Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[C:15]([CH3:24])=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:24][C:15]1[C:14]([O:13][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cccc(O)c1C
Reactant: BrCc1ccc2ccccc2c1
Product: COC(=O)c1cccc(OCc2ccc3ccccc3c2)c1C
Yield: 92 %

Procedure:
2-Bromomethylnaphthalene was reacted with methyl 3-hydroxy-2-methylbenzoate (Tetrahedron, 1969, 25, 4249) using the conditions described in Example 1 to give methyl 2-methyl-3-(naphth-2-ylmethoxy)benzoate in 92% yield, m.p. 47°-48° C. (recrystallised from a mixture of diethyl ether and pentane). The product so obtained was reacted with thiazol-2-yl-lithium using the procedure described in the 3rd paragraph of the portion of Example 3 which is concerned with the preparation of starting materials to give, after purification of the product by column chromatography using a 49:1 v/v mixture of toluene and ethyl acetate as eluent, 3-(naphth-2-ylmethoxy)-2-methylphenyl 2-thiazolyl ketone as an oil in 72% yield.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=CC=1.[C:21](O)(C(F)(F)F)=[O:22]>ClCCCl>[CH3:21][O:22][C:15]1[CH:16]=[N:17][C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][C:9]=2[NH2:8]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CNc2nccc3cccnc23)cc1
Solvent: ClCCCl
Product: COc1cnc2c(N)nccc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of N-(4-methoxybenzyl)-1,7-naphthyridin-8-amine (340 mg, 1.15 mmol) in 1,2-dichloroethane (5.80 mL) was added TFA (2.67 mL, 34.5 mmol). The reaction was stirred at 75° C. for 8 hours and then concentrated. The residue was partitioned between DCM and aqueous sodium bicarbonate. The organic layer was concentrated and purified by silica-gel chromatography, eluting with 50-100% EtOAc in DCM, to provide the title compound (171.7 mg, 0.98 mmol) as an off-white solid. LC/MS (ESI+) m/z=176 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3].[CH3:11][C:12](C)([O-:14])C.[K+].C(OCC)(=O)C>C1COCC1>[Cl:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:12](=[O:14])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 3-chloroacetophenone (1.30 mL, 10.0 mmol) in 20 mL THF was added Potassium tert-butoxide (11.0 mL of a 1.0 M solution in THF, 11.0 mmol) and then anhydrous ethyl acetate (1.05 mL, 10.7 mmol). The reaction was stirred at room temperature for 2 hours and then at 50° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 50% ethyl acetate in heptanes) to yield 0.75 g (38%) of 1-(3-chlorophenyl)butane-1,3-dione. LCMS (ESI) m+H=197.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](Cl)=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)=[O:25])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: Cc1noc(C)c1Cn1cnc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cnc(NC(=O)c2ccc3c(c2)OCO3)c1
Yield: 16.5 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-amine (example 10-40a) (110 mg, 0.57 mmol), benzo[d][1,3]dioxole-5-carbonyl chloride (105 mg, 0.57 mmol), and triethylamine (90 μL, 0.69 mmol) in dichloromethane was stirred for 16 hours. The reaction was diluted with dichloromethane (30 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated by rotary evaporation. The crude product was purified by reverse phase HPLC (Solvent system:acetonitrile/water, 10% to 100% gradient, 25 minute run) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)benzo[d][1,3]dioxole-5-carboxamide as a white crystalline solid (32 mg, 15% yield). MS M+H calculated 341.3. found 341.3. 1H NMR (400 MHz, DMSO-d6): δ 2.08 (s, 3H), 2.41 (s, 3H), 5.02 (s, 2H), 6.07 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.54 (m, 3H), 10.6 (s, 1H). The compound had an IC50 on hT2R8 bitter receptor of 12.1 μM.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[ClH:44]>CN(C)C=O>[O:20]1[CH2:21][CH2:22][N:17]([C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:18][CH2:19]1.[ClH:44]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(C1CCNCC1)N1CCOCC1

Procedure:
A mixture comprising N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (700 mg), morpholine (319 μL), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (702 mg), 1-hydroxybenzotriazole (495 mg) and N,N-dimethylformamide (9 ml) was stirred at room temperature for 16 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 4-(morpholinocarbonyl)piperidine•hydrochloride.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[K+].[CH3:6][O:7][C:8]([C@H:10]1[CH2:13][C@@H:12]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11]1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C@H:10]1[CH2:11][C@H:12]([O:14][C:1](=[O:3])[CH3:2])[CH2:13]1)=[O:9]
Reactant: CC(=O)[O-]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OC(C)=O)C1
Temperature: 120 °C

Procedure:
A mixture of potassium acetate (16.9 g, 172 mmol) and cis-3-(toluene-4-sulfonyloxy)-cyclobutanecarboxylic acid methyl ester (9.8 g, 34 mmol; trans/cis=1:5) in dry DMF (50 mL) was heated to 120° C. for 21 h. DMF was partially distilled off (≈30 mL), water was added, and the mixture was extracted with EtOAc (6×50 mL). The combined organic layers were washed with water (2×), brine, dried over MgSO4, filtered and concentrated to give the title compound as brown oil, trans/cis=5:1 based on 1H NMR. The material thus obtained was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]O)[N:9]=1)[C:2]#[CH:3].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][CH2:10][C:8]1[N:9]=[C:5]([O:4][CH2:1][C:2]#[CH:3])[S:6][CH:7]=1
Reactant: C#CCOc1nc(CO)cs1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C#CCOc1nc(CCl)cs1
Temperature: 25 °C
Yield: 135.3 %

Procedure:
0.20 g of [2-(2-propynyloxy)-thiazol-4-yl]methanol was dissolved in 5 ml of chloroform, and 0.2 g of thionyl chloride was added. The mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain 0.30 g of 4-(chloromethyl)-2-(2-propynyloxy)-thiazole.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=O)[CH2:4][CH3:5].[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:11]1([C@H:10]([NH:17][C@H:3]([CH2:4][CH3:5])[C:2]([CH3:8])([CH3:7])[CH3:1])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCC(=O)C(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC[C@@H](N[C@H](C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
To a cooled solution (0°) of 4,4-dimethyl-3-pentanone (106 g, 0.928 mol) and (R)-α-methylbenzylamine (111 g, 0.916 mol) in benzene (1 L), a solution of TiCl4 (50.5 mL, 0.461 mol) in benzene (200 mL) was added at a rate that kept the temperature of the mixture below 10°. Thereafter, the mixture was stirred mechanically for 3 h at 40°, cooled to room temperature (20°-22°) and filtered through diatomaceous earth. The diatomaceous earth was washed with Et2O. The combined filtrate and wash was concentrated. The residue was dissolved in dry MeOH (2 L). The solution was cooled to 0° and NaBH4 (20 g, 0.53 mol) was added portionwise while maintaining the temperature of the mixture below 5°. The methanol was evaporated. The residue was dissolved in Et2O. The solution was washed with brine, dried (MgSO4) and concentrated to give a reddish oil (a 18:1 mixture of diastereoisomers as indicated by NMR). The oil was purified by flash chromatography (SiO2, eluent: EtOAc/hexane, 7:93) to afford N-(1(R)-phenylethyl)-1(R)-ethyl-2,2-dimethylpropylamine as a liquid (110 g, 54% yield). This material was dissolved in hexane (1.5 L). 1N HCl in E2O (550 mL) was added to the solution over a period of 15 min. The resulting white solid was collected on a filter and then washed with hexane to provide N-(1(R)-phenylethyl)-1(R)-ethyl-2,2-dimethylpropylamine hydrochloride (125 g, 97% yield). 1H NMR(CDCl3) δ7.79-7.74 (m, 2H), 7.48-7.30 (m, 3H), 4.49-4.31 (m, 1H), 2.44-2.36 (m, 1H), 2.23 (d, J=6.5 Hz, 3H), 1.95-1.54 (m, 2H), 1.14 (s, 9H), 0.55 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C@@:24]12(O)[N:31](C)[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=C2.[Na].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][C@@:9]12[N:31]([CH3:24])[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=[CH:10]2)=[O:7]
Reactant: CCOC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1)CC2

Procedure:
4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. The residue remaining is mixed with diethylether/petroleum ether (1:9), suction filtered and washed. Yield: 2.50 g (46% of theory); TLC: Rf value: 0.29 (eluent: sec-butanol/formic acid/water (75:15:10)); melting point: 147° C.-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[N:6]([CH:9]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=3[CH:3]=2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (100 mg, 324 μmol) in dichloromethane (6 mL) was added triethylamine (100 μL, 710 μmol) and 4-nitrobenzoyl chloride (132 mg, 712 μmol). The solution was stirred at room temperature for 96 hours, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.92 min, MH+ 459].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][C:11]2=[O:21])[CH2:9][CH2:8]1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:27]1([O:33][CH2:2][C:3]2[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=2)[CH2:6][N:7]2[CH2:23][CH2:22][C:10]3([N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][NH:12][C:11]3=[O:21])[CH2:9][CH2:8]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc(CCl)c1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc(COc3ccccc3)c1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-(3-chloromethyl-benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4one, prepared as in Example 8 above, (203 mg, 0.500 mmol), phenol (56.8 mg, 0.603 mmol), KI (83.1 mg, 0.500 mmol) and K2CO3 (174 mg, 1.26 mmol) in DMF was stirred at room temperature for 1 day. The reaction mixture was diluted with H2O and a white solid precipitated. The solid was collected by filtration, washed with H2O and dried under house vacuum. The crude product was initially purified by flash chromatography (5% MeOH in CHCl3) and by tapered prep TLC (5% MeOH in CHCl3) to yield the title product as a white amorphous solid.
Reaction SMILES: [CH2:1](N1CCC(=O)CC1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].CI>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH3:1])[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CI
Product: CC1N(C)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=500.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and methyl iodide.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].FC(F)(F)S(O[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1[CH3:28])(=O)=O>CN(C=O)C.O>[CH3:24][C:23]1[CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=[C:19]([CH3:28])[C:18]=1[N:6]1[CH:7]=[C:3]([C:2]([F:9])([F:8])[F:1])[N:4]=[CH:5]1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a 0° C. solution of 4-(trifluoromethyl)-1H-imidazole (1.82 g, 13.4 mmol) in DMF (20 mL) was added sodium hydride (0.81 g, 20.1 mmol). The mixture was stirred at room temperature for 1 h. The crude 2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate prepared above (4.0 g, 13.4 mmol) was added. The mixture was stirred at 80° C. for 12 h. The reaction was diluted with water and extracted with ethyl acetate (30 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 1-(2,6-dimethyl-4-nitrophenyl)-4-(trifluoromethyl)-1H-imidazole (805 mg, 21%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 2H), 7.47 (s, 1H), 7.23 (s, 1H), 2.11 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)[OH:19])[OH:17])[OH:15])[OH:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(O[C:35](=[O:37])[CH3:36])(=O)C.C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:19][C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=1)[O:13][C:35](=[O:37])[CH3:36])[O:15][C:12](=[O:13])[CH3:11])[O:17][C:7](=[O:10])[CH3:6])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=1)(=[O:2])[CH3:4]
Reactant: O=C(O)c1ccc(OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)COc2ccc(C(=O)O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]([C@H](OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O
Temperature: 0 °C

Procedure:
2.10 g of 1,6-bis-O-(4-carboxy-phenyl)-D-mannitol were stirred at room temperature for 20 hours in 30 ml of pyridine with 5.1 ml of acetic anhydride. The reaction mixture was worked up extractively with ice-water and methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from methanol and methylene chloride. There was obtained 2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4-carboxy-phenyl)-D-mannitol, MS: m/z 589 ([M-H]-).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[OH-].[Na+].O1CCOCC1>O>[F:3][CH:2]([O:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][CH:9]=1)[F:4]
Reactant: FC(F)Cl
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(OC(F)F)c1
Temperature: 68 °C
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
260 parts by weight of chlorodifluoromethane are passed over 10 hours, whilst stirring, into a mixture of 221 parts by weight of m-cresol, 412 parts by weight of sodium hydroxide, 600 parts by volume of 1,4-dioxane and 500 parts by volume of water, at 67°-70° C. After stirring for 45 minutes at 68° C., the reaction mixture is cooled, diluted with 1,000 parts by volume of water and extracted four times with 200 parts by volume of diethyl ether. After drying, concentrating under reduced pressure and distilling, 209 parts by weight (yield: 64.5% of theory) of 3-tolyl difluoromethyl ether of boiling point 64°-67° C./24.7 mbar are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1([C:34]([CH:36]2[CH2:40][CH2:39][NH:38][CH2:37]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:38]2[CH2:39][CH2:40][CH:36]([C:34]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[O:35])[CH2:37]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CCNC1)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (105 mg, 0.28 mmol) and pyrrolidin-1-yl-1-pyrrolidin-3-ylmethanone (60 mg, 0.36 mmol) in DCE (6 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 70:30) to afford 364 as a white solid (110 mg, 74%). LCMS (Method G): RT=6.10 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.08 (m, 1 H); 7.70 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 3.93 (s, 2 H); 3.92-3.81 (m, 7 H); 3.50-3.38 (m, 4 H); 3.19-3.08 (m, 1 H); 2.99 (m, 1 H); 2.94 (s, 3 H); 2.86 (m, 2 H); 2.70 (m, 1 H); 2.12 (m, 2 H); 2.02-1.90 (m, 2 H) and 1.91-1.81 (m, 2 H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:8]([NH:10][C:11](=[O:19])[CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=1)([O-])=O>CCO.O1CCOCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:8]([NH:10][C:11](=[O:19])[CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CN1CCCCC1
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N)cc1NC(=O)CN1CCCCC1

Procedure:
N-(5-Nitro-2-tert-butylpheny)-2-piperidin-1-yl-acetamide (1.77 g, 5.5 mmol) was dissolved in EtOH (100 mL) and 1,4-dioxane (10 mL). The solution was degassed under vacuum with stirring. A catalytic amount of 5% Pd/C was added (as a slurry in EtOH). The mixture was degassed again, then the reaction vessel was charged with H2 gas (balloon) and stirred overnight at RT. The reaction was filtered through Celite® with MeOH and the filtrate was concentrated under reduced pressure. The recovered material was eluted through a column of silica gel with a 5 to 40% (90:10:1 CH2Cl2:MeOH:NH4OH(aq)) to CH2Cl2 linear gradient giving a brown foamy solid. MS: 290 (M+1). Calc'd. for C17H27N3O—289.42.
Reaction SMILES: CN(C)C1C=CC=CC=1.[F:10][C:11]([F:20])([F:19])[C:12]1[N:17]=[C:16](O)[CH:15]=[CH:14][N:13]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:11]([F:20])([F:19])[F:10])[N:17]=1
Reactant: Oc1ccnc(C(F)(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: FC(F)(F)c1nccc(Cl)n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylaniline (6.06 mmol. 2.3 eq.) was added dropwise to a stirring solution of 2-(trifluoromethyl)pyrimidin-4-ol (2.72 mmol, 1 eq.) in POCl3 (4 ml) and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was concentrated and the brown liquid was diluted with cold water (50 ml) and rendered basic with saturated sodium carbonate solution (50 ml). The mixture was extracted with methylene chloride (3×100 ml) and the combined organic phases were washed with water (2×50 ml) and sat. NaCl solution (50 ml) and dried over sodium sulfate. After concentration on a rotary evaporator, a blue liquid remained, which was employed in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10]>CCOC(C)=O>[C:9]([O:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: Cc1cccc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccccn1

Procedure:
A solution of the 2-methyl pyridine N-oxide (1.0 mmol) in acetic anhydride (5 mmol) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSO4), evaporation and purification by preparative TLC or flash chromatography afforded the 2-(acetoxymethyl)pyridine.