Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16].ClCC(=O)CC(OC)=O.FC1C=C(F)C=CC=1N=C=O.[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][N:47]=2)[C:42]([CH:49]=O)=[CH:41]1.N1CCC[C@H]1C(O)=O>CC(O)C>[NH:40]1[C:48]2=[N:47][CH:46]=[CH:45][CH:44]=[C:43]2[C:42]([CH:49]=[C:12]2[O:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]2=[O:19])=[CH:41]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2F)OCC1=O
Agent: COC(=O)CC(=O)CCl
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C=Nc1ccc(F)cc1F
Solvent: CC(C)O
Product: COC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a solution of methyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 2,4-difluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.30 g, y. 75%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37]([O:39][C:40](=[O:43])[CH2:41]Br)[CH3:38]>CN(C=O)C>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][N:25]1[CH2:24][CH2:23][C:22]([OH:28])([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:38]
Reactant: OC1(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Reaction time: 18 h

Procedure:
4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-4-ol (153 mg, 0.37 mmol, prepared by analogous procedures described above) was dissolved in DMF (2 mL) and to it was added K2CO3 (128 mg, 0.93 mmol) followed by bromo-acetic acid ethyl ester (0.050 mL, 0.44 mmol) added dropwise, and the reaction was stirred for 18 hours. The reaction mixture was partitioned between 40% EtOAc/hexanes and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to obtain the title compound as a crude oil, which was taken to the next step without purification: MS (M+H)+499.4.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:40])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:22])([F:20])[F:21])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(N3CCCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M169) (249 mg, 0.438 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (129 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].CO.C=O.[BH3-][C:42]#N.[Na+]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:42])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole and MeOH was added formaldehyde, followed by AcOH. The reaction was stirred for 20 min, NaCNBH3 was added to the reaction mixture and was continued to stir for another 30 min. After a routine aqueous work up, the crude product was purified by prep HPLC to give 2-[1-(2-chlorophenyl)-1-methylethyl]-4-(1-methylpyrrolidin-2-yl)-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazole: 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (s, 1H), 1.9 (s, 3H), 2.2-2.5 (m, 4H), 2.8 (s, 3H), 3.2 (s, 3H), 3.6 (br, 1H), 4.7 (m, 1H), 7.1 (m, 1H), 7.2 (m, 5H), 7.4 (s, 1H), 7.7 (m, 3H), 8.0 (m, 2H), 8.2 (m, 1H); LC/MS M+H 534 (observed).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[S:53](=[O:57])(=[O:56])CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:53](=[O:57])(=[O:56])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: O=S1(=O)CCNCC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCS(=O)(=O)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiomorpholine 1,1-dioxide and isolated as white solid (13.5 mg, 66%). MS (m/e): 435.4 (MH+).
Reaction SMILES: ClCCCC(OC(=O)C)CCCC(C)C.C([O:19][CH:20]([CH2:40][CH2:41][CH2:42][CH:43](C)[CH3:44])[CH2:21][CH2:22][CH2:23][N:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])(=O)C>>[OH:19][C@H:20]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:21]#[C:22][CH2:23][N:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[S:25]([CH3:28])(=[O:26])=[O:27]
Reactant: CCOC(=O)CCCCCCN(CCCC(CCCC(C)C)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(CCCCl)CCCC(C)C
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxy-8-methylnonane (Example B, Step 3). The product of Step A is thus ethyl 7-[N-(4-acetoxy-8-methylnonyl)-methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-8-methylnonyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
To an ice cold (˜0° C.) suspension of cis-2,6-dimethylpiperazine (4.0 g, 35 mmol) in DMF (100 mL) was benzyl bromide (6.0 g, 35.0 mmol) added in portions under a period of 45 min and the reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated from the suspension and the residue was dissolved in aqueous HCl and washed twice with CHCl3. The aqueous phase was made alkaline and extracted twice with CHCl3. The combined organic phases were washed with H2O and brine, dried (MgSO4), and concentrated to give 4.9 g (68%) of the title product as a colorless oil.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C([O:17]O)(C)(C)C.Cl>C1COCC1.O>[OH:17][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[N:9]=1
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: CC(C)(C)OO
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(O)n1
Temperature: -78 °C

Procedure:
To a cooled suspension of Na t-OBu (6.24 g, 64.9 mmol) in liquid ammonia was added dropwise a solution of 6-methoxy-3-nitropyridine (2.0 g, 12.98 mmol) and t-butyl hydrogenperoxide (1.53 mL, 14.31 mmol) in THF (20 mL). After the completion of addition, the resulting mixture was stirred at −78° C. under Ar and warmed gradually to room temperature, and then stirred at room temperature overnight, which gave a yellow solid. It was diluted with H2O (30 mL). The resulting mixture was neutralized with the addition of 1N HCl solution. The solid formed was collected and washed with H2O and DCM, and then dried (1.18 g). The filtrate was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give the second portion (0.59 g, total 1.77 g, 80%). NMR (MeOD-d3, 400 MHz) □ 8.20 (d, J=8.8 Hz, 1H), 5.79 (d, J=8.8 Hz, 1H), 4.87 (s, 3H). MS: m/z=171 (M+H+).
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])C)C.Cl[C:15](OCCl)=O.C(O)(=O)CCC>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6](=[O:10])[CH2:7][CH2:9][CH3:15]
Reactant: O=C(Cl)OCCl
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Solvent: CCCC(=O)O
Product: CCCC(=O)OCOC(=O)SC

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with n-butyric acid in Step B affords O-(butanoyloxymethyl) S-methyl thiocarbonate (8) as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])O[C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2].C[Si](C)(C)[NH:35][Si](C)(C)C.CO>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])[NH:35][C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)OC2=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 0.411 g of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)furan-2,5-dione in 50 ml of chloroform was treated with a mixture of 1.53 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.3 g of methanol and the mixture was heated at 60° C. for 1 hour. A further 1.53 g of hexamethyldisilazane and a further 0.3 g of methanol were added and the heating was continued overnight before adding further 1.53 g of hexamethyldisilazane and 0.3 g of methanol. The mixture was heated for a further 1 hour. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 5% methanol in dichloromethane to give 130 mg of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 77°-78° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:43]1([C:49]2[O:53][N:52]=[C:51]([NH2:54])[CH:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN1CCOCC1>CN1C(=O)CCC1>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:54][C:51]4[CH:50]=[C:49]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:53][N:52]=4)=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: Nc1cc(-c2ccccc2)on1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(-c2ccccc2)on1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
A 2-5 mL microwave reactor vial is charged with a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 25 mg, 0.10 mmol) in NMP (2 mL). HATU (47 mg, 0.12 mmol) is added and the mixture is stirred at room temperature for 30 min. 5-phenyl-3-aminoisoxazole (66 mg, 0.41 mmol) and N-methylmorpholine (41 mg, 0.41 mmol) are added and the vial is sealed with a Teflon lined septa cap and is irradiated in a microwave reactor at 100° C. for 30 min then at 150° C. for 90 min. The mixture is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/water with 0.1% TFA to obtain the title compound (2 mg, 5%). LCMS: 387.20 (M+H+). (System V1)
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1[S:10][CH:11]=[C:12]2[C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=12.O>CS(C)=O>[N:9]1[S:10][CH:11]=[C:12]2[C:17]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=12
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nscc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nscc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (60%, 1.08 g, 24.7 mmol) in dimethyl sulfoxide (100 mL) was added a solution of trimethylsulfoxonium iodide (5.43 g, 24.7 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl(2E)-3-(2,1-benzisothiazol-4-yl)acrylate (4.80 g, 20.6 mmol) in dimethyl sulfoxide (200 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (2.70 g, yield 53%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[NH:14][N:13]=NN=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[C:16](=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:24][C:16]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1cc2c(cc1-c1nnn[nH]1)CCO2
Reactant: CCOC(=O)CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 78.2 %

Procedure:
To a solution of 5-(2,3-dihydro-1-benzofuran-5-yl)-1H-tetrazole (4.40 g, 23.38 mmol) in pyridine (50 mL) was added ethyl 4-chloro-4-oxobutyrate (4.62 g, 28.06 mmol), and the resulting mixture was stirred at room temperature for 30 min and at 100° C. for 3.5 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, 1M hydrochloric acid, 1M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (5.27 g, yield 78%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5]([N:7]([C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH:13]=O)[CH3:8])[CH3:6]>>[CH2:5]([N:7]([C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH:13]=[N:3][CH2:2][CH2:1][N:4]=[CH:13][C:12]1[C:11](=[CH:10][C:9]([N:7]([CH3:8])[CH2:5][CH3:6])=[CH:16][CH:15]=1)[OH:17])[CH3:8])[CH3:6]
Reactant: CCN(C)c1ccc(C=O)c(O)c1
Reactant: NCCN
Product: CCN(C)c1ccc(C=NCCN=Cc2ccc(N(C)CC)cc2O)c(O)c1
Temperature: 70 °C

Procedure:
A solution of 80 mg (1.33 mmol) of ethylenediamine is added dropwise, at room temperature, to a solution of 500 mg (2.79 mmol) of 4-(N-ethyl-N-methylamino)salicylaldehyde and the reaction solution is heated for 4 hours at 70° C. After cooling to room temperature, the precipitate formed is filtered off, washed with a small amount of cold ethanol and dried in a vacuum drying cabinet at 30° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22]N(C)C=O.[H-].[Na+].S(OC)(OC)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:22])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)OC
Solvent: O
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride, and the solution was stirred for 20 minutes at room temperature. To this was added 2.2 g of dimethyl sulfite and stirring was further continued for 4 hours at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was mixed with water to precipitate a crude product. This product was recrystallized from methanol to afford 2.8 g of 1-(m-nitrophenyl)-3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 242°-243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].Cl.[NH2:15][CH:16]([P:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[C:17]([O:19][CH3:20])=[O:18].CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:26]([O:25][P:21]([O:22][CH2:23][CH3:24])[CH:16]([NH:15][C:5](=[O:6])[C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH3:13])[C:17]([O:19][CH3:20])=[O:18])[CH3:27]
Reactant: CCOP(OCC)C(N)C(=O)OC
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOP(OCC)C(NC(=O)c1c(OC)cccc1OC)C(=O)OC
Reaction time: 8 h

Procedure:
2,6-Dimethoxybenzoyl chloride (1.28 g, 6.42 mmol) was added to a mixture of methyl 2-amino-2-(diethoxyphosphino)acetate hydrochloride [1.5 g, 6.11 mmol, prepared by the method of Y. Nasukawa, et al, J. Org. Chem, (1992) 57, 5453] and NMM (1.5 ml, 13.44 mmol) in CH2Cl2 (30 ml). The mixture was stirred overnight at room temperatue then poured into 10% citric acid. The mixture was extracted with CH2Cl2 (×2) and the combined organic extracts washed with sodium hydrogen carbonate solution (×2) and brine, dried (MgSO4) and evaporated in vacuo to give a brown solid (1.62 g). δH (DMSO-d6) 8.82 (1H, dd, J 9.1, 2.5 Hz), 7.29 (1H, t, J 8.4 Hz), 6.65 (2H, d, J 8.4 Hz), 5.20 (1H, dd, J 20.0, 9.2 Hz), 4.15-4.03 (4H, m), 3.72 (3H, s), 3.71 (6H, s), 1.39-1.20 (6H, m); m/z (ESI) 390 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC>O1CCCC1>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([B:16]([OH:17])[OH:15])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of p-trifluoromethylbromobenzene (814.8 g) and triisopropoxyborane (681.0 g) in tetrahydrofuran (6300 mL) is cooled to −78° and n-butyllithium (2.5 m in hexanes, 1448 mL) is added over 30 minutes at a temperature below −60° to yield p-trifluoromethylphenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[Br:1][C:2]1[N:6]([S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:33]=2)(=[O:40])=[O:39])[CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(Br)c1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Yield: 91.9 %

Procedure:
Using methyl 5-bromo-1H-pyrrole-3-carboxylate (2.89 g), sodium hydride (60% in oil, 850 mg), 15-crown-5 (4.69 g) and 3-methylsulfonylbenzenesulfonyl chloride (4.38 g), a procedure as in Reference Example 146 was performed to give the title compound as white crystals (yield 5.50 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.[C:34](=O)(O)[O-].[K+]>CO.S(=O)(=O)(O)O.O>[CH3:34][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: O=C([O-])O
Reactant: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCOc1cc2c(cc1OC)NC(c1ccccc1)N2c1ccc(C)cc1
Reaction time: 2 h

Procedure:
40 mg of 6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid was dissolved in 2 ml of methanol, mixed with 1 drop of concentrated sulfuric acid, and the mixture was stirred for 2 hours. It was mixed with saturated potassium bicarbonate solution, diluted with water, extracted with ethyl acetate, the extracts were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][CH:32]=O)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH2:32][CH2:31][C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=CCc1cc(F)cc(F)c1
Product: CCCC(NCCc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with (3,5-Difluoro-phenyl)-acetaldehyde to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.4, 24.3, 26.7, 36.0, 36.4, 50.0, 56.0, 59.1, 63.1, 67.2, 101.8, 102.1, 102.3, 104.8, 111.5, 111.8, 131.2, 137.3, 143.5, 162.0, 162.1, 164.5, 164.6, 171.7; MS m/z 448.4 (M+1).