Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C2C(=CC=CC=2)C=CC=1.[CH:12]1[C:21]2[C:22]3[CH:31]=[CH:30][C:29]4C(OC(=O)[C:27]5[C:28]=4[C:23]=3[C:24](=[CH:25][CH:26]=5)[C:19]3[C:20]=2[C:15]2[C:16](C(OC(=O)[C:14]=2[CH:13]=1)=O)=[CH:17][CH:18]=3)=O.[C:42]1([NH2:49])[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH2:48].[OH-].[Na+]>CO.O>[CH:25]1[C:24]2=[C:23]3[C:22]([C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=5)[CH:14]=[CH:13][CH:12]=4)=[CH:31][CH:30]=[CH:29][C:28]3=[CH:27][CH:26]=1.[N:48]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[NH:49][CH:2]=1
Reactant: Clc1cccc2ccccc12
Reactant: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Product: c1ccc2[nH]cnc2c1
Reaction time: 6 h

Procedure:
78.7 Parts of 1-chloronaphthalene, 4.3 parts of perylene-3,4:9,10-tetracarboxylic dianhydride and 11.9 parts of o-phenylenediamine were charged in a stainless steel reactor equipped with a pitched blade turbine agitator, a circulation jacket connected to an oil supply system, a temperature measuring element and a distillation line with a condenser. After the aforementioned raw materials were charged and the agitator speed adjusted to 200 rpm, the reactor was purged with nitrogen gas, and the reactor contents were heated by raising the temperature of the jacket in about one hour to the desired reaction temperature of 240° to 245° C. The reaction was continued for an additional 6 hours at this temperature. The reactor was then cooled by cooling the jacket oil with water to about 90° C. and the reactor contents were then transferred to a Nutsche vacuum filter equipped with an agitator. The filtrate was drained by applying vacuum to the filter. The crude, wet pigment cake was reslurry washed twice using 80 parts of warm dimethylformamide, with the wash filtrate drained each time by vacuum filtration. The cake was subsequently reslurry washed nine times with alkaline methanol at room temperature to, for example, remove acidic impurities. Each alkaline methanol wash was prepared by dissolving 0.33 part of sodium hydroxide in 66 parts of methanol. The pigment cake was then reslurry washed four times with methanol (66 parts of methanol used in each wash) and dried in a vacuum dryer at 65° C. and full vacuum for 16 hours. 5.89 Parts of crude benzimidazole perylene powder were obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10]F>C(#N)C>[CH3:1][CH:2]([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: FF
Reactant: CCOC(=O)C(=O)CC
Solvent: CC#N
Product: CCOC(=O)C(=O)C(C)F

Procedure:
In the same manner as in Example 1, ethyl 3-methylpyruvate (1.0 g; 8.62 mmol) is dissolved in acetonitrile (22.5 g) and reacted with fluorine. By distilling off the solvent under reduced pressure, there is obtained a crude product, which is rectified to give ethyl 3-methyl-3-fluoropyruvate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=O)=O.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1OB(O)O.C(N(CC)CC)C.O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9][N:8]=1
Reactant: OB(O)Oc1c(F)cc(F)cc1F
Reactant: COC(=O)c1ccc2ccnc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2ccnc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (250 mg), 2,4,6-trifluorophenylboric acid (184 mg), tetrakis(triphenylphosphine)palladium (22 mg), triethylamine (189 mg), and 1,4-dioxane (15 mL) was heated under stirring in an oil bath at 95° C. for 18 hours. The reaction mixture was returned to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (228 mg).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].O>C(Cl)Cl>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[N:3][N:2]([CH3:1])[C:24]([O:26][CH3:27])=[O:25])[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:10][CH:9]=1
Reactant: CNN=C(c1ccc(Cl)cc1)C(C)(C)C
Reactant: COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(C)N=C(c1ccc(Cl)cc1)C(C)(C)C
Reaction time: 1 h

Procedure:
3 g (0.013 mol) of 4-chlorophenyl tert.-butyl ketone N-methylhydrazone was dissolved in 30 ml methylene chloride and treated with 1.5 g triethylamine (0.014 mol). Then, at 0° C., 1.33 g (0.014 mol) methyl chloroformate was added dropwise and the mixture stirred for one hour. The reaction mixture was then treated with water and methylene chloride and the organic phase dried and concentrated. After thin layer chromatography, there was obtained methyl 3-[1-(4-chlorophenyl)-2,2-dimethylpropylidene]-2-methylcarbazate, m.p. 58°-60° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].CO>ClCCl>[C:22]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@@H:10]1[CH3:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CN(Cc2ccccc2)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCN(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (S)-1-benzyl-3-methylpiperazine (588 mg) and triethylamine (0.47 ml) in dichloromethane (5 ml) was added acetic anhydride (0.32 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 4 hours. Methanol was added to this solution and evaporated. The residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography eluting with a mixture of ethyl acetate and n-hexane (2:1) to give (S)-1-acetyl-4-benzyl-2-methylpiperazine (660 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[C:10]1([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][NH2:26])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C(O)(=O)C>[C:10]1([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][N:26]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:2])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNc1nc2ccccc2n1-c1ccccc1
Reactant: CC(=O)c1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2n1-c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-acetyl pyridine (1.00 g, 8.26 mmol) and 1-phenyl-2-hydrazinobenzimidazole (1.85 g, 8.26 mmol) in 20 ml of methanol is stirred at room temperature for 2 days after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 1.35 g (50% of theory).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][Cl:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14].Cl>>[ClH:9].[ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1nc[nH]c1CCl
Agent: Cl
Product: Cc1nc[nH]c1CSCCN
Reaction time: 7 h
Yield: 98 %

Procedure:
84 parts of 4-methyl-5-chloromethyl-imidazole hydrochloride, in the form of a fine powder, and 57 parts of cysteamine hydrochloride, also in the form of a fine powder, are mixed intimately and the mixture is heated in a solidstate reactor for 2 hours at 80° and then for 7 hours at 100°; the progress of the reaction can be followed by NMR spectroscopy or from the evolution of hydrogen chloride. 120 parts (98%) of 4-methyl-5-[(2-amino-ethyl)-thiomethyl]-imidazole dihydrochloride are obtained; the substance melts at 186°-189° C., after first sintering at about 181° C. A single recrystallization of the product from ethanol raises the melting point to 193°-195° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCc2sccc2C(O)C1
Product: CN1CCc2sccc2C(Oc2ccc(Cl)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.O>CN(C=O)C>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:12]([NH:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:13])[CH2:17][CH2:18]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@H](O)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-adamantyl isocyanate (10 g, 56.4 mmol) and trans-4-aminocyclohexanol hydrochloride (10.3 g, 67.7 mmol) in DMF (300 mL) was added triethylamine (6.9 g, 67.7 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction mixture was poured into water, and the resulting precipitates were collected and washed with water. The crude product was recrystallized from methanol/water. Yield: 15.5 g (94% of theory). M.P.: 254° C. 1H NMR (300 MHz, DMSO-d6): δ 5.48 (d. J=9 Hz, 1H), 5.38 (s, 1H), 4.48 (d, J=4.7 Hz, 1H), 3.42-3.28 (m, 1H), 3.28-3.13 (m, 1H), 2.02-1.93 (m, 3H), 1.87-1.68 (m, 9H), 1.63-1.54 (m, 7H), 1.24-0.93 (4H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:9][CH:10]=1)=[N+]=[N-].C(OCC)(=O)C.C(O)C.[H][H]>[C].[Pd].ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[C:8]2[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Yield: 38.7 %

Procedure:
Under an argon atmosphere, 5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine (77 mg, 0.177 mmol), palladium carbon (14 mg), and ethyl acetate (2 ml) were added to ethanol (10 ml). The resulting mixture was stirred for 50 minutes in a hydrogen atmosphere of 1 atmospheric pressure. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. A fraction obtained from the dichloromethane:methanol=10:1 eluate was concentrated under reduced pressure to give the title compound (28 mg, 0.0685 mmol, 39%) as a white powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([CH3:21])=[CH:9][C:10](=[O:20])[N:11]3[CH2:14][CH:15]3OCC[O:16]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([CH3:21])=[CH:9][C:10](=[O:20])[N:11]3[CH2:14][CH:15]=[O:16])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(C3CC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2cc(C3CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.10 g of 7-cyclopropyl-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one, 3 mL of an 80% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 1 hour, and then stood still at room temperature for 13 hours. Thereto were added 3 mL of ethyl acetate and 4 mL of water, and the mixture was neutralized with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 59 mg of a light brown oily substance, (7-cyclopropyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccn1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccn1)C2
Yield: 95.2 %

Procedure:
A mixture of 4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.28 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.41 ml), water (0.41 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 75) (0.37 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-:22].[Na+].[CH3:24]O>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:22][CH3:24])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: CCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Yield: 73 %

Procedure:
To 6-amino-9-benzyl-8-bromo-2-ethoxypurine (35 mg, 0.101 mmol) in 5 ml of methanol was added 10N aqueous sodium hydroxide (50 ml) and the solution was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent the residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (22 mg, yield 73%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)[CH:11]=[CH:12][CH:13]=1.I[CH2:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C.[ClH:42]>C(#N)C.CO>[ClH:42].[CH3:34][NH:33][CH2:32][CH2:31][CH2:30][O:7][C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCCI)C(=O)OC(C)(C)C
Reactant: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: CNCCCOc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Dry dichloromethane (40 ml), triphenylphosphine (3.28 g), imidazole (1.05 g) and iodine (3.85 g) were combined in that order. A solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (1.90 g, J. Org. Chem., 1988, 53(10), 2229) in dichloromethane (10 ml) was added and the resulting reaction mixture stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen sulphite (6 g in 100 ml of water) was then added and the organic layer separated. The latter was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with iso-hexane:ether (7:3) to give tert-butyl N-(3-iodopropyl)-N-methylcarbamate (2.54 g) which was used immediately. Caesium carbonate (0.655 g) was added to a suspension of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.453 g, Example 26) in acetonitrile (35 ml) and the mixture heated at 100° C. for 10 minutes. After cooling to room temperature a solution of tert-butyl N-(3-iodopropyl)-N-methylcarbamate (0.600 g) in acetonitrile (5 ml) was added and the reaction heated at reflux for 90 minutes. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give a solid that was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (15 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a gum that was scratched under ether:hexane (1:1) (20 ml) to give the title compound as a pale yellow powder (0.477 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: BrCc1ccccc1
Reactant: O=C1CCOc2cc(O)c(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCOc2cc(OCc3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 6-fluoro-7-hydroxychroman-4-one (the compound of Preparation 29, 0.93 g, 5.11 mmol), benzyl bromide (0.61 mL, 5.13 mmol), potassium carbonate (1.41 g, 10.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The mixture was cooled, filtered, and concentrated to a yellow solid. This residue was recrystallized from ethyl acetate/ether to give 1.02 g (73%) of 6-fluoro-7-benzyloxychroman-4-one in two crops as cream white crystals which had: mp 155-156° C.; NMR δ7.58 (d, J=11 Hz, 1 H), 7.46-7.33 (m, 5 H), 6.54 (d, J=6.7 Hz, 1 H), 5.16 (d, 2 H), 4.50 (t, J=6.4 Hz, 2 H), 2.75 (t, J=6.4 Hz, 2 H). Analysis calculated for C16H13FO2: C, 70.58; H, 4.81. Found: C, 70.45; H, 4.80.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)C(C)C)(C)C.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.C(OCC)(=O)C>[CH:22]1([NH:28][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(CO)ccc1NC1CCCCC1

Procedure:
A mixture of (4-Fluoro-3-nitrophenyl)methanol (1.00 g, 0.0058 mol), N,N-diisopropylethylamine (2.036 mL, 0.0117) and cyclohexanamine (2.005 mL, 0.0175 mol) in N,N-Dimethylformamide (2.46 mL) was placed in a microwave vial, the contents were mixed thoroughly then microwaved at 130° C. for 7 minutes. The resultant gel was dissolved in ethyl acetate then washed with 5% citric acid, brine, dried and concentrated to give the title compound.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1.ClCCl>[CH3:36][S:37]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (433 mg, 1 mmol) in pyridine (15 ml) and dichloromethane (15 ml) was treated with triethylarnine (353 mg, 3.5 mmol) and stirred for 30 minutes at ambient temperature. Methanesulfonyl chloride (138 mg, 1.2 mmol) was added and the mixture stirred for 18 hours. The mixture was diluted with dichloromethane (50 ml), washed with water (2×25 ml), saturated brine (25 ml), and dried (magnesium sulfate). After evaporation to dryness and azeotroping with toluene (10 ml), the residue was triturated with diethyl ether to give the desired product (365 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([OH:18])=O.[Li+].[Cl-:20].S(Cl)([Cl:23])=O>>[Cl:20][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([Cl:23])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: [Cl-]
Reactant: O=C(O)c1nc(-c2ccccc2)sc1CCCO
Agent: [Li+]
Product: O=C(Cl)c1nc(-c2ccccc2)sc1CCCCl
Yield: 99 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-2-phenylthiazole-4-carboxylic acid (850 mg, 3.2 mmol) and LiCl (3.2 mmol) in thionyl chloride (10 mL) was heated at reflux for 16 h then concentrated to dryness. The crude product was dissolved in EtOAc, washed with brine, dried (MgSO4), and concentrated under reduced pressure to give 5-(3-chloropropyl)-2-phenylthiazole-4-carbonyl chloride (906 mg, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](C(OC(C)(C)C)=O)[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[NH:14][C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[O:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)OC[C@H]1c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC[C@@H](c2cc(F)cc(F)c2)NC1=O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholine-4-carboxylate from Step F (225 mg, 0.66 mmol) in CH2Cl2 (3 mL) at ambient temperature was added TFA (0.49 mL, 6.6 mmol). After stirring for 1 h, the reaction mixture was concentrated in vacuo to give the title compound. MS: m/z=242 (M+1).