Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:6]O>S(=O)(=O)(O)O>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:6][Br:1]
Reactant: OCc1cc(F)cc(F)c1
Reactant: Br
Agent: O=S(=O)(O)O
Product: Fc1cc(F)cc(CBr)c1
Reaction time: 3 h

Procedure:
A 120 ml portion of 48% hydrobromic acid was added to 120 g of 3,5-difluorobenzyl alcohol. At room temperature, 120 ml of sulfuric acid was added dropwise thereto, and the mixture after the dropwise addition was stirred for 3 hours. The reaction solution was poured onto crashed ice, extracted with 600 ml of hexane, washed with water and saturated brine in that order and then dried with anhydrous sodium sulfate. By evaporating the solvent, 176 g of 3,5-difluorobenzyl bromide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:25])[CH2:14][S:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([NH:23][NH2:24])[N:17]=1)[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13](=[O:25])[CH2:14][S:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([NH:23][N:24]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1)[CH3:11]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(NN)n1
Solvent: CC(=O)O
Product: CCOC(=O)CSc1nc(Cl)cc(NN=Cc2ccc(Cl)cc2)n1

Procedure:
To a solution of 2.1 g of p-chlorobenzaldehyde in 25 ml. of glacial acetic acid was added a solution of 3.9 g of (4-chloro-6-hydrazino-2-pyrimidinylthio) acetic acid ethyl ester in 100 ml. of glacial acetic acid. The reaction mixture was warmed on a steam bath for a few minutes and then cooled in ice. The resulting precipitate was collected, washed with petroleum ether and recrystallized twice from ethanol affording 3.6 g of product, mp. 162°-165°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>>[ClH:24].[CH2:22]([S:19]([C:16]1[S:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:18][CH:17]=1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Product: CCS(=O)(=O)c1cnc(N2CCNCC2)s1
Yield: 86 %

Procedure:
Prepared in analogy to example 4 (d) from 4-(5-ethanesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as a light brown crystalline solid (yield 86%). MS (m/e): 262.0 (M+H+, 100%).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13])C1C=CC=CC=1>CO.[Pd]>[Si:16]([O:15][CH2:14][C@@H:11]([NH2:10])[CH2:12][CH3:13])([C:29]([CH3:31])([CH3:32])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 88.5 %

Procedure:
A solution of [(1S)-1-(t-butyldiphenylsilyloxymethyl)propyl]carbamic acid benzyl ester (3.70 g, 8.00 mmol) (obtained as described in Reference Example 34(1)) in methanol (185 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (3.70 g) at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (9:1) as the eluant to afford (1S)-1-(t-butyldiphenylsilyloxymethyl)propylamine (2.32 g, yield 88%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH3:22])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17]S(C)(=O)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([N:32]2[CH:36]=[C:35](O)[CH:34]=[N:33]2)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:35]2[CH:34]=[N:33][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:38])([F:39])[F:24])[CH:27]=3)[CH:36]=2)[N:14]=1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Reactant: Oc1cnn(-c2cccc(C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2cnn(-c3cccc(C(F)(F)F)c3)c2)cs1
Temperature: 85 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
2-Methyl-2-[(4-{2-[(methylsulfonyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (1.0 g) synthesized in Example 5 and 1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-4-ol (600 mg) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (363 mg) was added, and the mixture was stirred at 85° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 4:1) to give the title compound (400 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34]C(C(O)=O)=C[CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:37][C:38]1[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:14])=[O:16])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=2)[C:31]2[C:43]([C:33]=1[CH3:34])=[CH:18][C:17]([C:15](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH:42][CH:32]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH2:12][CH2:13][OH:14].CCN(CC)CC.[CH3:22][NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][N+:28]([O-:30])=[O:29]>ClCCl>[CH3:22][NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH:27]([N+:28]([O-:30])=[O:29])[CH:13]([OH:14])[CH2:12][F:11]
Reactant: CNC(=O)CCC[N+](=O)[O-]
Reactant: OCCF
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CNC(=O)CCC(C(O)CF)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a clear solution of oxalyl chloride (2.0 M oxalyl chloride in dichloromethane, 0.868 g, 6.84 mmol) at −74° C. was added anhydrous DMSO (1.06 mL, 14.9 mmol) dropwise over 10 minutes while maintaining the internal temperature <−60° C. The white suspension was stirred for 15 min, then 2-fluoroethanol (0.273 mL, 4.65 mmol) was added dropwise while maintaining the internal temperature <−65° C. The yellow suspension was stirred for 20 minutes and then diluted with dichloromethane (19.5 mL), followed by the addition of anhydrous Et3N (3.90 mL, 28.0 mmol). The reaction mixture was stirred for 15 min at −71° C. and then allowed to warm to 0° C. and stirred at 0° C. for 2 h. To the reaction mixture was added a solution of N-methyl-4-nitro-butyramide (0.570 g, 3.90 mmol) in dichloromethane (2.3 mL). The reaction mixture was stirred at 0° C. for 1 h and then stirred at room temperature overnight. The mixture was concentrated to a white residue, diluted with ethyl acetate (50 mL), and the organic layer was washed with water (25 mL). The aqueous layer was then extracted with ethyl acetate (2×40 mL) and the combined organic layers were dried over MgSO4, concentrated and the residue was purified by flash chromatography (silica gel, gradient elution with EtOAc:Hexanes, 1:1 to 4:1) to give 0.325 g (40%) of the titled product as a colorless viscous oil. 1H NMR (CDCl3): 6.88 (br s, NH, 1H), 6.31 (br s, NH, 1H), 5.20-4.20 (m, 5H), 2.40-2.15 (m, 4H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH:17]1([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[CH:17]1([CH2:23][C:24]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 76.6 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and cyclohexylacetyl chloride (0.88 g, 5.5 mmol) in pyridine (10 mL) provided 2-cyclohexyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan-2-yl]acetamide (1.3 g). Mp 180-181° C.;MS (El) m/z 340 ([M+H]+); Anal. Calcd. for C22H29NO2: C, 77.84; H, 8.61; N, 4.13; Found: C, 77.96; H, 8.70; N, 4.16.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:25]1([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C)C(N(C)C)=N>CS(C)=O.O>[OH:33][CH2:32][CH:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)[CH3:34]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: CC(CO)N1CCNCC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)CO)CC4)n3)nc2c1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
A mixture of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.202 g, 0.67 mmol), 2-(piperazin-1-yl)propan-1-ol dihydrochloride (0.292 g, 1.34 mmol) and 1,1,3,3-tetramethylguanidine (0.310 g, 2.69 mmol) in dry DMSO (1.5 mL) was heated at 85° C. for 6 h. After that time the reaction was cooled to rt, diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(6-(4-(1-hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.155 g, 54%) as a yellow solid: mp 202-204° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.87 (d, J=7.42 Hz, 1H), 7.64-7.72 (m, 1H), 6.79-6.88 (m, 2H) 6.49 (d, J=2.34 Hz, 1H) 3.99 (s, 3H), 3.94 (s, 3H), 3.61-3.72 (m, 4H), 3.38-3.52 (m, 2H), 2.89-2.99 (m, 1H), 2.78-2.88 (m, 2H), 2.54-2.64 (m, 2H), 0.97 (d, J=6.64 Hz, 3H); ESI MS m/z 426 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([S:30][CH3:31])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([S:30][CH3:31])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CSc1cc2c(cc1Cl)nc(Br)n2[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cc2c(cc1Cl)nc(Br)n2[C@@H]1OC[C@@H](O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
An ethanolic solution of 2-bromo-5-chloro-6-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.047 g, 0.09 mmol) was deprotected in a modification of General Procedure VI with 0.036 g (0.34 mmol) of sodium carbonate in 0.5 ml of water. After stirring 1 h at ambient temperature, the mixture was treated as described in General Procedure VI. The product was dried overnight in vacuo to give 2-bromo-5-chloro-6-methylthio-1-beta-D-ribopyranosyl-1H-benzimidazole (0.035 g, 0.09 mmol, 98% yield). 1H NMR (DMSO-d6) δ7.73 (s, 1H), 7.37 (s, 1H), 5.63-5.60 (d, 1H), 5.16-5.14 (m, 2H), 4.91-4.89 (d, 1H), 4.00-3.99 (m, 2H), 3.86 (m, 1H), 3.71-3.68 (m, 2H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)[N:5]=[N:6][CH:7]=1.[I:17]NC(=O)CCC(N)=O.C(OCC)C>CN(C)C=O>[I:17][C:14]1[N:11]2[CH:12]=[CH:13][C:8]([C:4]3[N:5]=[N:6][CH:7]=[C:2]([CH3:1])[N:3]=3)=[CH:9][C:10]2=[N:16][CH:15]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: Cc1cnnc(-c2ccn3ccnc3c2)n1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cnnc(-c2ccn3c(I)cnc3c2)n1
Yield: 39.6 %

Procedure:
7-(5-Methyl-[1,2,4]triazin-3-yl)-imidazo[1,2-a]pyridine (200 mg, 0.9 mmol, 1 equiv) and N-iodosuccinamide (300 mg, 1.3 mmol, 1.4 equiv) in dimethylformamide (5 ml) was stirred at room temperature. After 3 hours diethyl ether was added and the resultant solid was isolated by vacuum filtration furnishing 120 mg of a yellow solid. MS: [M+H]+338
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.C(B(CC)CC)C.[Si:21]([O:38][CH2:39][C@H:40]1[O:44][C@@H:43]([N:45]2[CH:53]=[C:51]([CH3:52])[C:49](=[O:50])[NH:48][C:46]2=[O:47])[CH:42]([Se]C2C=CC=CC=2)[CH2:41]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)Cl.CO>C1C=CC=CC=1.C(#N)C>[Si:21]([O:38][CH2:39][C@H:40]1[O:44][C@@H:43]([N:45]2[CH:53]=[C:51]([CH3:52])[C:49](=[O:50])[NH:48][C:46]2=[O:47])[CH2:42][CH2:41]1)([C:34]([CH3:36])([CH3:35])[CH3:37])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2[Se]c2ccccc2)c(=O)[nH]c1=O
Agent: CCB(CC)CC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC#N
Solvent: CO
Solvent: c1ccccc1
Product: Cc1cn([C@H]2CC[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 4 h

Procedure:
Tri-butyltin hydride (0.18 mL, 0.67 mmol), followed by a 1M solution of triethyl borane in hexanes (0.5 mL, 0.5 mmol) were added under argon to a suspension of 5'-O-(t-butyldiphenylsilyl)-3'-deoxy-2'-phenylselenenylthymidine 6 (0.282 g, 0.45 mmol) in anhydrous benzene. The reaction mixture slowly became clear. After 4 hours of stirring, thin layer chromatography (CH2Cl2 /MeOH: 9.5/0.5) indicated complete disappearance of the starting material. The reaction mixture was diluted with acetonitrile then was concentrated to a thick syrup. The syrup was chromatographed through a column of silica gel (230-400 mesh), eluting first with dichloromethane, followed by 3% methanol in dichloromethane. Compound 10 was isolated as a foamy solid. Yield 0.186 g, 89%. 1H NMR (CDCl3, 90 MHz): δ 1.10 (s, 9 H, t-Bu); 1.65 (d, 3 H, 5-CH3, J=1.1 Hz); 1.9-2.4 (m, 4 H, 2' and 3'-H); 3.7-4.3 (m, 3 H, 4' and 5'-H); 6.11 (pseudo t, 1 H, 1'-H, J=4 Hz); 7.26 (s, 1 H, 6-H); 7.4-7.9 (m, 10 H, Ar-H); 8.32 (br s, 1 H, NH). Anal. Calcd for C26H32N2O4 : C, 67.21; H, 6.94; N, 6.03. Found: C, 67.09; H, 6.96; N, 6.01.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][C@H:22]([OH:24])[CH2:21][C@H:20]2[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:11]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:23][C:22](=[O:24])[CH2:21][C@H:20]2[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:18])=[CH:15][CH:16]=1
Reactant: COC(=O)C[C@@H]1C[C@@H](O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C[C@@H]1CC(=O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 130.4 %

Procedure:
A solution of DMSO (31.4 μl, 0.44 mmol) in dichloromethane (1 ml) was added drop wise to a solution of oxalyl chloride (19 μl, 0.22 mmol) in dichloromethane (2 ml) at −78° C. under argon. After 15 min at −78° C., A solution of methyl [(2S,4R)-1-(biphenyl-4-ylcarbonyl)-4-hydroxypyrrolidin-2-yl]acetate (50 mg, 0.15 mmol) in dichloromethane (1 ml) was added drop wise. The reaction mixture was stirred at −78° C. for 1 hour and triethylamine (0.102 ml, 0.74 mmol) was added and allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water then brine. The organic phase was dried (MgSO4) and concentrated to afford the methyl [(2S)-1-(biphenyl-4-ylcarbonyl)-4-oxopyrrolidin-2-yl]acetate (66 mg). Yield: 100%. HPLC purity: 99%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=[C:19]([CH3:20])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:21]([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:15]=3[CH:16]=2)=[O:22])=[CH:37][CH:36]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(C)cc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Orange solid, MS (ISP)=530.9 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][CH:38]=3)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OCC1CC1
Temperature: 70 °C
Yield: 16.5 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (15 mL) was added potassium carbonate (102 mg, 0.740 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (122 mg, 0.493 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-45% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 16%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[CH:18][CH:19]=[N:20][CH:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[C:14][C:18]1[CH:19]=[N:20][CH:21]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cccnc1
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C#Cc1cccnc1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
Triethylamine (10 mL) was degassed by bubbling argon over a period of 30 min. (S)-N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine (1.00 g, 5.12 mmol), tetrakis(triphenylphosphine)palladium (0.296 g, 0.256 mmol), palladium(II) acetate (0.0575 g, 0.256 mmol), copper (I) iodide (16.2 mg, 0.085 mmol) and 5-bromopyridine (2.43 g, 15.4 mmol) were added. The mixture was heated at 60° C. for 24 h, then cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in chloroform (50 mL) and the organic phase washed sequentially with water (25 mL), saturated aqueous NaHCO3 solution (3×20 mL) and water (25 mL). The solution was then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 1.00 g (71%) of a yellow oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), imidazole (680 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (5 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (662 mg, 61%). Melting point 113-114° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12]O)=[CH:4][CH:3]=1.O1CCCC1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:12][C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnoc1-c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: ClCc1cnoc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixture of 5-(5-chloro-2-thienyl)-4-isoxazolylmethanol (6.54 g), tetrahydrofuran (20 ml) and toluene (100 ml) was added dropwise thionyl chloride (5.41 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals of 4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.98 g, yield 98%) were obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) and recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 70–71° C.