Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[OH:19]O.CSC>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(CSc1ccc(O)cc1)Nc1ccccc1
Reactant: OO
Solvent: CC(=O)O
Solvent: CSC
Product: O=C(CS(=O)c1ccc(O)cc1)Nc1ccccc1
Yield: 93 %

Procedure:
6.0 g (23.2 mmol) of 2-(4-hydroxyphenylthio)acetoanilide and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 2.8 g (24.7 mmol) of 30k aqueous solution of hydrogen peroxide was added, and the resultant solution was stirred for 12 hours at a room temperature. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with MIBK to obtain 5.9 g of 2-(4-hydroxyphenylsulfinyl)acetoanilide. The yield was 93% and the melting point of the compound was in a range of 208 to 210° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccccc1OCCCBr
Product: Cc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.732 g of 1-(3-bromopropoxy)-2-methylbenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.57 (1:2 EtOAc-heptane); Rt=5.45.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Product: O=c1[nH]c2ccc(NCCCc3ccccc3)cc2s1

Procedure:
By reaction of 6-amino-2-benzothiazolone (1.66 g) with 3-phenylpropanal using the procedure of Example 1, the title compound (0.82 g) was prepared.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1>CCO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:15][N:16]([CH2:3][CH2:2][C:1]#[N:4])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: C=CC#N
Reactant: COc1ccc(C2(c3ccccc3)CCNCC2)cc1
Solvent: CCO
Product: COc1ccc(C2(c3ccccc3)CCN(CCC#N)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
Acrylonitrile (1.03 mL, 15.7 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-(4-methoxyphenyl)-4-phenylpiperidine (1.68 g, 6.28 mmol, 1.00 equiv) in EtOH (20 mL) and the resulting solution was stirred for 1.5 hours at room temperature. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-CHCl3 1:3) to give 1.41 g (70%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2CC(C)(C)C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2CC(C)(C)C)c1

Procedure:
1.74 g of compound 10 was obtained in a similar manner to those described in the Examples 1 and 2 using 3.16 g of ethyl 4-(2-aminophenoxy)butyrate and 1.93 g of 3-[1-(2,2-dimethylpropyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][OH:12]>C(O)C>[OH:12]/[N:11]=[C:1](\[NH2:10])/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C#N)cc1
Solvent: CCO
Product: COc1ccc(/C(N)=N/O)cc1
Yield: 99 %

Procedure:
A solution of anisonitrile (300 mg, 2.25 mmol) and hydroxylamine (275 μL, 9.01 mmol) in ethanol (5.0 mL) was refluxed for 3 hours. The reaction was cooled and then concentrated in vacuo to give the product (370 mg, 99%), which immediately formed white crystals and was taken to the next step without further purification. A small quantity was purified by column chromatography over silica gel (Hex/EtOAc 1:8) to give the product (370 mg, 99%) as a white solid. 1H NMR (500 MHz, CDCL3) δ(ppm): 3.83 (3H, s), 4.86 (2H, bs), 6.91 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 55.5 (CH3), 114.2 (CH), 125.1, 127.4 (CH), 152.7, 161.2. MS (FAB+): 167 (MH+). HRMS for O8H10N2O2 (MH+): calculated: 167.0821; found 167.0803.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([F:26])[CH:15]=3)[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].O1CCCC1.[BH4-].[Na+]>CO>[CH2:29]([O:28][C:7]1[C:8]2[C:9](=[O:27])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([F:26])[CH:15]=3)[CH:11]([OH:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=12)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)cc1F
Reaction time: 0.08 h
Yield: 107.8 %

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (24 g, 51.6 mmol) was suspended in methanol (75 ml) and tetrahydrofuran (200 ml) and cooled to 5° C. in an ice bath. Some solid did not go into solution. Sodium borohydride (2 g, 51.6 mmol) was added portionwise over 2 minutes (effervescence). Undissolved solid slowly went into solution and the colour lightened from dark brown to light brown. LC/MS after 5 minutes and 30 minutes indicated that the reaction had not proceeded to completion. Therefore, after 30 minutes, more sodium borohydride (1 g, 26.3 mmol) was added in one portion (effervescence). LC/MS after a further 30 minutes showed no starting material remaining. The mixture was concentrated in vacuo to give a brown oil that was partitioned between ethyl acetate (300 ml) and water (500 ml). The aqueous layer was further extracted with ethyl acetate (2×100 ml). Combined organics were washed with brine, dried over magnesium sulphate and concentrated to give the title compound as a brown solid (26 g).
Reaction SMILES: N1(C(OCC2C=CC=CC=2)=O)CCNCC1.BrC1C=CC(C=O)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C@@H:36](C)[CH2:35]2)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:40]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:41])[CH2:38][CH2:39]2)=[CH:31][CH:32]=1
Reactant: C[C@H]1CN(Cc2ccc(Br)cc2)CCN1C(=O)OCc1ccccc1
Agent: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=Cc1ccc(Br)cc1
Product: O=C(OCc1ccccc1)N1CCN(Cc2ccc(Br)cc2)CC1

Procedure:
The title compound was prepared from phenylmethyl 1-piperazinecarboxylate and 4-bromobenzaldehyde using a method to that described for D6
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, light brown solid (95 mg, 82%), MS (ISP) m/z=465.2 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-chloro-benzoic acid.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH:7]=[CH:8]/[C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][CH:14]([OH:17])[CH2:15]3)[CH2:11][C@H:10]2[OH:18])=[CH:4][C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]1=2.[H][H]>C(OCC)(=O)C.[Pd]>[S:1]1[C:5]([C@H:6]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:7][CH2:8][C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][CH:14]([OH:17])[CH2:15]3)[CH2:11][C@H:10]2[OH:18])=[CH:4][C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]1=2
Reactant: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@H](CC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(3aR,4R,5R,6aS)-4-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol (Example 2, Step E, 1 mol equivalent) is dissolved in ethyl acetate (0.05 M) under a nitrogen atmosphere. 10% Pd/C (10 mol %) is added and hydrogen gas is introduced. After stirring for several hours at room temperature the reaction mixture is filtered over Celite. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes (+0.4% acetic acid) to afford the title intermediate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1COCCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)[C@@H]1COCCN1
Yield: 92.3 %

Procedure:
A solution of ethyl (3S)-4-benzylmorpholine-3-carboxylate (6.50 g) in methanol (130 ml) was hydrogenated under atmospheric pressure of hydrogen over 20% palladium hydroxide on carbon (0.6 g) for 3 hours at ambient temperature. The catalyst was filtered off and the methanol was evaporated to give ethyl (3S)-morpholine-3-carboxylate (3.83 g) as a syrup.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][CH2:21][CH:20](O)[CH2:19]2)[N:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][CH2:21][C:20]3([O:5][CH2:1][CH2:2][O:3]3)[CH2:19]2)[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC1CCN(c2cccc(Br)n2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Brc1cccc(N2CCC3(C2)OCCO3)n1

Procedure:
Then, to a solution of 2.8 ml of oxalyl chloride in 100 ml of dichloromethane were added dropwise 4.6 ml of dimethyl sulfoxide in a dry ice-acetone bath while stirring, a solution of 5.9 g of the 2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine in 50 ml of dichloromethane and finally 17 ml of triethylamine, and the temperature was returned to room temperature over 1 hour. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. To the residue were added 50 ml of toluene, 7 ml of ethylene glycol and a catalytic amount of p-toluenesulfonic acid monohydrate, followed by heating under reflux for 3 hours while removing water. After cooling, it was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography with 5–7% ethyl acetate/hexane, to give 6.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8](C(O)=O)[O:9][C:5]=2[CH:4]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: COc1ccc2ccoc2c1
Yield: 99.9 %

Procedure:
A suspension of 6-methoxybenzofuran-2-carboxylic acid (22.2 g) and copper powder (3.7 g) in quinoline (200 ml) was refluxed under nitrogen atmosphere for 2 hours and cooled, and to the suspension was added 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with 2N hydrochloric acid (6 times) and then washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give dark brown oil of 6-methoxybenzofuran (17.1 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(C(O)=O)(F)F.[CH3:38][C:39]([CH3:45])([CH3:44])[CH2:40][C:41](Cl)=[O:42]>N1C=CC=CC=1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[C@@H:10]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH:1][C:41](=[O:42])[CH2:40][C:39]([CH3:45])([CH3:44])[CH3:38])[CH3:30]
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)CC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of Leu-DTrp-βAla-OEt.TFA (33.0 mg) obtained in Example 51-(1) in pyridine (0.5 ml) was added 3,3-dimethylbutyryl chloride (12.8 ml) at 0° C. under nitrogen. The reaction mixture was stirred for 10 min, quenched with water (0.1 ml), and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=15/1 for development to give the product (21.8 mg).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:22]CC2C=CC=CC=2)[CH:19]([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:30]([CH3:32])[CH3:31])[S:14]2)[C@H:10]1[O:33]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[F:21][CH:19]([F:20])[C@H:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:30]([CH3:31])[CH3:32])[S:14]2)[C@@H:10]([OH:33])[C@@H:9]1[OH:8])[OH:22]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](OCc3ccccc3)C(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)C(F)F)O[C@@H]2S1
Reaction time: 0.13 h
Yield: 4.8 %

Procedure:
A solution of 99 (600 mg, 1 mmol) in dichloromethane (20 mL) was treated with BCl3 (10 mL, 10 mmol, 1 M in dichloromethane) for 1 hour at −78° C., then quenched with methanol (20 mL). Volatiles were distilled out to give a residue, which was dissolved into methanol (5 mL) and neutralized with Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give a mixture of the two epimers; the two epimers were separated by Prep-HPLC with the following conditions: (Agilent Prep 1200 Detecl): Column, SunFire Prep C18; mobile phase, Water with 0.05% ammonia and CH3CN, 5% CH3CN up to 40% in 8 min; Detector, 220 nm) to afford (3aR,5S,6S,7R,7aR)-5-((S)-2,2-difluoro-1-hydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a light yellow solid (14.4 mg, 5%), faster eluting isomer; (ES, m/z) [M+H]+ 299.0, 1H NMR (300 MHz, D2O) δ 6.19 (d, J=6.6 Hz, 1H), 5.71-6.09 (m, 1H), 4.15 (t, J=6.0 Hz, 1H), 3.89-3.99 (m, 2H), 3.78-3.82 (m, 1H), 3.37 (t, J=8.7 Hz, 1H), 2.89 (s, 6H); and (3aR,5S,6S,7R,7aR)-5-((R)-2,2-difluoro-1-hydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a light yellow solid (53.9 mg, 17.4%), slower eluting isomer; (ES, m/z) [M+H]+ 299.0, 1H NMR (300 MHz, D2O) δ 6.20 (d, J=6.3 Hz, 1H), 5.62-6.00 (m, 1H), 4.07 (t, J=6.0 Hz, 1H), 3.87-3.96 (m, 2H), 3.72-3.77 (m, 1H), 3.62-3.65 (m, 1H), 2.88 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([NH:9][C:10]([CH:12]([NH:20][C:21]([CH2:23][NH:24][C:25]([CH2:27][NH:28][C:29]([CH:31]([NH2:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)=[O:30])=[O:26])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7])[CH3:3].C(OC(N=C=S)=O)C.C1C=CC(CN=C=S)=CC=1.C(S)[C@@H](O)[C@H](O)CS.N[C@H](C(O)=O)CC(C)C>O>[CH3:3][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([C@@H:12]([NH:20][C:21]([CH2:23][NH:24][C:25]([CH2:27][NH:28][C:29]([C@@H:31]([NH2:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)=[O:30])=[O:26])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7])[CH3:1]
Reactant: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)C(N)Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CCOC(=O)N=C=S
Agent: O[C@H](CS)[C@H](O)CS
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Temperature: 60 °C

Procedure:
Immobilized leucine enkephalin (urea linkage) was degraded for two cycles of chemistry. The couplings were performed with ethoxycarbonyl isothiocyanate (instead of BITC) for 5 minutes at 60° C. Cleavages were effected by adding 10 μl of 10% tetra-N-butyl ammonium hydroxide in water containing 1 mg/ml DTT to the dry resin, and heating for 45 minutes at 60° C. Chromatograms are shown in FIGS. 6A and 6B. The cycles were assigned as leucine and phenylalan respectively. The assignments were confirmed by coinjection.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C:14](=[O:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12.Cl>CO.O.[OH-].[Pd+2].[OH-]>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(=O)C(=O)N(C)C)c3)c(Cl)c12
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Temperature: 23 °C
Reaction time: 15 h
Yield: 108 %

Procedure:
2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-2-oxo-acetamide (57 mg, 0.129 mmol) was dissolved in methanol (7 mL), and hydrochloric acid solution was added (774 μL, 0.774 mmol, 1.0 M solution in water). The flask was purged with nitrogen gas before and after addition of Palladium hydroxide (1.8 mg, 0.013 mmol, 20 weight % on carbon, wet) The flask was purged with hydrogen gas and allowed to stir for 15 hours at 23° C. under 1 atm of hydrogen gas. The reaction mixture was filtered through Celite® and concentrated to afford 2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (79 mg, quantitative yield) as an orange-brown oil. MS [MH+] m/z: 573.0
Reaction SMILES: O=[C:2]([CH2:7]CC)[CH2:3]C(O)=O.[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([OH:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:3][C:2]1([CH3:7])[O:16][C:10](=[O:15])[CH2:11][C:12](=[O:14])[O:13]1
Reactant: CCCC(=O)CC(=O)O
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 50 °C
Reaction time: 3 h
Yield: 191.3 %

Procedure:
50 g of resin-bound 2-oxopentanecarboxylic acid (1) are swollen in 200 ml of acetic acid and treated with 20 g of malonic acid (2). 10 g of anhydrous ammonium acetate are added and the mixture is heated to 50° C. After stirring carefully for 3 h, the resin is freed from the solution, washed thoroughly with DMF and methylene chloride and dried. 53 g of (3) are obtained. Removal of a sample using anhydrous TFA yields the free Meldrum's. acid derivative (3, Li-P=H) (HPLC, MS).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br.CCOCC>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: COc1cccc(N)c1C(C)=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(N)c1C(C)(C)O
Temperature: 0 °C

Procedure:
1-(2-Amino-6-methoxyphenyl)ethanone (500 mg, 3.03 mmol) was dissolved in THF (7.5 mL) and cooled to 0° C. A 3M solution of Methyl magnesium bromide in Et2O (2.12 ml, 6.36 mmol) was added drop wise keeping the temperature below 10° C. The reaction was quenched with an aqueous saturated solution of NH4Cl (7.5 mL) keeping the temperature below 15° C. The mixture was diluted with water and ethyl acetate, two phases separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound (500 mg) as light orange solid.