Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:24])[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15]2)=[CH:10][CH:9]=1.C(C1OC1)Cl>O>[O:6]1[CH2:5][CH:3]1[CH2:4][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:24])[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15]2)=[CH:10][CH:9]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCC1CO1
Product: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Temperature: 70 °C

Procedure:
To a solution of 82.2 g (2.06 mol) of sodium hydroxide in 585 ml of water were added 3.7 liters of isopropanol and then 490 g (2.06 mole) of 7-hydroxyflavone. To the above mixture were then added 1645 ml (20.5 mole) of epichlorohydrin and the mixture heated at 70° C. for 2 hours with stirring. The hot reaction mixture was filtered to remove dimeric by-product. The filtrate was concentrated under reduced pressure (water aspirator) at 50°-60° C. The semisolid residue was treated with 4.4 liters of refluxing isopropanol and more of the dimer filtered from the hot mixture. The clear filtrate on cooling yielded a solid. This was filtered, washed with 600 ml of isopropanol and air dried; yield 434.3 g (72%) of a tan-colored product, mp 123°-130° C. (a pure sample melts at 133°-135° C. from i-PrOH). The crude epoxide was used for further reaction.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[SH:22][CH2:23][C:24](O)=[O:25]>C(S(O)(=O)=O)(F)(F)F.C1(C)C=CC=CC=1>[C:1]([S:14]([N:17]([CH2:19][CH2:20][O:21][C:24]([CH2:23][SH:22])=[O:25])[CH3:18])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:12])[F:13])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CN(CCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)CS
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(CCOC(=O)CS)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 500 mL three-necked round bottom flask was charged with 16.86 g of C4F9SO2N(CH3)CH2CH2OH (MW=357; 47.22 mmol; Example 2, A from WO 01/30873), 4.35 g HSCH2CO2H (MW=92.12, 47.22 mmol; available from Sigma-Aldrich), 2 drops of CF3SO3H catalyst, and 120 mL toluene. The mixture was heated to reflux under nitrogen at 115–120° C. with a mechanical stirrer for 8 hours. Water was removed by azeotropic distillation. Fourier Transform Infrared Spectroscopy (FTIR) analysis indicated the formation of ester. Toluene was stripped using a rotary evaporator (21.35 g solid).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([CH2:25][OH:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: NC1(CO)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OCC1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine followed by 1 g of 1-aminocyclopropanemethanol (see 4.2) are added. The reaction mixture is heated at 160° C. until there is no further reaction, and after cooling evaporated down. The residue is treated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-4) are obtained as a solid.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2.S(Cl)([Cl:14])=O>>[S:1]1[C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2
Reactant: O=C(O)c1cc2c(s1)CCC2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2c(s1)CCC2

Procedure:
1.0 g of 5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid was reacted with 4 ml of thionyl chloride for 3.5 hours under reflux. Then, excess thionyl chloride was distilled off under reduced pressure to obtain 5,6-dihydro-4H-cyclopenta[b]thiophene-2-carbonyl chloride.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][O:20]C1C=CC=CC=1C(C1C=CC=CC=1)=O>>[CH3:17][O:18][CH2:19][O:20][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][NH2:9]
Reactant: COCOc1ccccc1C(=O)c1ccccc1
Reactant: Cc1ccccc1C(CN)c1ccccc1
Product: COCOc1ccccc1C(CN)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of 2-phenyl-2-o-tolylethanamine (Example FF) in using (2-(methoxymethoxy)phenyl)(phenyl)methanone. 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.88-7.44 (9H, m), 5.16-5.18 (1H, m), 5.09-5.15 (2H, m), 3.41-3.46 (2H, m), 3.21-3.23 (3H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>N1C=CC=CC=1>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1c(N2CCCCC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (115 mg, 0.314 mmol, Eq: 1.00) and piperidine (150 mg, 174 μl, 1.76 mmol, Eq: 5.6) in pyridine (1.5 ml) was stirred at 135° C. for 3 h in a sealed tube. The solution was allowed to cool to RT and cold water and ice were added. A light yellow solid precipitated which was filtered off, washed with water and dried (42 mg, 6,8-dichloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid methyl ester, MS (ESI): 415.3 (M+H)). The mother liquor was evaporated, water was added to the remaining residue and the pH was adjusted to 2 with 0.1N HCl. The mixture was extracted with chloroform and the combined organic extracts were dried with Na2SO4 and evaporated to yield the title compound (64 mg, yellow solid). MS (ESI): 401.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+]>ClCCl.CN(C=O)C.C1COCC1>[C:23]([O:14][C:13]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:15])([CH3:26])([CH3:24])[CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(C2(C(=O)O)CCCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C2(C(=O)OC(C)(C)C)CCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 1-(4-methylphenyl)cyclopentane carboxylic acid (3.00 g, 14.7 mmol) in dichloromethane (50 ml,) at 0° C. was added oxalyl chloride (1.54 mL, 17.4 mmol) and DMF (2 drops). The mixture was stirred at 0° C. for 1 hour, and at rt for 2 hours. The solution was concentrated, diluted with THF (40 mL), and cooled to 0° C. Potassium t butoxide (1.80 g, 16.2 mmol) in THF (20 mL) was slowly added, and the mixture was stirred overnight at rt. Additional potassium t butoxide (0.660 g, 5.88 mmol) was added. After 20 minutes the solution was concentrated to dryness, and taken up in ethyl acetate. The organic phase was washed with 10% citric acid, saturated NaHCO3 and brine, dried (MgSO4), and concentrated. Flash column chromatography (10% ethyl acetate/hexane) gave 1-(4-methylphenyl)cyclopentane carboxylic acid t butyl ester (3.27 g, 87%).
Reaction SMILES: OO.C=CCCCC.C(=O)([O-])[O-:10].[Na+].[Na+].[F:15][C:16]([F:42])([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)[CH:17]([F:19])[F:18]>CO>[F:42][C:16]([F:15])([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40](=[O:10])[NH2:41])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)[CH:17]([F:19])[F:18]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Agent: OO
Agent: [Na+]
Solvent: C=CCCCC
Solvent: CO
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.58 ml of hydrogen peroxide (30%), 0.16 ml of 1-hexene, 11 mg of sodium carbonate and 2 ml of methanol are added to 50 mg (0.12 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine and the reaction mixture is stirred for 14 h at RT. The product is isolated by filtration, washed with methanol/water (9:1) and dried to give N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine; m.p. 224°-225°, FAB-MS: 408 (M+ +H), 290.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH:22](SC2C=CC(Cl)=CC=2)[C:21]2[C:16](=[C:17]([F:32])[CH:18]=[CH:19][C:20]=2[F:31])[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35](C(OO)=O)[CH:34]=1.[S:44]([O-:48])([O-])(=[O:46])=S.[Na+].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH:22]([S:44]([C:34]2[CH:33]=[CH:38][C:37]([Cl:39])=[CH:36][CH:35]=2)(=[O:48])=[O:46])[C:21]2[C:16](=[C:17]([F:32])[CH:18]=[CH:19][C:20]=2[F:31])[O:15][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)c2c1OCC(COCCOCc1ccccc1)C2Sc1ccc(Cl)cc1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-Benzyloxy-ethoxymethyl)-4-(4-chloro-phenylsulfanyl)-5,8-difluoro-chroman (0.42 g, 0.88 mmole) was dissolved in 15 ml DCM and MCPBA (77%, 0.6 g, 2.6 mmole) was added. The reaction was stirred at room temperature for 30 minutes. 0.5 g sodium thiosulfate in 50 ml water and 50 ml EtOAc were added. The organic layer washed with 1N NaOH solution (50 ml), brine (50 ml), dried over sodium sulfate and concentrated. The product was purified by column (EtOAc/hexane from 0/100 to 50/50 in 45 minutes). Yield: 0.40 g, 89%. 1H NMR (CDCl3 400 MHz δ 7.73 (d, J=8.8 Hz, 2H), 7.4 (d, J=8.1 Hz, 2H), 7.25-7.37 (m, 5H), 7.02 (m, 1H), 6.42 (m, 1H), 4.90 (dd, J=11.7 and 2.9 Hz, 1H), 4.63 (s, 1H), 4.50 (s, 2H), 4.38 (t, J=11.0, 1H), 3.45-3.62 (m, 5H), 3.30 (t, J=9.5 Hz, 1H), 3.13 (m, 1H).
Reaction SMILES: C(C1C(O)=C[C:14](O)=[C:13]2C=1[N:5]=[C:6]1[C:11](=[N:12]2)C(C(OC)=O)=CC=C1O)=O.[CH:24]([C:26]1[C:39]([OH:40])=[C:38]([CH3:41])[C:37]([OH:42])=[C:36]2[C:27]=1[N:28]=[C:29]1[C:34](=[N:35]2)[C:33]([C:43](OC)=[O:44])=[CH:32][CH:31]=[C:30]1[OH:47])=[O:25].[CH3:48]OC(C1C=CC(O)=C2NC3C(=NC=12)C(=O)C=C(O)C=3C=O)=O>>[CH2:13]([N:12]([CH3:48])[CH2:11][CH2:6][NH:5][C:43]([C:33]1[C:34]2[C:29](=[N:28][C:27]3[C:36]([N:35]=2)=[C:37]([OH:42])[C:38]([CH3:41])=[C:39]([OH:40])[C:26]=3[CH:24]=[O:25])[C:30]([OH:47])=[CH:31][CH:32]=1)=[O:44])[CH3:14]
Reactant: COC(=O)c1ccc(O)c2nc3c(C=O)c(O)c(C)c(O)c3nc12
Reactant: COC(=O)c1ccc(O)c2nc3c(C=O)c(O)cc(O)c3nc12
Reactant: COC(=O)c1ccc(O)c2[nH]c3c(C=O)c(O)cc(=O)c-3nc12
Product: CCN(C)CCNC(=O)c1ccc(O)c2nc3c(C=O)c(O)c(C)c(O)c3nc12

Procedure:
Compounds in accordance with the present invention are prepared from the starting materials 6-formyl-4,7,9-trihydroxy-1-phenazinecarboxylic acid, methyl ester or from 6-formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylic acid, methyl ester. The former compound, 6-formyl-4,7,9-trihydroxy-1-phenazinecarboxylic acid, methyl ester, is known variously in the chemical literature as lomofungin or lomondomycin and is produced in isoluble quantities from fermentation broth mixtures containing the microorganism Streptomyces lomondensis NRRL 3252 as detailed in U.S. Pat. No. 3,359,165.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>C(O)C>[ClH:1].[C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=1)([CH3:18])([CH3:17])[CH3:10]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A stirred solution of cyclohexylhydrazine hydrochloride (1.5 g, 9.96 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.5 g, 11.98 mmol) in ethanol (5 mL) was refluxed for 15 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure and the obtained crude product was recrystallized from a mixture of diethyl ether and petroleum ether to afford 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (1.0 g, 39%) as colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 13.24 (brs, 1H), 7.02 (brs, 2H), 5.52 (s, 1H), 4.30 (m, 1H), 1.63-1.98 (m, 7H), 1.10-1.40 (m, 12H); LC-MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.O1CCCC1.O>[N:1]1([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1cccc(N2CCOCC2)c1
Yield: 85.3 %

Procedure:
A 500 mL roundbottom flask equipped with stir bar and 3-way stopcock charged with MeOH/tetrahydrofuran/water (200 mL of 2:1:1) was purged thoroughly with nitrogen. To this was added 1.0 g of 10% Pd/C followed by addition of 10 g (48.0 mmol) of 3-morpholinyl nitrobenzene. The mixture then was stirred under a hydrogen atmosphere for 4 days (1 atm). The reaction was filtered over GF/F filter paper and the filtrate concentrated in vacuo to remove MeOH and THF. The resulting solid was recovered by filtration, washed with water, air dried, then dried in vacuo to give 7.3 g (83% yield) of the desired aniline as beige crystals.
Reaction SMILES: [H-].[Na+].O.C(OP([CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=CC=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
Under an atmosphere of nitrogen, 0.583 g of sodium hydride (as a 50% w/w dispersion in mineral oil) were added to a 4 ml of tetrahydrofuran and the mixture was cooled with water. A solution of 3.04 g of ethyl 4-(diethylphosphono)crotonate in 5 ml of tetrahydrofuran was added dropwise to the cooled mixture, which was then stirred for 30 minutes. At the end of this time, a solution of 1.84 g of 1-benzyl-4-piperidone in 2 ml of tetrahydrofuran was added to the mixture over a period of 30 minutes, whilst the mixture was kept at 0° C. by ice-cooling, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then stirred at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water. The solvent was then removed by distillation under reduced pressure. The red brown residue was subjected to column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.81 g (29% yield) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]([F:29])([F:28])[C:5]([F:27])([F:26])[O:6][C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[O:9][C:10]([F:21])([F:20])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[CH2:32]([C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:32]([C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:22])([F:23])[C:7]([F:24])([F:25])[O:6][C:5]([F:26])([F:27])[C:4]([F:28])([F:29])[O:3][C:2]([F:1])([F:31])[F:30])([F:21])[F:20])=[CH:48][CH:47]=2)=[N:42][CH:41]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 6-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromohexane (85 g, 0.155 mol; prepared from 1,6-dibromohexane (500 g, 0.7 mol), 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (150 g, 0.37 mol), and potassium t-butoxide (412 mL of 1M solution in t-butanol)) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (45 g, 0.162 mol). The crude product was further purified by recrystallization from heptane and subsequently dried in a vacuum oven (yield of 93.0 g).
Reaction SMILES: [NH:1](F)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])O.N[C@H](C(O)=O)C[C:14](O)=[O:15].C(OC(=O)C)(=O)C>C(O)=O>[CH:14]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:15]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(O)C[C@H](NF)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
F-Asp=O is prepared by reacting L-aspartic acid with formic acid in the presence of an effective amount of acetic anhydride under conditions sufficient to form N-formyl-L-aspartic anhydride. Then an effective amount of acetic anhydride and a C3 -C6 secondary alcohol are added to the reaction mixture to consume excess formic acid. The resulting N-formyl-L-aspartic anhydride reaction mixture is suitable for further reactions without modifications.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]2[N:18]=[CH:19][CH:20]=[CH:21][C:9]=2[N:8]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: CN(C)CCCCl
Reactant: c1ccc(C2=Nc3cccnc3Nc3ccccc32)nc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccccn2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:16][CH:15]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39].C(C1SC(S(NC(C)(C)C)(=O)=O)=C(C2C=CC(CN3N=NC=N3)=CC=2)C=1)C(C)C>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:13][S:10]([C:8]1[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[N:25]=[N:24][CH:23]=[N:22]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11])=[O:39])[CH2:42][CH2:43][CH3:44]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCOC(=O)Cl
Agent: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ncnn2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 54 %

Procedure:
The crude product from step (d) above was dissolved in pyridine (1 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (14 mg, 0.0095 mmol) and butyl chloroformate (120 μL, 0.97 mmol) were added to the mixture, which was then stirred for 30 hours under N2(g) at room temperature. The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification using column chromatography with CHCl3:MeOH (35:1) as eluent yielded the title compound (24.9 mg, 0.052 mmol) in 54% yield (from 5-iso-butyl-N-tert-butyl-3-(4-tetrazol-2-ylmethylphenyl)thiophene-2-sulfonamide).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28]CC1C=CC(OC)=CC=1)=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)Cc2ccccc2OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccccc1CC(=O)O
Reaction time: 0.67 h
Yield: 80.3 %

Procedure:
4-Methoxybenzyl 2-(N-CBz-L-valyloxy)phenylacetate (4.25 g, 8.4 mmol), was dissolved in dichloromethane (40 ml). Triflouroacetic acid (8 ml) was added with cooling on ice. The mixture was allowed to reach room temperature and stirred for 40 min. The solvent was removed under reduced pressure and the crude product was recrystallized twice (hexan-ethyl acetate+a small amount of dichloromethane) to give the title compound (2.6 g, 80%). The compound can be activated and esterified to a drug or further modified as described below.
Reaction SMILES: [CH:1]1([C:4]2[S:43][C:7]3[N:8]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[NH:41][C:40](=[O:42])[O:39][N:38]=5)=[CH:27][CH:26]=4)[C:9](=[O:23])[N:10]([CH2:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[O:15])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.O1CCCC1.[BH4-].[Na+]>CO>[CH:1]1([C:4]2[S:43][C:7]3[N:8]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[NH:41][C:40](=[O:42])[O:39][N:38]=5)=[CH:27][CH:26]=4)[C:9](=[O:23])[N:10]([CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[OH:15])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2-c2ccc(Cn3c(=O)n(CC(O)c4ccc(F)cc4)c(=O)c4cc(C5CC5)sc43)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of 6-cyclopropyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.1 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride-(0.038 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with chloroform and saturated aqueous ammonium chloride solution. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.074 g, 74%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[O:11][CH:10]=[CH:9][C:8]2=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)([CH3:3])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl>[Br:25][C:10]1[O:11][C:7]2[C:8](=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC(C)C)cc2occc12
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC(C)C)cc2oc(Br)cc12
Temperature: 60 °C
Reaction time: 1.2 h
Yield: 87 %

Procedure:
A mixture of methyl 6-isopropoxybenzofuran-4-carboxylate (344a) (2.17 g, 9.25 mmol) and NBS (4.12 g, 23.1 mmol) in 50 mL of CHCl3 was heated at 60° C. for 5 hrs, followed by addition of another batch of NBS (2.50 g, 14.0 mmol). After stirring for an additional 1.2 h, the reaction was concentrated, and the residue was purified with Biotage column chromatography eluting with CHCl3 to give a yellow oil (2.52 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.27 Hz, 1 H) 7.22 (s, 1 H) 7.18 (d, J=2.01 Hz, 1 H) 4.56-4.64 (m, 1 H), 3.97 (s, 3H), 1.37 (d, J=6.04 Hz, 6 H); LCMS for C13H13BrO4m/z 312.0 (M+H+).