Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][O:15]C(=O)C)[C:8]=2[N:7]=[C:6]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].O.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][OH:15])[C:8]=2[N:7]=[C:6]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC(=O)OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 95.9 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (Example 103) (1.45 g, 3.38 mmol) dissolved in methanol (19 mL) and water (1.0 mL) was added K2CO3 (0.40 g). After 30 min. the reaction was concentrated, redissolved in EtOAc, and washed with NaHSO4 (10% soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. Recrystallization of the crude product from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxymethylbenzimidazole (1.25 g, 3.24 mmol, 96% yield). M.p. 157-158° C. 1H-NMR (300 MHz, CD2Cl2): δ7.54 (m, 1H, H4′), 7.43 (d, J=7.9 Hz, 1H, H7), 7.30-7.22 (m, 2H, H6,4″), 7.18 (d, J=7.5 Hz, 1H, H5), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.37 (s, 2H, CH2PhF2), 5.06 (d, J=5.4 Hz, 2H, CH2O), 3.51 (t, J=5.4 Hz, 1H, OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(CCl)c(Cl)cc1Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 21 h
Yield: 27 %

Procedure:
To a solution of 1,5-dichloro-2-(chloromethyl)-4-nitrobenzene (Hagmann, William K.; Dorn, Conrad P.; Frankshun, Robert A.; O'Grady, Laura A.; Bailey, Philip J.; et al.; JMCMAR; J. Med. Chem.; EN; 29; 8; 1986; 1436-1441, 10.6 g, 44 mmol) in methanol (30 ml) was added sodium methoxide (44 ml, 66 mmol) at room temperature. The mixture was stirred at 80° C. for 21 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (6:1/4:1) to afford 2.8 g (27%) of the title compound as pale yellow oil.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[C:11](#[N:13])[CH3:12]>>[CH3:12][C:11]1[N:13]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: N[n+]1ccccc1
Reactant: CC#N
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 1-aminopyridinium iodide (139 g, 626 mmol) in acetonitrile (1.25 L) was added 10% aqueous sodium hydroxide solution (751 mL, 1.88 mmol), and the mixture was stirred at room temperature for 12 hr. Half of the reaction mixture was evaporated under reduced pressure, and the residue was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (47.0 g, yield 56%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:14][CH2:15]O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H][H]>[Pd].C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]2[CH2:14][CH2:15][CH:18]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[C:17]2=[O:31])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: [H][H]
Reactant: COc1cc(CC(=O)C(CCO)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC

Procedure:
A mixture of 2.38 g of the compound of Example 1 as a 0.1M ethanol solution and 900 mg of 10% palladium on carbon was stirred, under a 50 psi. atmosphere of hydrogen gas, for 17 hours. The mixture was then filtered through Celite and the crude residue was flash chromatographed on silica gel employing ethyl acetate as the eluent to yield the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27](Cl)=[N:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1C(=O)CCC1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)=[N:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ccc(OCc2ccccc2)cn1
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: c1ccc(COc2ccc(OC3COC(c4ccccc4)OC3)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Phenyl-[1,3]dioxan-5-ol (164 mg. 910 μmol) was dissolved in 5 ml of NMP. Addition of sodium hydride (60% in oil, 72.8 mg, 1.8 mmol) was followed by stirring at RT for 30 min and, after addition of 5-benzyloxy-2-chloropyridine (200 mg, 910 μmol), stirring in a microwave reactor at 200° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and water, and the organic phase was concentrated. The resulting crude product (386 mg) was directly reacted further.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cc1ccc(CNc2ccc(C(C)C)cc2)c(C)c1
Product: Cc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)c(C)c1
Yield: 14.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(2,4-dimethylphenyl)methyl](4-isopropylphenyl)amine (2.2 g) and 2,6-diisopropylphenyl isocyanate (2.7 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(2,4-dimethylphenyl)methyl]-N-(4-isopropylphenyl)urea (0.56 g) was obtained. melting point: 100° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH:13]2[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])[C:3]=1[CH3:16].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.CC(C)([O-])C.[K+].O>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]2[C:18](=[O:20])[NH:12][C:10](=[O:11])[C:9]([CH:13]3[CH2:15][CH2:14]3)=[C:4]2[C:3]=1[CH3:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(C(C(N)=O)C2CC2)ncc(F)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a −60° C. solution of 2-(4-chloro-5-fluoro-3-methylpyridin-2-yl)-2-cyclopropylacetamide (2.7 g, 11.0 mmol (Example 1)) and triphosgene (7.2 g, 24.0 mmol) in dichloromethane (250 mL) was added portionwise potassium tert-butoxide (4.5 g, 40.0 mmol). After the addition was complete, the mixture was stirred at −50° C. for 30 minutes. Water was then added at this temperature. The organic layer was separated, washed with brine (3×), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography (7:3 ethyl acetate/hexanes) to afford the title compound (2 g). 1H NMR (200 MHz, CDCl3) δ 8.95 (bs, 1H), 8.16 (d, 1H), 2.66 (s, 3H), 1.75-1.71 (m, 1H), 1.11-1.01 (m, 2H), 0.46-0.37 (m, 2H). MSCI: m/z=269 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15](=[O:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Br:17])[O:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=[O:21]>CO.Cl.O>[C:15]([CH2:14][C:13]1[C:8]([O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=1[Br:17])([OH:21])=[O:16]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C1Oc2cccc(Br)c2CC1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOC(=O)COc1cccc(Br)c1CC(=O)O
Reaction time: 18 h
Yield: 53 %

Procedure:
A suspension of 2-ethoxycarbonyl-5-bromo-3-chromanone (300 mg, 1 mMol) in methanol (5 mL) and 10% hydrochloric acid (3 mL) was heated at reflux for 2 hours. All of the solid had not dissolved; therefore, trifluoroacetic acid (1 mL) was added, and heating was continued for 18 hours. The reaction mixture was diluted with water and extracted well with diethyl ether. The ether phases were combined, dried over sodium sulfate, and concentrated in vacuo to give a yellow glass. Purification by flash chromatography (1:1 hexane:ether) gave the title compound as a light yellow glass (120 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].BrC[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Br)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:37]=2)=[CH:31][C:30]=1C(F)(F)F>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][C:32]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)=[CH:37][C:38]=2[C:44]([F:45])([F:46])[F:47])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1cc(Oc2ccc(CBr)c(C(F)(F)F)c2)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(Oc3ccccc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
To 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(45 mg, 0.20 mmol) in dry THF (3.0 ml) under nitrogen at room temperature was added 1.0 M lithium bis(trimethylsilyl)amide in THF (0.20 ml, 0.20 mmol) dropwise. The solution was stirred for approximately 30 min and then 4-(bromomethyl)-3-(trifluoromethyl)phenyl ether (67 mg, 0.20 mmol) in THF (2 ml) was added. The solution was stirred for 3 h and then left to stand overnight. The solvent was removed under a stream of nitrogen. To the residue was added aqueous sodium bicarbonate and then the residue extracted with chloroform three times. The combined chloroform extracts were filtered through a hydrophobic frit. The filtrate was concentrated in vacuo. The residue was purified on MDAP (Method B). The appropriate fractions were combined and the residue dried under high vacuum to give the title compound as a thick white gum (72.3 mg); LCMS: (System 4) MH+=474, tRET=3.35 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:44][C:45]([F:52])([F:51])[CH2:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH2:46][C:45]([F:52])([F:51])[F:44])(=[O:49])=[O:48])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and pyridine (0.06 g, 0.75 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of 2,2,2-trifluoroethanesulphonyl chloride (0.095 g, 0.52 mmole) in methylene chloride (1 ml) and the resulting mixture was stirred for 0.5 hour. The reaction was quenched by the addition of aqueous citric acid, the resulting organic phase separated, washed with water and dried over magnesium sulphate. After concentration under reduced pressure the residue was purified by flash chromatography on silica gel eluting with ethyl acetate (80):hexane (20) to yield, after collection and evaporation of appropriate fractions, the desired product as a foam, m.p. 74°-75° (0.159 g, 62%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][CH3:16].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[O:15][CH3:16])[NH2:12]
Reactant: COc1ccc([N+](=O)[O-])cc1OCCCCl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1OCCCCl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 39.8 %

Procedure:
A mixture of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene (2.15 g, 8.77 mmol) and tin (II) chloride dihydrate (6.1 g, 27.11 mmol) in 50 mL of ethyl acetate was heated at reflux for 6.5 hours. The reaction mixture was cooled to room temperature and poured into 250 mL of saturated aqueous sodium bicarbonate. After stirring for 40 minutes, additional ethyl acetate was added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and water then dried over magnesium sulfate and filtered. The solution was concentrated in vacuo and purified by flash column chromatography, eluting with 1:1 hexane: ethyl acetate, to provide 753 mg of 3-(3-chloropropoxy)-4-methoxyaniline as a dark brown oil; 1H NMR (400 MHz, DMSO-d6) δ 2.13 (m, 2H), 3.62 (s, 3H), 3.78 (t, J=6 Hz, 2H), 3.96 (t, J=6 Hz, 2H), 4.77 (br s, 2H), 6.10 (dd, J=8, 2 Hz, 1H), 6.29 (d, J=2 Hz, 1H), 6.66 (d, J=8 Hz, 1H); MS (ES) m/z216.1, 218.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([NH2:31])=[O:30]>CN(C)C=O>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([O:5][CH2:28][C:29](=[O:30])[NH2:31])=[O:4]
Reactant: NC(=O)CCl
Reactant: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)O)cc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)OCC(N)=O)cc1C2
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 2.7 g of α,2-dimethyl-5H-[1]benzopyrano [2,3-b]pyridine-7-acetic acid in 15 ml of dimethylformamide are added 0.8 g of potassium carbonate and 1.1 g of 2-chloroacetamide, and stirred at 80° C. for 1 hour under a nitrogen atmosphere. The reaction mixture is poured into ice water, and the precipitated crystals are collected by filtration, washed with water, and then recrystallized from ethanol to obtain 2.7 g of carbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano [2,3-b]pyridine-7-acetate as white crystals having a melting point of 175° to 177° C.
Reaction SMILES: [N+](C1C=CC(S(O[CH2:14][C:15]([C:18]2[O:22][N:21]=[C:20]([NH2:23])[CH:19]=2)([CH3:17])[CH3:16])(=O)=O)=CC=1)([O-])=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:16][C:15]([C:18]1[O:22][N:21]=[C:20]([NH2:23])[CH:19]=1)([CH3:17])[CH2:14][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(N)no1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CN1CCOCC1)c1cc(N)no1
Temperature: 140 °C
Yield: 59.2 %

Procedure:
Six equivalent batches of a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-methylpropyl 4-nitrobenzenesulfonate (50 mg, 0.15 mmol), morpholine (0.016 mL, 0.179 mmol), DBU (0.027 mL, 0.179 mmol) and acetonitrile (0.75 mL) were heated in a microwave reactor at 140° C. for 2.5 h. After cooling to rt, the reactions were combined and concentrated under reduced pressure. The residue was partitioned between chloroform and saturated aqueous sodium carbonate solution. The organic layer was separated and washed with brine. The organic layer was separated and dried over sodium sulfate, filtrated and concentrated under reduced pressure to give the crude product. Purification via silica gel column chromatography (eluting with a gradient of 100% chloroform to 5% methanol in chloroform) afforded 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-amine (20 mg, 10%) as a solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:22]=[CH:21][O:20][CH:19]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[O:20]1[CH:21]=[CH:22][C:18]([C:14]2[C:11]3[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=3[CH:17]=[CH:16][CH:15]=2)=[CH:19]1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccoc3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(-c3ccoc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 174 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 2 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 124 mg of of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:11]1[C:12]2[C:8](=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21

Procedure:
In analogy to the procedure described in example 6 a], 4-(tert-butyl-dimethyl-silanyloxy)-1H-indole (EP 206225 A2) was reacted with bromo-acetic acid ethyl ester in the presence of cesium carbonate to obtain the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])=[O:5].[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1.C(O)C>[Pd].O>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]([C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH3:16])[CH:9]=1
Reactant: C1=CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1F
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)ccc1N(C(=O)c1ccccc1F)c1ccccc1
Temperature: 4 °C

Procedure:
A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4° C. for 12 hours. Filtration provides the product as a tan solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(-c2cccc(CO)c2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Compound 17 (0.400 g, 1.66 mmol) was placed in ethanol (10 ml) and stirred in an ice-water bath while sodium borohydride (0.063 g, 1.66 mmol) was added. The reaction was brought to room temperature and stirred for 2 hours. The reaction was quenched with water (2 ml), diluted with a saturated NH4Cl solution, and extracted with ethyl acetate. The solution was concentrated in vacuo to yield 18 as a pale orange solid (0.390 g, 99% yield). The product was used in the next step without further purification. Methyl 3′-(hydroxymethyl)bi-phenyl-4-carboxylate 18 (0.210 g, 0.867 mmol) was dissolved in dichloromethane (4 ml) and placed under argon in an ice-water bath. To this solution was added dropwise 0.870 ml of 1.0 M phosphorous tribromide in dichloromethane. The reaction was stirred at room temperature for 2.5 hours and then quenched with 1:1 saturated NaHCO3:water followed by extraction with diethyl ether. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 19 as a white solid (0.277 g, quant. yield). The product was used for the next reaction without further purification. Methyl 3′-(bromomethyl)biphenyl-4-carboxylate 19 (0.278 g, 0.876 mmol) and sodium azide (0.113 g, 1.73 mmol) were heated to 70° C. in DMF (4 ml) overnight with vigorous stiffing. After 12 hours, the reaction was quenched with water (10 ml) and the product extracted with ethyl acetate (3×10 ml). The organic layers were washed with brine (15 ml), dried over Na2SO4, and concentrated in vacuo to yield 20 as a yellow oil. The product was purified by column chromatography (6:1 Hexane:ethyl acetate) to afford 3′-(azidomethyl)biphenyl-4-carboxylate as a pale orange solid (0.225 g, 92%). 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H), 4.42 (s, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.55-7.60 (m, 2H), 7.66 (d, J=8.4 Hz, 2H), 8.11 (d, J=8.4 Hz, 2H). 3′-(azidomethyl)-biphenyl-4-carboxylate 20 (0.150 g, 0.561 mmol) was heated to reflux in EtOH (4 ml, 80° C.) in the presence of hydrazine monohydrate (0.96 ml of a 20.63 M solution), and the solution was left to stir overnight (12 hours). The reaction was then concentrated in vacuo to remove excess ethanol. Water (10 ml) was added, and the product extracted with ethyl acetate (5×10 ml), dried over Na2SO4, and concentrated in vacuo to yield 5 as a pale yellow solid. The product was isolated by crystallization in 2:1 ethanol:ethyl acetate (0.127 g, 85%). 1H NMR (400 MHz, (CD3)2SO) δ 4.51 (s, 2H), 7.39 (d, J=7.2, 1H), 7.50 (t, J=7.6, 1H), 7.68-7.75 (m, 4H), 7.91 (d, J=8.0 Hz, 2H) 13C NMR (100 MHz, (CD3)2SO) δ 54.0, 127.0, 127.4, 128.1, 128.5, 130.0, 132.8, 136.9, 140.0, 142.6, 165.9; MS (ESI) calculated for C14H13N5O [M+H]+: m/z 268.3. found [M+H]+: 268.2