Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.31-0.33 (m, 2H), 0.53-0.56 (m, 2H), 1.22 (br s, 1H), 2.43 (s, 3H), 3.76-3.81 (m, 2H), 3.81 (s, 3H), 7.05-7.11 (m, 2H), 7.25-7.28 (m, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.80 (s, 1H), 8.14 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 495.10 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:18]=[C:13]1[CH2:14][CH2:15][C:16](=[O:17])[N:12]1[O:9][C:8](=[O:10])[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CN1CCCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6 g (42 mMol) (piperidine-1-yl)-acetic acid 10 was added to 4.83 g (42 mMol) N-hydroxysuccinimide and 9.53 g (46.2 mMol) dicylohexyl-carbodiimide in 100 ml CH2Cl2. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated in vacuum to dryness. The residue was then dissolved in diethylether and the solution was filtered off. The filtrate was reduced once again and the residue was dissolved in Diisopropylether. After filtration of the solution and evaporation of the solvent, the compound was then recrystallised from diisopropylether.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])=[O:13]>>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18]([C:17]2[CH:16]=[C:15]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1

Procedure:
The entitled compound was produced according to the method of Reference Example 1 but using 4-isopropylaniline and 3-(chlorosulfonyl)benzoyl chloride as the starting materials.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:4]=1.[CH2:16]([N:18]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:21][NH:20][C:19]1=[S:28])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:15][C:9]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=1[C:5]1[N:4]=[C:3]([CH2:2][S:28][C:19]2[N:18]([CH2:16][CH3:17])[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[N:21][N:20]=2)[O:7][N:6]=1
Reactant: CCn1c(-c2cccs2)n[nH]c1=S
Reactant: Fc1ccc(F)c(-c2noc(CCl)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(SCc2nc(-c3cc(F)ccc3F)no2)nnc1-c1cccs1
Yield: 49.3 %

Procedure:
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole (23 mg, 0.10 mmol) and 4-ethyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg, 0.11 mmol) was dissolved in anhydrous DMF (1 ml) and potassium carbonate (21 mg, 0.15 mmol) was added. After stirring for 22 h ethyl acetate was added, the resulting mixture was washed twice with water and once with brine, dried over MgSO4 and evaporated. Flash chromatography using heptane:ethyl acetate 1:1 yielded the title compound (20 mg, 50%). 1H NMR (CDCl3) d (ppm): 7.64 (m, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.10 (m, 3H), 4.70 (s, 2H), 4.08 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: [SH:1][C:2]1[C:3]2[N:10]=[C:9]([CH2:11][OH:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.I[CH3:14]>[OH-].[Na+]>[CH3:14][S:1][C:2]1[C:3]2[N:10]=[C:9]([CH2:11][OH:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CI
Reactant: OCc1nc2c(S)ncnc2s1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncnc2sc(CO)nc12
Yield: 53 %

Procedure:
A solution of (7-mercapto[1,3]thiazolo[5,4-d]pyrimidin-2-yl)methanol (Intermediate 75) (48.3 g) and iodomethane (16.6 mL) in 2M NaOH (450 mL) was stirred at ambient temperature for 5 hours. The crude product was collected by filtration, suspended in water and acidified by addition of 2N HCl. The flocculant solid was collected by filtration, washed with water (200 mL) and ether (200 mL) and dried under vacuum over phosphorus pentoxide to give the title compound as a pale brown solid (27.5 g, 53%);
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:15]([O:19][C:20]([NH:22][C:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=S)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:29]([O:28][C:26]([NH:25][C:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:9]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cccnc1-c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a suspension of 3-(3-methylpyridin-2-yl)aniline (184 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (331 mg) and diisopropylethyl-amine (0.4 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (332 mg), and the mixture was stirred for 3 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=2:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methylpyridin-2-yl)phenyl)guanidine (327 mg).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][CH:35]=[N:36][C:37]=2[NH:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:7][C@@H:6]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH:41][C:42](=[O:49])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@](CO)(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O)c1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of nucleoside 58 (4.18 g, 6.28 mmol) in methanol (50 cm3) was added sodium methoxide (0.75 g, 13.8 mmol) at 0° C. The reaction mixture was stirred for 2 h, and ice was added. The mixture was neutralised using a 20% aqueous solution of HCl. Extraction was performed using dichloromethane (3×75 cm3), the organic phase was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give nucleoside 59 as a white solid material (2.68 g, 73%). δH (CDCl3) 9.42 (1H, br s, NH), 8.58 (1H, s, H-8), 8.16 (1H, s, 2-H), 7.96 (2H, d, J 7.2, Bz), 7.52-7.08 (13H, m, Bn, Bz), 6.18 (1H, d, J 2.5, 1′-H), 4.85-4.38 (4H, m, Bn, 2′-H, 3′-H), 4.33 (2H, s, Bn) 3.90 (1H, d, J 11.9, 1″-Ha), 3.71 (1H, d, J 11.8, 1″-Hb), 3.50-3.39 (2H, m, 5-H). δC (CDCl3) 164.98 (NHCO), 152.19 (C-6), 151.00 (C-2), 149.34 (C-4), 142.28 (C-8), 137.32, 137.25, 133.46, 132.70, 128.69, 128.49, 128.40, 128.11, 128.03, 127.94, 127.83, 127.62, (Bz, Bn), 122.92 (C-5), 90.94, 88.75 (C-1′, C-4′), 77.65, 74.08, 73.44, 73.20, 71.12, 62.39 (C-1″, C-5′, C-2′, C-3′, 2×Bn). FAB-MS m/z 582 [M+H]+. Found: C, 65.6; H, 5.5; N, 11.7; C32H31N5O6 requires C, 66.1; H, 5.4; N, 12.0%.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([CH:35]1[CH2:40][CH2:39][C:38]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=2[F:55])([CH:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].O>C1COCC1.C1(C)C=CC=CC=1>[CH2:30]([CH:35]1[CH2:36][CH2:37][C:38]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=2[F:55])([CH:41]2[CH2:42][CH2:43][C:44](=[CH:2][O:3][CH3:4])[CH2:45][CH2:46]2)[CH2:39][CH2:40]1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=COC)CC2)CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (8.6 g) and THF (100 ml) were mixed under a nitrogen atmosphere, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 2.8 g) was put in thereto in twice in the temperature range of −30° C. to −20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (38) (7.6 g) dissolved in THF (100 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction mixture had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 8.1 g of 1-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-4-methoxymethylenecyclohexane (39). The yield based on the compound (38) was 99.0%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:18])[C:5]([N+:19]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:19])=[C:6]([OH:18])[C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][S:14](=[O:17])[CH2:15][CH2:16]1)(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Yield: 94.5 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-2-hydroxy-3-nitro- 1-(1-oxidothiomorpholinosulfonyl)benzene (103 mg, 0.29mmol) was reduced with hydrogen and 10% Pd/C (59 mg) to form the desired product (89 mg, 95%). LC-MS (m/z) 325.0 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][O:8][C:9]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+]>CO>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([C:9]2[O:8][CH:7]=[N:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ncoc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a stirred solution of tert-butyl 4-[4-(methoxycarbonyl)-1,3-oxazol-5-yl]piperidine-1-carboxylate (8.90 g, 28.7 mmol) in methanol (340 mL) was added 1 M NaOH solution (86 mL). After being stirred at room temperature for 2 h, the reaction mixture was concentrated to about one quarter. To this mixture was added ethyl acetate (80 mL) and the mixture was acidified with 10% KHSO4 solution under ice-cooling. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light yellow solid was triturated with diisopropyl ether to give the title compound (7.32 g, 86%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]2[O:12][C:11]([NH2:13])=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:16](OCC)(=[O:19])[C:17]#[CH:18]>C(O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]2[O:12][C:11]3=[N:13][C:16](=[O:19])[CH:17]=[CH:18][N:10]3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC1=NCC(COc2ccc(F)cc2)O1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: O=c1ccn2c(n1)OC(COc1ccc(F)cc1)C2
Temperature: 25 °C
Yield: 43.9 %

Procedure:
To a solution of 5-(4-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (4.20 g, 2.00 mmol) in ethanol (8 mL) was added ethyl propiolate (0.25 g, 2.60 mmol). The reaction mixture was stirred at reflux for 6 hours. The mixture was stirred at 30° C. for a few minutes after which it was cooled to room temperature. The resulting crystals were collected and washed twice with hexane. The solid was dried under high vacuum at 65° C. for 18 hours to afford 0.23 g (50%) of 2-(4-fluorophenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: [BrH:1].[CH:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6])([CH3:4])[CH3:3].BrBr>C(Cl)(Cl)Cl>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]([C:2]([Br:1])([CH3:4])[CH3:3])=[O:6])=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)c1ccc(Cl)cc1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=S)[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(OCC)(=[O:59])C>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:59])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CC(C)c1c(C(=S)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamothioyl)-1H-pyrrol-1-yl)ethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate obtained in Example 5-3 was dissolved in 70 ml of ethanol, and 0.83 g of sodium hydroxide and 35 ml of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature for 3 hours. 300 ml of ethyl acetate and 200 ml of purified water were added to the reaction mixture and stirred slowly for 30 minutes, and the organic layer was separated and washed one time with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining oil. The oil was crystallized from isopropylether and heptane, thus obtaining the target compound as a solid compound.
Reaction SMILES: [C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[CH:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH:16]1[C:37]([O-:39])=[O:38])([O:3]C)=[O:2].[OH-].[Na+]>O1CCOCC1>[C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[CH:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH:16]1[C:37]([OH:39])=[O:38])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)OC)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2

Procedure:
To a solution of methyl (1RS, 2SR, 3SR)-3-[2-[(E)-2-carbomethoxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.15 mmol) in dioxane (2 ml) was added 1 N NaOH (0.5 ml, 0.5 mmol). The resulting mixture was heated to reflux for 3 h, then cooled and concentrated under reduced pressure. The residue was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the title compound was obtained as a white solid (73 mg, 96%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[S:28][C:27]3=[N:33][CH:34]=[CH:35][N:26]3[C:25]=2[CH3:24])=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)O)sc2nccn12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2sc3nccn3c2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=512.3.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])CO.[CH:14]([Cl:17])(Cl)[Cl:15]>C1S(=O)(=O)CCC1.S(Cl)(Cl)=O>[ClH:15].[ClH:1].[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])[CH2:14][Cl:17]
Reactant: ClC(Cl)Cl
Reactant: CC(c1c[nH]cn1)C(N)CO
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: O=S(Cl)Cl
Product: CC(c1c[nH]cn1)C(N)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 g (13.2 mmol) 2-amino-3-(1H-imidazol-4-yl)butanol dihydrochloride are solved in a mixture of 25 ml tetramethylenesulfone and 10 ml thionyl chloride and stirred 12 hours at room temperature. Dropwise addition of 200 ml chloroform affords 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane dihydrochloride. Yield: 2.87 g (88.2%) of a hygroscopic precipitate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:25][C:26]([CH3:33])([CH3:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)CC(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 26 (˜700 mg, a mixture obtained from the above) and CH2Cl2 (8 mL) was treated with CF3CO2H (2 mL) at RT. The reaction mixture stirred at RT under N2 for 1.5 h and then concentrated under reduced pressure to afford the crude product. The crude material was purified by column chromatography to afford 165 mg of the desired product 27 as a white solid. A portion (350 mg) of the starting triflate 25 was also recovered. Data for 27: 1H NMR (400 MHz, CD3OD): δ 7.64 (d, J=16.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.18 (d, J=5.6 Hz, 1H), 7.16 (d, J=5.6 Hz, 1H), 7.00 (t, J=8.8 Hz, 2H), 6.44 (d, J=16.00 Hz, 1H), 1.99 (s, 2H), 1.97 (s, 2H), 1.31 (s, 2H), 0.93 (s, 12H). LCMS (APCI): m/z 391 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35]Cl)[CH3:32].O>CC(C)=O>[CH2:31]([N:33]([CH2:38][CH3:39])[C:34]([CH2:35][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:13])=[O:37])[CH3:32]
Reactant: C[C@H](Cc1c[nH]c2c(O)cccc12)N1C(=O)c2ccccc2C1=O
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N3C(=O)c4ccccc4C3=O)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A residue 10.27 g containing (R)-7-hydroxy-3-(2-phthalimidopropyl)indole was dissolved in 200 ml of acetone, and 8.00 g of potassium carbonate was added thereto. After addition of N,N-diethylchloroacetamide 15.5 ml, the solution was heated to reflux in an oil bath of 80° C. For 3 hours. After cooling down 200 ml of water was added, and a deposited crystal was collected by filtration and washed with water, whereby 9.56 g of the title compound was obtained in the form of a pale yellowish white substance.