Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.Cl.[C:24]([S:43][CH2:44][CH2:45][NH2:46])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:46][CH2:45][CH2:44][S:43][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:13])=[CH:8]2
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.31 g), 2-(tritylthio)ethylamine hydrochloride (0.33 g), 1H-1,2,3-benzotriazol-1-ol (0.15 g), triethylamine (0.15 mL) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.21 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.54 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point>188° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.[F:34][C:35]([F:49])([F:48])[C:36]1[O:40][N:39]=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[N:37]=1.COC1C=C(C=CC=1OC)C=O.CC1ON=C(C2C=CC(N)=CC=2)N=1.FC1C=C(OC)C(OC)=CC=1C=O>>[CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6]([C:20]1[CH:21]=[CH:22][C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1)=[N:47][C:44]1[CH:43]=[CH:42][C:41]([C:38]2[N:37]=[C:36]([C:35]([F:48])([F:34])[F:49])[O:40][N:39]=2)=[CH:46][CH:45]=1
Reactant: Nc1ccc(-c2noc(C(F)(F)F)n2)cc1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Agent: COc1cc(F)c(C=O)cc1OC
Agent: COc1ccc(C=O)cc1OC
Agent: Cc1nc(-c2ccc(N)cc2)no1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1ccc(OC)c(OC)c1

Procedure:
The same procedure was carried out as in Example (1a) to (1d), except that 4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamine (Example (188a)) and 3,4-dimethoxybenzaldehyde were used instead of respectively 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine and 2-fluoro-4,5-dimethoxybenzaldehyde in Example (1a), to give the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([C@@H:6]([OH:36])[C:7]([NH:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][NH:21][C:22]([CH2:24][CH2:25][NH:26][C:27]([C@H:29]([OH:35])[C:30]([CH2:33][OH:34])([CH3:32])[CH3:31])=[O:28])=[O:23])=[O:13])=[O:8])([CH2:4][OH:5])[CH3:3].C[O:38][C:39](OC)([CH3:41])[CH3:40]>FC(F)(F)C(O)=O.CC(C)=O>[CH3:3][C:2]([C@@H:6]([OH:36])[C:7]([NH:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][NH:21][C:22]([CH2:24][CH2:25][NH:26][C:27]([C@H:29]([OH:35])[C:30]([CH2:33][OH:34])([CH3:31])[CH3:32])=[O:28])=[O:23])=[O:13])=[O:8])([CH2:4][OH:5])[CH3:1].[CH2-:40][C:39]([CH3:41])=[O:38]
Reactant: COC(C)(C)OC
Agent: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: [CH2-]C(C)=O
Reaction time: 48 h

Procedure:
A mixture of 1.0 g of D-pantethine, 5 ml of 2,2-dimethoxypropane, 5 drops of trifluoroacetic acid and 5 ml of acetone was stirred for 2 days and then evaporated. The resulting white foam was purified by flash chromatography [dichloromethane:methanol (10:1)], giving 1.0 g of the desired compound as a white hygroscopic foam.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([CH2:25][OH:26])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)(Cl)Cl>[OH:5][CH:6]([CH2:25][OH:26])[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:1](=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Acetyl chloride (1.15g. 14.8 mmoles) was added dropwise to a reactor containing N-(2,3-dihydroxypropyl)-hexadecylamine (1.5 g, 4.3 mmoles) in 3 mL of chloroform. The reaction was stirred for 16 hours at room temperature. When the reaction was completed, the, mixture was concentrated, ethanol and water was added, and the pH of the reaction was adjusted to 14. This mixture was extracted with chloroform, and organic layer was collected and concentrated. The sample was purified on a silica column chromatography to give 0.4 g of product.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([C:23]([N:1]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:24])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: C1COCCOCCOCCN1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N1CCOCCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8]/[C:7](=[CH:10]/O)/[C:6](=[N:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:5]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[SH:40]>O1CCCC1.O>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40][CH:10]=[C:7]1[C:6](=[N:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH2:9][CH2:8]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: CCOC1=CC(=Nc2ccc(C)cc2)/C(=C\O)CC1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC1=CC(=Nc2ccc(C)cc2)C(=CSc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
100 mg (0.39 mmol) of (Z)-4-ethoxy-2-[(4-methylphenyl)imino]cyclohex-3-en-1-ylidene methanol are dissolved in 10 ml of anhydrous tetrahydrofuran, and 325 μl (2.3 mmol) of triethylamine and 60 μl (0.78 mmol) of methanesulphonyl chloride are added at 0° C. After 30 min of stirring at 25° C., the mixture is once more cooled to 0° C., 40 μl (0.35 mmol) of 2,4-difluorobenzenethiol are added and the mixture is stirred at 25° C. for a further 30 min. The reaction mixture is diluted with water and extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 41 mg of N-(6-{[(2,4-difluorophenyl)sulphanyl]methylene}-3-ethoxycyclohex-2-en-1-ylidene)-4-methylaniline as an isomer mixture (ratio about 1:1).
Reaction SMILES: [C:1]1([CH:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2].C(OCC)C>C1COCC1.O>[C:1]1([CH:7]([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:8][NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: NCC(c1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,3,3-triphenylpropionitrile (10.00 g, 0.035 mol) and THF (80 ml) was added dropwise to a solution of LiAlH4 (3.40 g, 0.089 mol) in THF (100 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature and then refluxed for 24 hours. After cooling in an ice bath, the reaction mixture was treated with water (3.40 ml), 3N sodium hydroxide (10.20 ml) and water (3.4 ml) followed by the addition of magnesium sulfate. The mixture was filtered and the filtrate was evaporated to an oil. This material was dissolved in diethyl ether (30 ml) and diethyl ether/anhydrous hydrochloric acid (25 ml, 0.025 mol) was added. A white solid was filtered and partitioned between diethyl ether and 3N sodium hydroxide. The organic layer was separated, dried over potassium carbonate, filtered, and evaporated affording 2,3,3-Triphenylpropylamine as a crystalline solid.
Reaction SMILES: [C:1]([O:7][CH:8]1[CH2:11][C:10](=[O:12])[C:9]1(Cl)Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CC(O)=O.[Zn]>[C:1]([O:7][CH:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC1CC(=O)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)OC1CC(=O)C1
Reaction time: 1 h

Procedure:
To a stirred suspension of zinc dust (103 g, 1568 mmol) in HOAc (200 ml) was added a solution of 2,2-dichloro-3-oxocyclobutyl pivalate (75 g, 314 mmol) in HOAc (400 ml) dropwise in an ice bath. The reaction mixture was stirred for 1 h, filtered the solid through celite and washed with DCM. The DCM layer was washed with H2O, NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude material was purified by ISCO (10% EtOAc/Hexanes) to give the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)[CH2:2][CH3:3].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[C:16]=1[CH3:23]>CS(C)=O>[CH3:22][C:17]1[C:16]([CH3:23])=[C:15]([O:11][CH2:10][CH2:9][C:4]2([CH2:1][CH2:2][CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[CH:20]=[CH:19][N+:18]=1[O-:21]
Reactant: CCCC1(CCO)OCCO1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC1(CCOc2cc[n+]([O-])c(C)c2C)OCCO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a dimethylsulfoxide (22.5 ml) solution of the 2-(2-propyl-1,3-dioxolan-2-yl)ethanol (1.5 g, 9.35 mmol) obtained in the step (3b), sodium hydride, in oil (561 mg, 14 mmol as the content was regarded as 60%) and 4-chloro-2,3-dimethylpyridine 1-oxide (1.33 g, 8.42 mmol) were added in a nitrogen stream and stirred at 60° C. for 2 hours. The mixture was allowed to stand at room temperature for 3 days and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran. NH silica gel was added to the resultant mixture, which was then concentrated to dryness and subjected to NH silica gel column chromatography (elution solvent: n-heptane/ethyl acetate/methanol=1/1/0→0/1/0→0/10/1) to obtain the title compound (1.53 g, yield: 58.2%) as a light brown oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[N+:13]([O-:14])[C:8]=2[CH:7]=[C:6]([CH3:16])[CH:5]=1.C(OCC)(=O)C.O.[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27]>O1CCCC1>[Br:3][C:4]1[C:9]2[N:10]=[C:11]([O:27][CH2:26][C:25]([F:29])([F:28])[F:24])[N:12]=[N+:13]([O-:14])[C:8]=2[CH:7]=[C:6]([CH3:16])[CH:5]=1
Reactant: OCC(F)(F)F
Reactant: Cc1cc(Br)c2nc(Cl)n[n+]([O-])c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c2nc(OCC(F)(F)F)n[n+]([O-])c2c1
Reaction time: 2 h

Procedure:
To 0.5 g of 60% sodium hydride stirring in 30 ml of tetrahydrofuran, 3.0 ml of 2,2,2-trifluoroethanol was added dropwise at ambient temperature. A solution resulted and 2.0 g (7.29 mmol) of the above 5-bromo-3-chloro-7-methyl-1,2,4-benzotriazine-1-oxide was added and at ambient temperature and the mixture stirred 2 h. Ethyl acetate (200 ml) and excess water were added and the separated organic extract washed with water, brine, and dried over magnesium sulfate. The solvent was removed in vacuo, hexane added to the residue, and the suspended yellow solid filtered and dried to afford 1.7 g of 5-bromo-7-methyl-3-(2,2,2-trifluoroethoxy)-1,2,4-benzotriazine-1-oxide, m.p. 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(NC(C)C)(C)C.[NH2:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(C)(O)CN
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)(O)CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (2 g, 11.98 mmol) in acetonitrile (10 mL) was cooled to −40° C., avoiding freezing. To this solution was added diisopropylamine (3.82 mL, 21.88 mmol) followed by 1-amino-2-methylpropan-2-ol (1.5 g, 16.83 mmol). The reaction mixture was removed from the cooling bath, warmed to room temperature and allowed to stir overnight (˜18 hours). Solvents were removed in vacuo and the residue was taken up in a minimum of dichloromethane (˜1.5-2 mL) and diluted with heptane until slightly cloudy. This mixture was loaded onto a 40 gram BioRad silica gel cartridge. Purification by flash chromatography (Analogix System, 20 min gradient, 0-25% methanol/dichloromethane, 40 mL/min.) provided 1-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropan-2-ol as a white solid. LCMS m/z 220.1, 221.8 (M+H)+, Rt 0.49 min.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1cc(-c2cc3c(O)cccc3o2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)on1
Yield: 86.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 5-(4-hydroxybenzo(b)furan-2-yl)-3-methylisoxazole (2.6 g), (S)-glycidyl nosylate (3.1 g) and potassium carbonate (5.0 g), the title compound (2.8 g) was obtained as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7][CH2:29][C:24]2[C:21]3[CH2:22][CH2:23][N:17]([C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[CH2:18][CH2:19][C:20]=3[CH:27]=[CH:26][C:25]=2[Cl:28])=[N:4][N:3]=1
Reactant: Nc1nnc(S)s1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(N)s3)c2CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (0.33 g, 2.5 mmol) in anhydrous DMF (8.5 mL) at room temperature add sodium hydride (0.1 g, 2.6 mmol, 60% dispersion in mineral oil) in portions. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.75 g, 2.3 mmol) in anhydrous DMF (5.6 mL). Stir at room temperature overnight and quench the reaction mixture with 10% aqueous NaHCO3 (25 mL). Extract the mixture with DCM (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (hexane over 10 min; 100:0 to 50:50 hexane/EtOAc over 23 min; 50:50 to 0:100 hexane/EtOAc over 33 min; 35 mL/min) to obtain an oil. Add EtOAc (16 mL) to precipitate product. After stirring overnight, filter the slurry, wash the solid with EtOAc (10 mL) and dry to obtain the desired intermediate (0.583 g, 61%) as a white solid. MS (ES+) m/z: 427.1 (M+H)+.
Reaction SMILES: C(C1OC2C=CC(Br)=CC=2C=1)C1C=CC=CC=1.[Cl-].[CH2:19]([C:26]1[O:27][C:28]2[CH:45]=[CH:44][C:43]([Br:46])=[CH:42][C:29]=2[C:30]=1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40]C)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C:26]1[O:27][C:28]2[CH:45]=[CH:44][C:43]([Br:46])=[CH:42][C:29]=2[C:30]=1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1
Agent: Brc1ccc2oc(Cc3ccccc3)cc2c1
Agent: [Cl-]
Product: O=S(=O)(c1ccc(O)cc1)c1c(Cc2ccccc2)oc2ccc(Br)cc12

Procedure:
2-Benzyl-5-bromobenzofuran is acylated with 4-methoxyenzenesulfonyl chloride as described above and the resulting 2-benzyl-5-bromo-3-(4-methoxyphenylsulfonyl)benzofuran is demethylated to give 2-benzyl-5-bromo-3-(4-hydroxyphenylsulfonyl)benzofuran.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([N:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]2[S:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:12]1([N:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]2[S:29]([CH2:30][C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1c2ccccc2nc(SCc2ccncc2)n1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2nc(S(=O)Cc2ccncc2)n1-c1ccccc1
Reaction time: 2 h

Procedure:
0.7 g Of m-chloroperbenzoic acid was added under an ice-cold water cooling to 1.12 g of a solution of 3-phenyl-2(4-pyridylmethylthio)-4(3H)-quinazolinone in 50 ml of chloroform and the stirring was continued for 2 hours.
Reaction SMILES: [CH:1]([C:4]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:25](=[O:27])[NH2:26])[N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:6]1=[O:24])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39].O>CN(C)C=O>[CH:1]([C:4]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:25](=[O:27])[NH2:26])[N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([C:15]2[N:16]([CH2:37][C:38]([OH:40])=[O:39])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:6]1=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1CCCC[C@@H](NC(=O)c2cc3ccccc3[nH]2)C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C(N)=O)(c1ccccc1)N1CCCC[C@@H](NC(=O)c2cc3ccccc3n2CC(=O)O)C1=O

Procedure:
To a solution of example 46 (1.200 g) under nitrogen in anhydrous dimethylformamide (10 mL) at 0°-5° C. was added sodium hydride (60% dispersion in mineral oil, 0.113 g). After stirring until the reaction mixture was homogeneous, tert-butyl bromoacetate (0.434 mL) was added. The reaction mixture was maintained at 0°-5° C. for 1.5 h and then added to water (100 mL). The resulting slurry was cooled to 0°-5° C., filtered and the filter cake was dried under high vacuum to provide the title compound as an off-white solid (1.482 g). MS(ESI): [M+H]+ =561.2. 1H NMR (300 MHz, CDCl3) d=1.07 (d, J=6.8 Hz, 6H), 1.47-2.20 (m, 6H), 1.56 (s, 9H), 3.17 (m, 1H), 3.64-3.77 (m, 2H), 3.85 (d, J=16.6 Hz, 1H), 4.75 (m, 1H), 4.98 (m, 1H), 5.27 (m, 2H), 7.01 (b, 1H), 7.13 (m, 1H): 7.19-7.31 (m, 3H), 7.41-7.50 (m, 4H), 7.63 (m, 1H), 7.71 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH3:5].[Br:6][C:7]1[CH:12]=[CH:11]C(O)=[CH:9][CH:8]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCOC
Product: COCOc1ccc(Br)cc1
Yield: 49 %

Procedure:
4-Methoxymethoxy-1-bromobenzene was prepared from formaldehyde dimethyl acetal and 4-bromophenol by the method of Y. P. Yardley and H. Fletcher, Synthesis 1976, p. 244. The boiling point of this derivative is 54° to 56° C. at 0.1 hPa, and the yield is 49 percent theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16]C3CCCCO3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][OH:16])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1ccn2CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2c1ccn2CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester (120 mg, 0.396 mmol) in MeOH (10 ml) is added p-toluenesulfonic acid monohydrate (7.25 mg, 0.04 mmol). The reaction is stirred at room temperature for 16 hours and the solvent is removed in vacuo. The residue is dissolved in MeOH (3 ml) and loaded onto a 1 g PEAX cartridge washed with MeOH (20 ml). The filtrate is concentrated in vacuo to give 1-(2-Hydroxy-ethyl)-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 220
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1cc(CCN)cc(Cc2ccc(F)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
4-chlorobenzenesulphonyl chloride (352 mg) was added portionwise to a stirred solution of ethyl 3-(2-aminoethyl)-5-[(4-fluorophenyl)methyl]benzenepropanoate (500 mg) and triethylamine (0.25 ml) in dry dichloromethane (5 ml) at room temperature. The solution was stirred at room temperature for 5 hours and then washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product. The product fractions were combined and evaporated to give the title compound as an oil (560 mg); Rf 0.2 (SS 3). Found: C,62.08; H,5.47; N,2.73. C26H27ClFNO4S requires C,61.96; H,5.40; N,2.78%.