Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[C:7]([CH3:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11]C(C)=O.N1CCCC1.C(O[CH2:23][CH3:24])C>CO.O>[C:1]([C:5]1[CH:11]=[C:23]([CH3:24])[C:8](=[C:7]([CH3:6])[CH3:10])[CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CCOCC
Reactant: CC1=CCC(C(C)(C)C)=C1
Solvent: CO
Solvent: O
Solvent: C1CCNC1
Product: CC1=CC(C(C)(C)C)=CC1=C(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 13.0 g (95.6 mmol) of 1-tert-butyl-3-methylcyclopentadiene in 130 ml of dehydrated methanol, 55.2 g (950.4 mmol) of dehydrated acetone was dropwise added in a nitrogen atmosphere at 0° C. with ice cooling, and 68.0 g (956.1 mmol) of pyrrolidine was further dropwise added, followed by stirring at room temperature for 4 days. After the reaction solution was diluted with 400 ml of diethyl ether, 400 ml of water was added. The organic phase was separated, washed with a 0.5N hydrochloric acid aqueous solution (150 ml×4), water (200 ml×3) and a saturated saline solution (150 ml), and then dried over anhydrous magnesium sulfate. The drying agent was filtered, and from the filtrate the solvent was distilled off to obtain a liquid. The liquid was subjected to vacuum distillation (70-80° C./0.1 mmHg) to obtain 10.5 g of a yellow liquid. The analyzed values are given below.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li].[CH2:9]([CH:16]1N[C:19](=[O:21])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Br)CC.C(O)(=[O:28])C>C1COCC1>[CH2:9]([CH:16]1[O:28][C:19](=[O:21])[CH:18]([CH2:7][CH2:5][CH3:6])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)NC(C)C
Reactant: CC(=O)O
Reactant: O=C1CCC(Cc2ccccc2)N1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCBr
Product: CCCC1CC(Cc2ccccc2)OC1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 5-benzylpyrrolidin-2-one and the mixture is stirred for 1.5 hours at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 hours at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted 3 times with dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 5-benzyl-3-propyldihydrofuran-2(3H)-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:16][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:9][C:10]1[CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:16][C:12]=2[CH:11]=1)[S:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(CNCc3ccccc3)cc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-[(benzylamino)methyl]-1-benzothiophene-2-carboxylate (0.147 g, 0.452 mmol) and triethylamine (0.20 mL, 1.43 mmol) in anhydrous CH2Cl2 (1 mL) was slowly added benzene sulphonylchloride (100 μL, 0.784 mmol). The resulting mixture was allowed to stir overnight at room temperature. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was washed three times with ethyl acetate. The combined organic layer was dried with sodium sulfate, filtered, and concentrated. The resultant residue was purified by column chromatography yielding the desired product. 1H NMR (CDCl3, 600 MHz) δ 7.97 (d, J=0.6 Hz, 1H), 7.86 (dt, J=8.4, 1.6 Hz, 2H), 7.68 (d, 8.2 Hz, 1H), 7.60 (tt, J=7.2, 1.2 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.40 (broad s, 1 μl), 7.16-7.19 (m, 3H), 7.09 (dd, J=8.3, 1.5 Hz, 1H), 6.99-7.05 (m, 2H), 4.43 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.35 (s, 2H), 1.40 (t, J=7.1 Hz, 3H). MS: cal'd (MH+), exp 466 (MH+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[F:13][C:14]([F:52])([F:51])[C:15]1[CH:16]=[C:17]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:18][N:19]([C:42]#[N:43])[CH:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]2[C:33]([CH3:41])=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:21]1=2.Cl>C1(C)C=CC=CC=1.ClCCl>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:17]([CH:16]=[C:15]([C:14]([F:52])([F:51])[F:13])[CH:46]=1)[CH2:18][N:19]([C:42]1[NH:43][N:3]=[N:2][N:1]=1)[CH:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]2[C:33]([CH3:41])=[C:34]([C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:36][C:21]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Add sodium azide (42 mg, 0.64 mmol) and triethylamine hydrochloride (88 mg, 0.64 mmol) to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (124 mg, 0.21 mmol) in toluene (2 mL). Stir the mixture at 110° C. overnight. Cool down the mixture to room temperature, add 1N HCl (5 mL) and dichloromethane. Separate the layers, dry the organic phase over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure to provide 117 mg (89%) of the title compound. MS (ES−): 623 (M−H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:21])[CH:14]=[C:13]([C@@H:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][N:29]3C(OC(C)(C)C)=O)[CH3:23])[N:12]=1.O>C1COCC1>[N:33]1[C:25]([NH:24][C@H:22]([C:13]2[N:12]=[C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:21])[CH3:23])=[C:26]2[C:30]([NH:29][CH:28]=[N:27]2)=[N:31][CH:32]=1
Reactant: CC(=O)NCCO
Reactant: C[C@H](Nc1ncnc2c1ncn2C(=O)OC(C)(C)C)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCOc1nc([C@H](C)Nc2ncnc3[nH]cnc23)cc2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of N-(2-hydroxyethyl)acetamide (110 mg, 1.07 mmol, 2.43 eq) in THF (20 mL) at 0° C., NaH (60% in mineral oil, 110 mg, 2.75 mmol, 6.25 eq) was added and the resulting mixture was stirred for 15 min. To this mixture, (S)-tert-butyl 6-(1-(1,8-dichloroisoquinolin-3-yl)ethylamino)-9H-purine-9-carboxylate 39 (200 mg, 0.44 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux for 2 h, cooled to RT and then poured into water (30 mL). The mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)—N-(2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)ethyl)acetamide 40. ESI-MS m/z: 426.0 [M+H]+.
Reaction SMILES: C[Si](C)(C)CC[S:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([F:18])[CH:7]=1.[F:21]C1C=C(C2C=CC=CC=2)C=C(F)C=1>>[F:18][C:8]1[CH:7]=[C:6]([SH:5])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:21])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(-c2ccccc2)c1
Reactant: Fc1cc(F)cc(-c2ccccc2)c1
Product: Fc1ccc(-c2cc(F)cc(S)c2)cc1

Procedure:
Following the procedure described in Thiophenol 1, Step 3, but substituting S-(2-trimethylsilylethyl)-3-fluoro-5-(4-fluorophenyl)thiophenol for S-(2-trimethylsilylethyl)-3-fluoro-5-phenylthiophenol, the title compound was obtained as a liquid.
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])=[C:10]([O:25][Si](C(C)(C)C)(C)C)[C:9]=1[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34].[N:39]#CN.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])=[NH:39])=[C:10]([OH:25])[C:9]=1[S:33]([N:36]([CH3:37])[CH3:38])(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2cccc(F)c2F)c1O[Si](C)(C)C(C)(C)C
Reactant: N#CNC(=N)N
Reactant: N#CN
Agent: [Cs+]
Agent: [F-]
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2cccc(F)c2F)c1O
Yield: 3.4 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3-difluorophenyl)carbodiimide (340 mg, 0.68 mmol), cyanamide (114 mg, 2.72 mmol) and N,N-disopropylethylamine (106 mg, 0.82 mmol) were reacted, followed by desilylation with Cesium fluoride (124 mg, 0.82 mmol) to form the desired product (10 mg, 3.4%). EI-MS m/z 430.0 (M+). 1H NMR (DMSO-d6) δ 2.87 (s, 6H), 7.21 (m, 3H), 7.30 (m, 1H), 7.54 (d, 1H), 9.2 (s, 1H), 10.54 (s, 1H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[I-:1].[C:34]1([P+:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C[Si](C)(C)O[Si](CCCI)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)O[Si](CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)(O[Si](C)(C)C)O[Si](C)(C)C
Product: [I-]
Reaction time: 48 h

Procedure:
1.0 g of 3-iodopropyltris(trimethylsiloxy)silane (28) described in Step 6.1, 1.7 g of triphenylphosphine and 0.69 g of sodium carbonate are added to 50 ml of tetrahydrofurane. The reaction mixture is stirred for 2 days at reflux. The solvent is evaporated and the residue purified by column chromatography on silica gel to give the desired phosphonium salt (37); ESI-MS: M+599.58.
Reaction SMILES: [C:1]([N:8]1CCC(N)C[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[N:17]=1.C([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])C)(C)C>O1CCOCC1.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:29][CH2:27][N:26]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[N:17]=2)[CH2:30][CH2:31]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nccc(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nccc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 150 °C

Procedure:
A suspension of Boc-4-aminopiperidine (715.3 mg, 3.5 mmol), 4-chloro-2-methylpyrimidine (521 mg, 3.85 mmol) and N,N-diisopropylethyl amine (899 L, 5.25 mmol) in dioxane (14 mL) was heated to 150° C. in the microwave for 30 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained after stirring of the crude product with diethyl ether and drying as white crystals (649.5 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Cl)cc1CO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1ccc(Cl)cc1CO
Reaction time: 1 h

Procedure:
To a solution of (2-amino-5-chloro-phenyl)-methanol (1.58 g, 10 mmol, 1 equiv) in 15 mL of DCM was slowly added ethyl chloroformate (1.05 mL, 1.1 equiv) and pyridine (1.2 mL, 1.5 equiv). After stirring for 1 h, the resultant mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the crude product, (4-Chloro-2-hydroxymethyl-phenyl)-carbamic acid ethyl ester (71), which was used in subsequent reactions without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>[O-]CC.[Na+]>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 58.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (8.3g.) in sodium ethoxide solution (1.15g. sodium in 70 ml. of absolute ethanol) was added p-chlorobenzylchloride (8.1g.) in one portion. The mixture was heated under reflux for 16 hours, allowed to cool and poured into water (500 mls.) and the product extracted into ether. The organic layer was separated and dried (anhydrous MgSO4) and filtered. Evaporation of the solvent under reduced pressure gave the crude product which on recrystallation from ethanol, yielded by 4-ethoxycarbonylphenoxy-4-chlorophenyl methane (8.5g.), m.pt. 83°-84° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[N:33]([C@@:39]1([CH3:47])[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]2=[O:48].CC#N>CN(C=O)C>[CH3:47][C@:39]1([N:33]2[C:32](=[O:48])[C:31]3[C:35](=[CH:36][CH:37]=[C:29]([CH2:28][NH:27][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=4)[CH:30]=3)[C:34]2=[O:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@]1(N2C(=O)c3ccc(CNC(=O)c4ccc(S(C)(=O)=O)cc4)cc3C2=O)CCC(=O)NC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A mixture of 4-(methylsulfonyl)benzoic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and stirring proceeded at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (2×100 mL) and evaporated. The residue was chromatographed on silica gel using 99:1 methylene chloride-methanol as the mobile phase, providing 0.30 g, in 32% yield. The product was obtained as a white solid; mp 165.5-167.5° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.08 (96.23%); 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 2.22-2.28 (m, 1H), 2.73-2.95 (m, 3H), 3.47 (s, 3H), 4.86 (d, J=5.7 Hz, 2H), 7.98-8.04 (m, 3H), 8.25 (d, J=8.7 Hz, 2H), 8.32 (d, J=8.7 Hz, 2H), 9.58 (t, J=5.7 Hz, 1H), 11.21 (s, 1H); 13C NMR (DMSO-d6) δ 23.0, 30.6, 31.1, 44.8, 45.6, 60.8, 123.7, 125.2, 129.2, 130.3, 131.7, 133.4, 135.5, 140.4, 145.2, 149.0, 167.2, 169.7, 169.9, 174.1, 174.2; Anal. Calcd for C23H21N3O7S+0.3H2O: C, 56.50; H, 4.45; N, 8.59. Found: C, 56.61; H, 4.42; N, 8.30.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10]Br.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(C)=O.C1COCC1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[Br:1])=[CH:16][CH:15]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Br)c(CNCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-3-bromomethylanisole (35 g, 125 mmol) in anhydrous DMSO (50 mL) and dry THF (50 mL) was added 4-trifluoromethylbenzylamine (30 g, 171 mmol) followed by triethylamine (18 mL, 129 mmol). After stirring for 18 h at RT the reaction was concentrated, diluted with aqueous 1 N NaOH (250 mL) and extracted with Et2O (2×250 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The residue which remained was purified by flash chromatography on silica gel (10 to 20% EtOAc/CHCl3) to give the title compound (34.17 g, 73%): TLC (20% EtOAc/CHCl3) Rf 0.63; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.6 Hz, 1H), 6.96 (d, J=3.1 Hz, 1H), 6.70 (dd, 1H), 3.86 (s, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 1.75 (br s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[C@H:17]([CH2:19][OH:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:22])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[C@H:17]([CH2:19][OH:20])[NH:18][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
L-seryl-L-proline benzylester hydrochloride (1.64 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The mixture was stirred for 1 hour at less than 0° C. and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The mixture was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-benzenesulfonyl-L-seryl-L-proline benzylester (yield: 1.96 g, 90.6%).
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:68])[CH:10]([NH:25][C:26]([NH:28][CH:29]([C:56]([O:58]CC2C=CC(OC)=CC=2)=[O:57])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([Sn](CCCC)(CCCC)CCCC)[CH:42]=2)=[O:36])=[O:27])[CH2:11][CH2:12][C:13]([O:15]CC2C=CC(OC)=CC=2)=[O:14])=CC=1.C(O)(=O)C.[I-:75].[Na+].ClN1C(=O)CCC1=O>CO>[C:56]([CH:29]([NH:28][C:26](=[O:27])[NH:25][CH:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:8])=[O:68])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41]([I:75])[CH:42]=1)=[O:36])([OH:58])=[O:57]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(=O)NCCCCC(NC(=O)NC(CCC(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)c1
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1cncc(I)c1)C(=O)O)C(=O)O
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a solution of 7 (0.025 g, 0.023 mmol) in 2 mL methanol was added 0.020 mL acetic acid and sodium iodide (0.017 g, 0.113 mmol), followed by N-chlorosuccinimide (0.025 g, 0.187 mmol). After 20 min at room temperature, the solvent was removed under a stream of nitrogen. A solution of TFA in CH2Cl2 (1:1, 2 mL) was then added to the residue. After 1 h at room temperature, 8 (0.008 g, 62%) was isolated by HPLC (Econosphere C18 10μ., 250×10 mm, H2O/CH3CN/TFA (85/15/0.1), 4 mL/min, product peak eluting at 10 min). 1H NMR (400 MHz, D2O) δ 9.00-9.15 (m, 3H), 4.18-4.24 (m, 2H), 3.40-3.41 (m, 2H), 2.45-2.49 (m, 2H), 2.12-2.13 (m, 1H), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 3H), 1.44 (m, 2H). ESI-Mass calcd for C18H24IN4O8 [M+H]+ 551.1. found 551.0. FAB-HRMS calcd for C18H24IN4O8 [M+H]+ 551.0639. found 551.0607.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)[CH:25]=2)=[CH:35][CH:34]=1)=[O:37]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C=O)cc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccc(-c3ccc(C=O)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-(4-{2-[2-(4′-formylbiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH (aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield a white, crystalline solid: Rf=0.14 in 6:4 ethyl acetate:hexanes; MS (EI) 486.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4[O:24][CH:25]=[CH:26][C:20]=4[CH2:19]3)=[O:17])=[CH:11][C:10]=2[S:9](=[O:28])(=[O:27])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:29][NH:30][CH3:31].[CH2:32]=O>C(O)(=O)C>[CH3:29][N:30]([CH2:32][C:25]1[O:24][C:21]2[CH2:22][CH2:23][N:18]([C:16]([C:12]3[CH:13]=[CH:14][C:15]4[C:2](=[O:1])[C:3]5[C:8]([S:9](=[O:28])(=[O:27])[C:10]=4[CH:11]=3)=[CH:7][CH:6]=[CH:5][CH:4]=5)=[O:17])[CH2:19][C:20]=2[CH:26]=1)[CH3:31]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(C(=O)N3CCc4occc4C3)ccc21
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc3c(c1)S(=O)(=O)c1ccccc1C3=O)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.190 g (0.483 mmol) of 5-(9,10,10-trioxo-9,10-dihydro-10λ6 -thioxanthene-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.065 ml (0.72 mmol) of 50% aqueous dimethylamine and 0.059 ml (0.72 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1 to 25/1) to yield the desired product.