked flask under an argon atmosphere, heat, at 80° C. for 2 hours, a solution of 3 g of the (2-amino-phenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid obtained in the preceding stage, in 150 ml of acetic acid. After cooling, the precipitate that formed is drained. After purification by silica gel flash chromatography, eluting with mixtures of dichloromethane and ethyl acetate (90-10 then 80-20 and finally 70-30 by volume), we obtain 1.73 g of 4-(1H-benzimidazol-2-yl)-fluoren-9-one in the form of a yellow powder, which is used as it is in the next stage, with the following characteristics:
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[CH2:8][CH:9]([CH:13]2[CH2:18][CH2:17][CH2:16][S:15][CH2:14]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][O:27][NH2:28].C(=O)(O)[O-].[Na+]>CO>[OH:12][C:11]1[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][CH2:16][S:15][CH2:14]2)[CH2:8][C:7](=[O:19])[C:6]=1[C:1](=[N:28][O:27][CH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][O:21]1)[CH2:2][CH2:3][CH3:4]
Reactant: NOCC1CCCO1
Reactant: CCCC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCC(=NOCC1CCCO1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 81 %

Procedure:
2.82 g (10 millimoles) of 2-butyryl-3-hydroxy-5-(tetrahydrothiopyran-3-yl)-cyclohex-2-en-1-one was stirred together with 1.69 g (11 millimoles) of tetrahydrofur-2-ylmethoxyamine hydrochloride and 0.93 g (11 millimoles) of sodium bicarbonate in 20 ml of methanol for 12 hours at 25° C. The mixture was evaporated down, the residue was taken up with dichlorbmethane and the solution was extracted by shaking with water. The dried dichloromethane solution was evaporated down to give 3.1 g (8.1 millimoles) of 3-hydroxy-2-(1-tetrahydrofur-2-ylmethoxyiminobutyl)-5-(tetrahydrothiopyran-3-yl)-cyclohex-2-en-1-one as a viscous oil. ##STR9##
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[N-:13]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>C(Cl)Cl>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([S:2]([CH3:1])(=[NH:13])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CS(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
1.56 g (8.5 mmol) of 1-(methylsulfinyl)-4-nitrobenzene in 20 ml of DCM is mixed with 0.70 g (9.5 mmol) of sodium azide. The batch is slowly mixed at 0° C. with 2.3 ml of concentrated sulfuric acid and then heated to 45° C. After 16 hours, the batch is cooled to room temperature, mixed with water and extracted from DCM. The aqueous phase is set at pH 11 with 15% NaOH solution and extracted from DCM. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 1.08 g (5.4 mmol, corresponding to 63% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[O:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2B(O)O)[CH2:23][CH2:22][CH2:21]1>>[O:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cccc2c1OCCC2
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OCCC4)n2)c1

Procedure:
Example 12 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 3,4-dihydro-2H-chromen-8-ylboronic acid (Parkway Scientific LLC).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>CO.N1CCCCC1>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10]
Reactant: Cc1cccc[n+]1C
Reactant: COC(COc1ccccc1C=O)OC
Agent: [I-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(COc1ccccc1C=Cc1cccc[n+]1C)OC
Yield: 86.6 %

Procedure:
In 6 ml of methanol, 1.50 g of 1,2-dimethylpyridinium iodide and 1.50 g of o-(2,2-dimethoxyethoxy)benzaldehyde. The resultant solution, with two drops of piperidine added thereto, was refluxed for five hours and then left to stand and cool off. The crystals which deposited consequently were collected and thoroughly washed with acetone. Consequently, there was obtained 2.36 g of 1-methyl-2-[o-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide which melted at 169°~173° C. This product showed the highest absorption at 353 nm (ε=1.78×104). The infrared absorption spectrum (KBr) showed peaks at 1630, 1610, 1595, 1567, 1515, 1500, 1450, 1280, 1248, 1130, 1065, 971, 780, 760 and 750 cm-1. The yield was 87%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]2[O:16][C:17]3[C:23]([C:24]([O:26]C)=O)=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:29]>>[C:24]([C:23]1[C:17]2[O:16][C:15]([CH:13]3[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12]3)=[N:19][C:18]=2[CH:20]=[CH:21][CH:22]=1)(=[O:26])[NH2:29]
Reactant: N
Reactant: COC(=O)c1cccc2nc(C3CN(C(=O)OCc4ccccc4)C3)oc12
Solvent: O
Product: NC(=O)c1cccc2nc(C3CN(C(=O)OCc4ccccc4)C3)oc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)azetidin-3-yl)benzo[d]oxazole-7-carboxylate (280 mg, 0.76 mmol) was added to ammonia water (10 ml) and the mixture was stirred at 35° C. for overnight. Then the solid was filtered. 160 mg of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)azetidine-1-carboxylate was obtained, yield 60%. LC-MS (ESI) m/z: 352 (M+1)+. (M+1)+,
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>COCCOC.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:9]1([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1sccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=Cc1sccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
3-Bromothiophene-2-carbaldehyde (3 g, 1.67 ml, 14.8 mmol, CAS RN 930-96-1) was dissolved in DME (180 mL) and the resulting solution was evacuated and purged with argon three times. Pd(Ph3P)4 (512 mg, 443 μmol) was added, the reaction flask purged again with argon and stirring was continued at RT for 15 min. Then 2M aqueous Na2CO3 solution was added (14.8 mL, 29.5 mmol) followed by phenylboronic acid (1.98 g, 16.2 mmol). Again the reaction flask was purged with argon and the reaction mixture was heated to 80° C. and stirred for 6.5 h. After evaporation of the solvent, the residue was taken up in Et2O and H2O and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was suspended in CH2Cl2 and n-heptane and the solid was filtered off. The filtrate was evaporated and the crude product purified by flash chromatography on silica gel (gradient EtOAc/n-heptane, 0% to 10%). The product-containing fractions were pooled and further purified by preparative HPLC to give the title compound as a yellow oil (0.939 g, 34%). MS (ESI): m/z=189.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:31]3[CH:32]=[CH:33][O:29][CH:30]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccoc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccoc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and furan-3-carbaldehyde. MS (ESI) m/z 459.
Reaction SMILES: [CH:1]([O:14][N:15]1[C:24](=[O:25])[CH:23]2[CH:17]([N:18]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:19][CH:20]=[CH:21][CH2:22]2)[C:16]1=[O:37])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1([Mg]Br)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.C(OCC)C>[CH:1]([O:14][NH:15][C:16]([CH:17]1[CH:23]([C:24](=[O:25])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:22][CH:21]=[CH:20][CH2:19][N:18]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:37])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC3C(=O)N(OC(c4ccccc4)c4ccccc4)C(=O)C32)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
7-Benzhydryloxy-1-(4-methoxybenzenesulfonyl)-2,5,5a,8a-tetrahydro-1H-pyrrolo[3,4-b]azepine-6,8-dione (100 mg, 0.19 mmol) was dissolved in THF (2 mL) and cooled to -78° C. This solution was treated dropwise with a 3 M solution of phenyl magnesium bromide in diethyl ether and then warmed to ambient temperature. The reaction mixture was stirred another 2.5 hrs at room temperature, cooled to 0° C., and quenched with saturated aqueous NH4Cl (2 mL). This mixture was then diluted with H2O and diethyl ether and the layers were separated. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 5 to 10% ethyl acetate in toluene) to give 3-benzoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide; MS: (M+H)+ 596.9, (M+NH4)+ 614.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
4′-Hydroxyacetophenone (13.62 g, 100 mmol), benzylbromide (17.1 g, 100 mmol), and cesium carbonate (35.83 g, 100 mmol) were added to tetrahydrofuran at room temperature and stirred overnight. The product was concentrated to dryness and recrystallized from ether and hexane to yield 15 g of 4′-benzyloxyacetophenone which appeared as a white powder. An Rf of 0.42 was observed when resolved by thin layer chromatography using methylene chloride. 1H nmr (δ, ppm, CDCl3), 7.94 (2H, δ, 8.8 Hz, O—Ar—C(O)), 7.42 (5H, m, Ar′CH2O—), 7.01 (2H, δ, 8.8 Hz, O—Ar—C(O)), 5.14 (2H, s, Ar′CH2O—), 2.56 (3H, S, CH3).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([NH:35][CH2:36]C4C=CC=C(C(F)(F)F)C=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:47][C:48]([F:58])([F:57])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52]N>>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([NH:35][CH2:36][CH2:52][C:51]4[CH:54]=[CH:55][CH:56]=[C:49]([C:48]([F:58])([F:57])[F:47])[CH:50]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared by the route used to prepare 3-(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylamino)pyridin-2-yl)phenylcarbamoyl)benzylthio)propanoic acid 69, substituting 3-(trifluoromethyl)phenethylamine for 3-(trifluoromethyl)benzylamine. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 13.37 (s, 1H), 12.23 (s, 1H), 8.22 (s, 1H), 7.82-7.74 (m, 2H), 7.64-7.50 (m, 6H), 7.12 (m, 3H), 6.99 (s, 1H), 6.70 (s, 1H), 3.82 (s, 2H), 3.47 (s, 2H), 3.21 (t, 4H), 2.92 (t, 2H), 2.58-2.50 (m, 4H), 1.66 (m, 4H), 1.58 (m, 2H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cc4ccccc4s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-benzothiophene-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 193.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(OC)c(OC)c2)cc1

Procedure:
As described under 1.2., 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 11.37 g (0.055 mol) of 4-methoxyphenylsulfonic acid chloride in the presence of 7.6 g of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 3.26 g (17%) of α-(4-methoxy-phenylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 161-167° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 349 nm (ε=11700) that extends to 435 nm. Elemental analysis: C17H16N2O6S (376.38)
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.O>S1(CCCC1)(=O)=O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][NH:27][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:2]=2[I:1])[CH:26]=[CH:25][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(I)c(OCC2CO2)c1
Reactant: COc1ccc(CCN)cc1OC
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(I)c(OCC(O)CNCCc2ccc(OC)c(OC)c2)c1
Yield: 89.8 %

Procedure:
A solution of 5.0 g (0.016 mole) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane, the product of Example 5b. and 3.25 g (0.0179 mole) of homoveratrylamine in 10 ml of sulfolane was heated at 60°-70° C. for 18 hr. Water was added and the precipitate which formed was collected by filtration. It was recrystallized from acetonitrile to give 7.0 g (87% yield) of crystalline 1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-(2-iodo-5-methoxyphenoxy)-2-propanol, mp 83°-88° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:40])[C:9]1[S:10][C:11]([S:38][CH3:39])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[CH:25][C:24]=3[CH3:37])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH3:39][S:38][C:11]1[S:10][C:9]([C:8]([NH2:40])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]([F:35])([F:34])[F:36])(=[O:31])=[O:32])=[CH:25][C:24]=2[CH3:37])[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(NS(=O)(=O)C(F)(F)F)cc2C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccc(NS(=O)(=O)C(F)(F)F)cc2C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
A mixture of {imino-[5-methylsulfanyl-4-(2′-methyl-4′-trifluoromethanesulfonylamino-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (9 mg, 14 μmol) in TFA/DCM (1:1, 3 mL) was stirred at ambient temperature for 40 min. The mixture was concentrated, and flashed chromatographed on silica gel column, eluting with MeOH/DCM (5 to 8%) to give the title compound (5 mg, 54% yield) as a pale yellow solid. 1H NMR (CDCl3): δ 8.32 (s, 1H), 8.04–8.01 (m, 1H), 7.96–7.95 (m, 1H), 7.68–7.66 (m, 2H), 7.17 (m, 3H), 2.72 (s, 3H), 2.21 (s, 3H), ESI-MS (m/z): Cald. For C20H19F3N3O4S4: 550.0 (M+H); found: 550.0.