Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 28) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>100° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-3.00 (m, 7H), 3.60-4.00 (m, 11 H), 6.66(d, J=9.2 Hz, 2 H), 6.74 (d, J=8.9 Hz, 2 H), 7.02(d, J=9.2 Hz, 2 H), 7.45(d, J=8.9 Hz, 2 H), 7.54 (s, 1 H); MS (ES) m/z: 270.0 ((M+2 H)2+, 100%); 539.1(MH+, 40%); HRMS Calcd. for C28H35N4O5S (MH+): 539.2328. Found: 539.2322.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1-c1c(F)cnn1C
Yield: 29 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chloro-3-trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.68, providing 15 mg (29% yield) of Compound 84: LCMS m/z (%)=445 (M+H37Cl, 34), 443 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.69 (s, 1H), 8.39 (s, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.74 (dd, J1=8.6 Hz, J2=2.2 Hz 1H), 7.65 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.14 (d, J=9.2 Hz, 1H) 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −63.75 (s, 3F), −177.40 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][C:52]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:54][CH2:53]1>C1COCC1.O>[C:58]([O:57][C:56]([NH:55][C:52]1([CH2:51][N:37]2[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]2)[CH2:54][CH2:53]1)=[O:62])([CH3:61])([CH3:59])[CH3:60]
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC2(NC(=O)OC(C)(C)C)CC2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (80.0 mL) cooled to 0° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (8.00 g, 23.66 mmol) was added as a solution in THF (20 mL) at 0° C. and stirred at RT for 45 min. A solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (5.32 g, 28.4 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 350A as a pale yellow liquid (10 g, 85%). MS(ES): m/z=508 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 4.45 (s, 2H), 4.41-4.25 (m, 4H), 1.46 (s, 9H), 1.40-1.30 (m, 4H), 1.24 (s, 3H), 1.03-0.94 (m, 2H), 0.90-0.78 (m, 2H).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)C>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Clc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: Nc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
20 M NH3 in H2O (2 mL) was added to a suspension of 8-chloro-3-cyclopentyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (21 mg, 0.054 mmol) in i-PrOH (2 mL). The mixture was heated in an oil bath set at 105° C. overnight. Reaction mixture was concentrated in vacuo and purification by prep TLC using 10% MeOH in DCM afforded 9 mg of the title compound as an off white solid. The compound was registered as OSIP 700099. 1H NMR (400 MHz, CDCl3): δ=1.61-1.95 (m, 4H), 2.02-2.23 (m, 4H), 3.30-3.43 (m, 1H), 5.07 (br. s., 2H), 7.03-7.08 (m, 3H), 7.08-7.16 (m, 3H), 7.23 (d, J=5.05 Hz, 1H), 7.30-7.41 (m, 2H), 7.61 (d, 2H). MS (ES+): m/z 370.83 (100)[MH+]. HPLC: tR=2.61 min (Open Lynx polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].O>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH3:15])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH3:12]
Reactant: CCNCC
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a 50 ml flask fitted with a stirrer, condenser, drying tube and an addition funnel is added m-fluorobenzoyl chloride (15.9 g, 0.10 mole) and benzene (100 ml). Then a solution of diethylamine (14.6 g, 0.20 mole) in benzene (100 ml) is added dropwise over 1 hour and the reaction mixture allowed to stir at room temperature overnight. Water (150 ml) is then added rapidly and after trituration for a few minutes, the benzene layer is decanted and washed repeatedly with water (5×150 ml), dried (anhyd. Na2SO4) and the solvent removed under vacuum to afford 18 grams of N,N-diethyl-3-fluorobenzamide as a yellow oil. Elemental analysis calculated for C11H14FNO: C, 67.70; H, 7.22; F, 9.72; N, 7.16; Found: C, 66.40; H, 7.08; F, 9.65; N, 6.92
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:27][C:28]1[S:32][C:31]([SH:33])=[N:30][N:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:33][C:31]2[S:32][C:28]([CH3:27])=[N:29][N:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: Cc1nnc(S)s1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSc2nnc(C)s2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: COc1cc(O)ccc1CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCOCC1
Temperature: 80 °C
Yield: 105.9 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.30 g, 6.88 mmol) in dry DMF (5 mL) under nitrogen was cooled by a water-bath. A solution of 7A (1.17 g, 5.24 mmol) in DMF (10 mL) was added drop-wise over 15 minutes. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.77 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. for 3 days and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 2.1 g (104%) of 7B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.39-2.56 (m, 4H), 3.48 (s, 2H), 3.65-3.75 (m, 4H), 3.79 (s, 3H), 3.95-4.04 (m, 2H), 4.23-4.33 (m, 2H), 4.82-4.91 (m, 1H), 6.19 (d, 1H), 6.38 (s, 1H), 7.21 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(CO)cc1

Procedure:
A mixture (50 ml) of 4-hydroxybenzyl alcohol (1.5 g), 1-bromopropane (1.3 ml), potassium carbonate (2.5 g) and acetone (50 ml) was stirred at 60° C. for 8 hours. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 4-propoxybenzyl alcohol (1.37 g) as a yellow oily substance.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl[CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11][O:3][C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: Oc1ccc(O)cc1
Reactant: COC(CCCl)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCOc1ccc(O)cc1)OC
Temperature: 90 °C

Procedure:
The monosodium salt of hydroquinone (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-3,3-dimethoxypropane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is carefully neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 4-(3,3-dimethoxypropoxy)phenol.
Reaction SMILES: C[O-].[Na+].[OH:4][N:5]1[C:9](=[O:10])[CH:8]2[CH2:11][CH2:12][CH:13]=[CH:14][CH:7]2[C:6]1=[O:15].[CH2:16](Cl)[CH3:17].O>CO>[CH2:16]([O:4][N:5]1[C:6](=[O:15])[CH:7]2[CH2:14][CH2:13][CH:12]=[CH:11][CH:8]2[C:9]1=[O:10])[CH3:17]
Reactant: O=C1C2C=CCCC2C(=O)N1O
Reactant: CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCON1C(=O)C2C=CCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
In an autoclave a solution of 3.5 g of sodium methoxide (0.065 mol) in 40 ml of methanol, 11.0 g of N-hydroxytetra-hydrophthalimide (0.066 mol) and 4.6 g (0.072 mol) of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was held at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction mixture comprised a large quantity of solid material. This was dissolved by the addition of water and the whole was afterwards extracted with toluene to obtain the product. Gas chromatographic analysis of the toluene extract showed that the yield was 74% of N-ethoxytetra-hydrophthalimide (0.049 mol).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-butylperoxy)-1-cyclopentanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (24.41 g, 0.2500 moles) to 95% ethyl 2-oxo-cyclopentanecarboxylate (16.44 g, 0.1000 mol) in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer at room temperature. The solution was cooled to −10° C. via a dry ice-acetone bath and 70% sulfuric acid (16.81 g, 0.1200 mol) was added dropwise to the solution with temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed for purity by gas chromatography (87.98% by area). Purification by chromatography (silica gel, 90:10 petroleum ether/diethyl ether) afforded a liquid product: 13C NMR (75 MHz, CDCl3) δ 171.8 (C═O), 116.8 (O—C—O, cyclic), 79.6 (C(CH3)3, 79.2 (C(CH3)3, 59.8 (O—CH2CH3), 49.5 (CH, cyclic), 32.9 (CH2, cyclic), 27.7 (CH2, cyclic) 26.2 ((CH3)3), 26.1 ((CH3)3), 22.1 (CH2, cyclic) 13.8 (CH2CH3); IR (neat) ν 1735, 1364, 1198, 878 cm−1; Analysis calculated for C16H30O6; C, 60.36, H, 9.50; O, 30.15; found: C, 60.36; H, 9.58; O, 29.11.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[O:29][CH:30]=1>>[CH3:39][C:35]1[CH:34]=[C:33](/[CH:32]=[CH:31]/[C:28]2[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=3)[N:27]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(/C=C/c2nc(CCl)co2)c1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CC(O)CO)cc3)co2)c1
Yield: 60.3 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (154 mg), 65% oily sodium hydride (21 mg) and 4-(chloromethyl)-2-[(E)-2-(3-methylphenyl)ethenyl]-1,3-oxazole (131 mg), the same reaction as Example 2 was carried out to yield the titled compound (156 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22]>CCOCC>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:20](=[O:24])[C:21](=[O:22])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCc1ccc2oc(=O)c(=O)oc2c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 4.16 g (25 mM) of 4-n-butylcatechol, 5.06 g (50 mM) of triethylamine and 50 ml of dry ether was cooled in an ice water bath so to maintain the temperature at 5° C. or below. The mixture was added dropwise over 2 hours under stirring with a solution of 3.50 g (28 mM) of oxalyl chloride in 10 ml of dry ether. After completing the dropwise addition, the temperature of the reaction mixture was gradually raised to the room temperature and then aging was conducted for an hour. The resultant mixture was heated under reflux for 3 hours in order to complete the aging. The separated crystals of triethyl ammonium chloride was filtered. After thoroughly washing the crystals with ether, the ether solution was collected and dried with anhydrous sodium sulfate. After distilling off ether, the reaction product was recrystallized from a solvent mixture of carbontetrachloride and petroleum benzine to obtain 5.26 g (23 mM) of 6-n-butyl-1,4-benzodioxine-2,3-dione 2/5 hydrate as colorless crystals having a melting point of 88°-93° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]([N:21]([CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1ccccc1S(=O)(=O)NC(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CN(C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of compound 2c (500 mg, 1.1 mmol) in DMF (10 mL) at 10° C., NaH (60 wt %, 44 mg, 1.1 mmol) was added in portions. The mixture was stirred for an additional 30 min and then the solution of methyl 2-(bromomethyl)-benzoate (253 mg, 1.1 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 10° C. for 30 min and warmed to rt overnight. The reaction was quenched with water and diluted with EA (40 mL), washed with brine (3×20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purification by silica gel flash chromatography (PE:EA=2:1) to give compound 2d as a white solid (520 mg, 79% yield).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[N:15]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:17]3[C:22]=2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]3[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:10]=[CH:11][CH:12]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[N:15]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:17]3[C:22]=2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]3[CH2:26][CH:27]([CH3:28])[CH3:29])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Sc2c3c(=O)n(C)c(=O)n(CC(C)C)c3cn2Cc2cccc3ccccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(O)c3)n(Cc3cccc4ccccc34)cc21
Reaction time: 6 h
Yield: 61.7 %

Procedure:
A solution of boron tribromide in dichloromethane (1M, 3 ml) was added to a solution of 5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (200 mg) (compound of Example 23) in dichloromethane (20 ml) at ambient temperature. After 6 hours, water (10 ml) was added carefully and the reaction mixture was partitioned between dichloromethane and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by chromatography on silica gel, eluting with isohexane/ethyl acetate (2:1 to 1:1) followed by recrystallisation from isohexane/ethyl acetate (3:1), gave the title compound (120 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[Br:17][C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=3)[CH2:10][CH2:11]2)=[CH:22][N:23]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Yield: 28.9 %

Procedure:
Alternative preparation: Step 1: 2-Bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 29%) was prepared as a white solid from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 348 mg, 2.0 mmol), 6-bromo-3-pyridinol (348 mg, 2.0 mmol) and Ph3P (629 mg, 2.4 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.51 mL, 2.6 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 7.37 (d, 1H, J=8.8 Hz), 7.08 (d, 1H, J=8.8 Hz), 4.26-4.16 (m, 2H), 3.85 (d, 2H, J=6.2 Hz), 3.14-3.04 (m, 2H), 2.95-2.76 (m, 1H), 2.11-1.96 (m, 1H), 1.98-1.88 (m, 2H), 1.52-1.36 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 381/383 (M+H).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[Cl-].[K+:16]>C(OC(=O)C)(=O)C>[K+:16].[S:6]1[CH:7]=[C:8]([S:1]([O-:3])(=[O:5])=[O:2])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)([O-])c1csc2ccccc12

Procedure:
Concentrated sulphuric acid (0.43 ml) was added to a cooled, stirred mixture of benzothiophene (1 g) in acetic anhydride (0.93 ml), giving a brown viscous oil, which was left to stir for 50 mins under nitrogen. The mixture was then diluted with ice to give 20 ml, extracted with ether (2×10 ml) and the aqueous phase concentrated in vacuo to give 5 ml. This was then treated with a hot saturated solution of potassium chloride (2 g), cooled and filtered to give the title compound as a pale brown solid (3.935 g).