Azzindani/Open_Reaction_Data huggingface dataset:
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][CH2:13][CH2:14][N:15]([C:35](=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:16]1[C:17]([C:30](OCC)=[O:31])=[N:18][CH:19]=[C:20]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:21]=1.C1CCN2C(=NCCC2)CC1.OS([O-])(=O)=O.[Na+]>CCO.O>[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][CH2:13][CH2:14][N:15]1[C:16]2[C:17](=[N:18][CH:19]=[C:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:21]=2)[C:30]([OH:31])=[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:35]1=[O:42]
Reactant: CCOC(=O)CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 3-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl][3-(ethyloxy)-3-oxopropanoyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (1.17 g, 2.04 mmol) in EtOH (10 mL) under nitrogen was treated with DBU (0.45 mL, 3.05 mmol). After stirring at ambient temperature for 15 min., the reaction mixture was treated with 1N NaHSO4 (3.1 mL). The resulting slurry was diluted with water, filtered and dried under high vacuum to provide the title compound as a white solid: 1H NMR (CDCl3) δ 13.93 (1H, b), 8.51 (1H, s), 7.82-7.86 (2H, m), 7.71-7.75 (2H, m), 7.36 (1H, s), 7.12 (2H, m), 6.99 (2H, t, J=9 Hz), 4.49 (2H, q, J=7 Hz), 4.22 (2H, t, J=7 Hz), 4.08 (2H, s), 3.79 (2H, t, J=7 Hz), 1.96-2.07 (2H, m), 1.45 (3H, t, J=7 Hz); ES+ MS: 530 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:7]2.[C:30]1([S:36]([N:39]=C=O)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:39][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[NH:7]2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-[2-(t-butoxycarbonylamino) benzoyl]-1,4-dihydroquinol-4-one (2 mmol) and benzenesulfonyl isocyanate (2.2 mmol) in acetonitrile (9 mL) and heat at reflux for 48 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:20]([CH:24]=1)[C:21]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)=[O:22]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1ccccn1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Neat triethylamine (0.27 ml, 1.95 mmol) and pyridin-2-amine (61.3 mg, 0.65 mmol) were added to a stirred suspension of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.65 mmol), EDC (250 mg, 1.30 mmol) and HOBT (199 mg, 1.30 mmol) in DMF (3 ml) at 20° C. The reaction mixture was stirred at 20° C. overnight and was then poured into 15 ml water and filtered. The residue was washed with methanol (10 ml) to yield the title compound. The mother liquid was evaporated and the solid was purified by preparative HPLC, (A: 10 mmol ammonium carbonate/water B: acetonitrile) to yield the title compound. The two batches of product were mixed. 47 mg.
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:18]([O-:20])=[O:19])=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=2)[CH:7]=[C:6]1[C:21]([OH:31])([CH2:29][CH3:30])[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.[OH-].[Na+]>>[N+:18]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[C:14]([F:15])([F:16])[F:17])[NH:5][C:6]([C:21]([OH:31])([CH2:29][CH3:30])[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:7]2)([O-:20])=[O:19]
Reactant: CCC(O)(CSCC(F)(F)F)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the standard de-protection procedure, as described in General Procedure Example B, starting from 2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol (0.65 g, 1.31 mmol) and using 4N sodium hydroxide as base (1 mL, 4.0 mmol) to yield the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]3[C:22]([CH:23]=[C:24]4[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:30]1([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:37]1([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:17]4[C:22]([CH:23]=[C:24]5[C:29]=3[CH:28]=[CH:27][CH:26]=[CH:25]5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2c3ccccc3c(-c3c4ccccc4cc4ccccc34)c3ccccc23)cc1
Yield: 68.1 %

Procedure:
In a flask were placed 35 g of 9,9′-bianthryl, 18.0 g of N-bromosuccinimide and 500 mL of carbon tetrachloride, and the mixture was stirred overnight. The reaction mixture was filtered, the filtrate was passed through a column filled with alumina. Carbon tetrachloride was evaporated from the solution under a reduced pressure, and then the residue was recrystallized from petroleum ether, to give 35 g(yield: 80%) of 10-bromo-9,9′-bianthryl. Then, in a 100 mL three-necked flask were placed 18.3 g of 10-bromo-9,9′-bianthryl, 10 g of diphenylamine, 8.5 g of potassium carbonate, 0.2 g of copper powder and 50 mL of nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 15 g(yield: 60%) of 10-diphenylamino-9,9′-bianthryl.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:5][C:4]=2[N:3]=1.[H-].[Na+].Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1)C2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 30, (109 mg, 0.38 mmol) in DMF (2 ml) under nitrogen was added sodium hydride (60% dispersion in oil) (18 mg, 0.44 mmol) and the mixture was stirred at ambient temperature for 10 min. 2-Dimethylaminoethylchloride hydrochloride (54 mg, 0.38 mmol) and triethylamine (52 μl, 0.38 mmol) were added to the reaction mixture, which was stirred and heated at 80° C. until complete disappearance of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime was observed by LC-MS. Ethyl acetate (5 ml) was added to the mixture and the solution was washed three times with water (3×5 ml). The organic phase was dried with MgSO4, filtered and the solvent removed under reduced pressure to furnish the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]2[CH2:35][O:34]2)[CH:28]=1>C(O)C>[CH3:1][C:2]([NH:25][CH2:35][C@@H:33]([C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[OH:34])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: c1cncc([C@@H]2CO2)c1
Reactant: C[C@H](Oc1cccc2c(CC(C)(C)N)c[nH]c12)C(=O)N1CCOCC1
Solvent: CCO
Solvent: O
Product: C[C@H](Oc1cccc2c(CC(C)(C)NC[C@H](O)c3cccnc3)c[nH]c12)C(=O)N1CCOCC1
Temperature: 10 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-methyl-1-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}propan-2-amine (68.4 mg, 0.198 mmol) in ethanol (4 mL)- water (0.4 mL) is added (R)-(pyridin-3-yl)oxirane (36.0 mg, 0.297 mmol), and the mixture is refluxed for 8 hours. To the reaction solution is added (R)-(pyridin-3-yl)oxirane (144.0 mg, 1.19 mmol) in 4 portions, and the mixture is heated with stirring at 100 to 1 10° C. in a sealed tube for 18 hours. After the reaction is completed, the solvent is evaporated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (chloroform/methanol=20/1→10/1→chloroform/a saturated ammonia methanol=10/1) to give (1R)-2-[(1,1-dimethyl-2-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}ethyl)amino]-1-pyridin-3-ylethanol (23.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CCCCC)=[O:8])[N:4]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.C(O)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1
Reactant: CCCCCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a 100 mL flask, pentyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (5.00 g, 97%, 12.94 mmol), ethanol (30 mL), water (30 mL) and sodium hydroxide (0.52 g, 12.94 mmol) were added. The reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was concentrated by rotary evaporator to remove ethanol. Then water (250 mL) was added. Aqueous solution was extracted with ethyl acetate (100 mL), acidified with concentrated hydrochloric acid to pH=2 and extracted with dichloromethane (3×200 mL) again. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (3.60 g) as a white solid in 90% yield. HPLC area normalization method content is 98% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=12)=[O:2].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:13]([N:4]1[CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]2=[C:3]1[CH:1]=[O:2])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: O=Cc1[nH]cc2c1OCCO2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc2c(c1C=O)OCCO2
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of aldehyde 19 (0.8 g, 5.2 mmol) in dichloromethane was added (BOC)2O (1.1 g, 5.2 mmol), triethylamine (1.1 g, 10.4 mmol), and 4-dimethylaminopyridine (DMAP) (61 mg, 0.5 mmol). The reaction mixture was stirred for 3 h and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to yield a colorless crystalline product (1.2 g, 90%): mp 94-95° C.; 1H NMR (300 MHz, CDCl3) δ10.24 (s, 1H), 6.88 (s, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 1.60 (s, 9H); 13C NMR (75 MHz, CDCl3) δ180.9, 148.8, 143.2, 134.2, 116.6, 107.9, 85.1, 66.1, 64.9, 27.9; FT-IR (CDCl3) 2930, 2859, 1653, 1544, 1460, 1380, 1322 cm−1; Anal. Calcd for C12H15NO5: C, 56.91; H 5.97; N, 5.53. Found: C, 56.90; H, 5.80; N, 5.73.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH2:29]([N:36]=[C:37]=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:13][N:12]([CH3:14])[C:9]1[CH:8]=[CH:7][C:6]([N:5]([CH2:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=2[NH:1][C:37]([NH:36][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:38])[CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])\[CH3:18])=[CH:11][CH:10]=1
Reactant: CC(C)=CCC/C(C)=C/CN(Cc1ccccc1N)c1ccc(N(C)C)cc1
Reactant: CCCCCCCN=C=O
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1CN(C/C=C(\C)CCC=C(C)C)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of N-(2-aminobenzyl)-N-geranyl-N',N'-dimethyl-1,4-phenylenediamine (0.54 g) in dichloromethane (10 ml) was added under ice-cooling heptyl isocyanate (0.3 g) and the mixture was stirred overnight while returning slowly to room temperature. After distilling off the solvent, the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1-[2-[N-(4-dimethylaminophenyl)-N-geranylaminomethyl]phenyl]-3-heptylurea (0.62 g, 85%) as an oily product.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=1[F:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1nc2ccccc2[nH]1
Reactant: O=C(Cl)c1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCN(Cc1nc2ccccc2[nH]1)C(=O)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
2-butylaminomethylbenzimidazole (2.6 g, 13 mmol) was dissolved in 30 mL toluene. Saturated NaHCO3 solution (30 mL) was added followed by 2,3-difluorobenzoyl chloride (1.3 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL ethyl acetate then washed 1×100 mL 1N NaOH followed by 1×100 mL H2O. The organic phase was dried over MgSO4, filtered, and then concentrated. The residue was purified by flash chromatography eluting with 1/1 ethyl acetate/hexane followed by ethyl acetate to afford 2.0 g N-butyl-N-(1H-benzoimidazol-2-ylmethyl)-2,3-difluorobenzamide.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[I:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]3[NH:23][C:22]([C:24]([C:61]4[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=4)=[C:25]4[N:60]=[C:28]([C:29]([C:53]5[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=5)=[C:30]5[NH:52][C:33](=[C:34]([C:40]6[CH:45]=[CH:44][C:43]([C:46]#C[Si](C)(C)C)=[CH:42][CH:41]=6)[C:35]6[CH:36]=[CH:37][C:38]=2[N:39]=6)[CH:32]=[CH:31]5)[CH:27]=[CH:26]4)=[CH:21][CH:20]=3)=[CH:14][CH:13]=1>COCCOCCOC>[I:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]3[NH:23][C:22]([C:24]([C:61]4[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=4)=[C:25]4[N:60]=[C:28]([C:29]([C:53]5[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=5)=[C:30]5[NH:52][C:33](=[C:34]([C:40]6[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=6)[C:35]6[CH:36]=[CH:37][C:38]=2[N:39]=6)[CH:32]=[CH:31]5)[CH:27]=[CH:26]4)=[CH:21][CH:20]=3)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2c3nc(c(-c4ccc(C)cc4)c4ccc([nH]4)c(-c4ccc(C#C[Si](C)(C)C)cc4)c4nc(c(-c5ccc(I)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: COCCOCCOC
Product: Cc1ccc(-c2c3nc(c(-c4ccc(C)cc4)c4ccc([nH]4)c(-c4ccc(I)cc4)c4nc(c(-c5ccc(C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1

Procedure:
The following is a refined version of the standard procedure (Gross et al. (2001) Inorg. Chem., 40: 4762) designed to minimize exposure of the reaction mixture to moisture and air. A Schlenk flask was equipped with a reflux condenser and all essential inlets and outlets at the beginning of the procedure. A solution of CeI[N(SiMe3)2]2 was prepared in situ by reaction of CeI3 (75.0 mg, 0.144 mmol) and LiN(SiMe3)2 (288 μL, 0.288 mmol, 1.0 M in THF) in bis(2-methoxyethyl) ether (1.5 mL). This flask was not opened. A deaerated solution of porphyrin 12 (25.0 mg, 28.9 μmol) in bis(2-methoxyethyl) ether (1 mL) was added by syringe. The mixture was refluxed for 1 h, affording the metalated porphyrin as determined by UV/Vis. Then the double-decker complex (TTP)Eu(t-Bu4Pc) (45.2 mg, 28.9 μmol) was added. The mixture was refluxed for 6 h. After cooling to room temperature, chromatography [silica, toluene/hexanes (1:1), then CH2Cl2] gave three bands (green). The first and second band were combined and concentrated, affording a solid, which was further purified by SEC (THF), affording a brownish-green solid (40 mg, 54%): A 1H NMR spectrum was recorded, but the complexity due to the mixture of regioisomers prevented a complete interpretation. LD-MS obsd 2557.5 [M+], 2542.9, 2459.8, 2431.7 [M+-I]; FAB-MS obsd (LR) 2559.86, calcd exact mass 2559.72 (C147H123CeEuIN16Si); λabs363, 421, 425, 492, 560, 609 nm.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])=[N:12][N:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[N:12][N:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nnc(SCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
In 7.8 ml of 90% methanol was dissolved 0.98 g of ethyl [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]acetate obtained in Example 1 with heating at 60° C. Further 6.1 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 30 minutes. A 1N aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with, in sequence, water, a saturated aqueous sodium chloride solution and water and then, dried over anhydrous magnesium sulfate. The solvent was then distilled off. Recrystallization of the thus obtained solid from isopropyl alcohol gave 0.75 g of [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]-acetic acid.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:8])[CH2:6][CH:5]([NH2:7])[CH2:4]1.OC1C=CC2NN=NC=2N=1.C(N=C=NCCCN(C)C)C.[Cl:30][C:31]1[CH:32]=[C:33]([C@@:39]2([C:54]([F:57])([F:56])[F:55])[O:43][N:42]=[C:41]([C:44]3[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[C:46]([CH3:53])[CH:45]=3)[CH2:40]2)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:30][C:31]1[CH:32]=[C:33]([C@@:39]2([C:54]([F:56])([F:57])[F:55])[O:43][N:42]=[C:41]([C:44]3[CH:52]=[CH:51][C:47]([C:48]([NH:7][CH:5]4[CH2:6][S:3](=[O:8])(=[O:2])[CH2:4]4)=[O:49])=[C:46]([CH3:53])[CH:45]=3)[CH2:40]2)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NC1CS(=O)(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1ccc2[nH]nnc2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A 100 mL vessel was charged with 1,1-dioxothietan-3-amine hydrochloride (1.2 g) in 25 mL of N,N-dimethylformamide followed by successive addition of triethylamine (2.1 mL), hydroxyazabenzotriazole (1 g), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.4 g) and 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (2.6 g) dissolved in N,N-dimethylformamide (5 mL). The mixture was then stirred overnight at room temperature. The reaction mixture was diluted in 600 mL of ethyl acetate, washed 3-times with 500 mL of brine, then with 0.5N HCl cold, dried over MgSO4 and evaporated to yield 4.6 g of the crude title compound. The product was purified over a silica gel column (eluent: CH2Cl2/EtOAc) to yield 2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:23][CH2:24][C@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][C@H:27]1[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[N:28]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[OH-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:23][CH2:24][C@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][C@H:27]1[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[N:28]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:11]
Reactant: CC(C)[C@@H](CN)C[C@H]1COC(C)(C)N1NC(=O)OC(C)(C)C
Reactant: COCCCOc1ccccc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H]1COC(C)(C)N1NC(=O)OC(C)(C)C)C(C)C
Reaction time: 1 h

Procedure:
The solution of 2.99 g of 2-(3-methoxypropoxy)benzoic acid [179992-98-4] and 3.95 ml of triethylamine in 60 ml of dichloromethane is cooled to 15° C. and admixed with 3.70 g of bis-(2-oxo-3-oxazolidynyl)phosphinoyl chloride. The mixture is stirred over 1 hour and subsequently admixed with the solution of 2.22 g of tert-butyl 4(S)-(2(S)-aminomethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carbamate in 3 ml of dichloromethane and 0.703 g of 4-dimethylaminopyridine, and stirred overnight. The reaction mixture is poured onto 1M NaOH and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.29 (1:1 EtOAc-heptane); Rt=5.49 (gradient I).
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)C1=O)C(O)=O.[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[CH2:68][CH2:69][C:70]([O:72]CC)=[O:71]>>[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:49]=[CH:50][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:66])([F:65])[F:67])[CH:59]=4)=[O:56])=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[CH2:68][CH2:69][C:70]([OH:72])=[O:71]
Reactant: CCOC(=O)CCN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: O=C(O)CCN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 95 %

Procedure:
The compound of example 379 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 378.