Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14][O:15][CH:16](Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[C:4]([CH3:13])=[C:5]([CH3:12])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:3]=[O:2]
Reactant: COC(Cl)Cl
Reactant: COc1cc(C)c(OC)c(C)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C=O)c1C

Procedure:
1,4-Dimethoxy-2,3,5-trimethylbenzene, 9.00 g (50 mmole), was dissolved in CH2Cl2 (60 ml) and stirred with ice-cooling. After addition of 14.4 g (50×2.5 mmole) of dichloromethyl methyl ether, 13.8 ml (50×2.5 mmole) of titanium tetrachloride dissolved in CH2Cl2 (30 ml) was added dropwise over 15 minutes. After stirring for further 15 minutes with ice-cooling, the ice bath was removed and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into crashed ice (about 200 g) and stirred vigorously for 30 minutes. The CH2Cl2 layer was washed with water (3 times), and dried (MgSO4), from which CH2Cl2 was evaporated off. The residue was recrystallized from isopropyl ether/hexane (1:1), to give 6.18 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was concentrated, and the residue was purified with silica gel (60 g) column chromatography (eluted with isopropyl ether), to give 3.70 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. Yield 9.88 g (95%), m.p. 85°-86° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC(=O)Cl
Reactant: Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (3.5 g, 28 mmol) was added dropwise to a solution of 2-chloro-N4-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}quinoline-3,4-diamine (9.0 g, 23.5 mmol) and anhydrous triethylamine (10.0 mL, 35.3 mmol) in anhydrous dichloromethane (75 mL) at 6° C. After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (2.0 g) was added. After the reaction was stirred for another 30 minutes, it was still incomplete, and additional ethoxyacetyl chloride (2.0 g) was added. The stirring was continued for an additional 30 minutes, and the work-up procedure described in Part A of Example 19 was followed to provide 11.12 g of N-[2-chloro-4-({2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}amino)quinolin-3-yl]-2-ethoxyacetamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9]OS(C)(=O)=O)=[O:4].[CH3:23][S-:24].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9][S:24][CH3:23])=[O:4]
Reactant: C[S-]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCSC
Reaction time: 4.75 h
Yield: 79 %

Procedure:
A solution of 1-tert-butoxycarbonylamino-2-(2-methanesulfonyloxyethyl)cyclopropanecarboxylic acid methyl ester (0.52 g, 1.53 mmol) in 5 mL MeOH was added dropwise to a rt solution of sodium thiomethoxide in 3 mL MeOH. After 4.75 h, the solvent was removed in vacuo and the residue was taken up in EtOAc and H2O (15 mL each). The aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, 1-tert-butoxycarbonylamino-2-(2-methylsulfanylethyl)cyclopropanecarboxylic acid methyl ester (0.350 g, 79%) was obtained as a colorless oil that was used without further purification. LCMS found 312.0 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])(O)=O.[Na+]>O1CCCC1>[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: C1CCONC1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNc1nc(NCCC)nc(N2CCCCO2)n1
Temperature: 100 °C
Yield: 89 %

Procedure:
An ACE® pressure tube was charged with 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.50 g, 6.53 mmol), N-ethyldiisopropylamine (19.59 mmol), 1,2-oxazinane hydrochloride (1.61 g, 13.06 mmol) and tetrahydrofuran. The reaction mixture was heated at 100° C. for 2 h, then cooled and poured into saturated NaHCO3 solution (50 mL). The suspension was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield 6-[1,2]oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII) (1.63 g, 89%). ESI-MS (m/z): 281 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[CH:17]1([C:22](=O)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH:17]1([C:22]2[C:23]([C:24]#[N:25])=[C:10]([OH:9])[C:5]3[C:6](=[CH:13][CH:14]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Reactant: N#CCC(=O)C1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
A mixture of 6-trifluoromethyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.5 g, 4.22 mmol), 3-cyclopentyl-3-oxopropanenitrile (579 mg, 4.22 mmol), triethylamine (5.98 g, 8.23 ml, 59.1 mmol) and DMF (638 μl) was stirred for 72 h at room temperature. 1N HCl was added and the reaction mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated in EtOAc (8 ml) for 3 h. The solid was filtrated off and washed two times with EtOAc to afford the title compound (421 mg, 24%) as white solid. MS (ESI): 307.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C.[Na]>[CH2:15]([O:14][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)[CH3:16]
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=S)c1cnc(C)nc1OCC
Temperature: 0 °C
Yield: 283 %

Procedure:
An ice-cooled suspension of 50 g (215 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 300 ml of ethanol was treated dropwise with a solution of sodium ethoxide (prepared from 5.1 g (222 mg.atom) of sodium and 300 ml of ethanol). After 1 hour the mixture was evaporated and the residue partitioned between 400 ml of dichloromethane and 400 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 48 g (92%) of ethyl 4-ethoxy-2-methylthiopyrimidine-5-carboxylate as a colorless oil. [Mass spectrum (ESI) MH+ =243].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Yield: 83 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, step 2) (300 mg, 1.18 mmol), aniline (0.12 ml, 1.3 mmol) and p-toluenesulfonic acid (25 mg) in toluene (50 ml) was heated to reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude brownish solid (420 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole (305 mg, 83%) as a white solid: mp (DSC) 148° C. Anal Calc'd. for C18H17NSO2 : C, 69.43; H, 5.50; N, 4.50; S, 10.30. Found: C, 69.18; H, 5.42; N, 4.42; S, 10.06.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH:16]=O)[CH:11]=[C:12]([F:14])[CH:13]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:16]=[C:15]([C:10]2[CH:11]=[C:12]([F:14])[CH:13]=[C:8]([Cl:7])[CH:9]=2)[N:4]=1
Reactant: CSC(=N)NN
Reactant: O=CC(=O)c1cc(F)cc(Cl)c1
Product: CSc1nncc(-c2cc(F)cc(Cl)c2)n1
Yield: 38.6 %

Procedure:
3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 38.4%) was prepared from methyl hydrazinecarbimidothioate (25.5 g, 243 mmol) and 2-(3-chloro-5-fluorophenyl)-2-oxoacetaldehyde (30 g, 162 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]([O:12][CH2:13]C)=[O:11])=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:13][O:12][C:10]([C:4]1[C:3]([CH2:2][O:16][CH3:15])=[CH:8][CH:7]=[C:6]([Cl:9])[CH:5]=1)=[O:11]
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(Cl)cc1C(=O)OC

Procedure:
Ethyl α-Bromo-4-chloro-o-toluate (26.4 g.) is added to a solution (10°) of sodium methoxide (5.4 g.) in 110 ml. of methanol. When the addition is complete, the mixture is refluxed for two hours, then cooled and concentrated in vacuo. The oily residue is partioned between ether-water. The ether layer is separated and dried. Removal of the drying agent and concentration of the filtrate in vacuo leaves 17.3 g. of a white solid. A sample of the product recrystallized from methanol had mp 44°-45°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C:5](=[O:18])[C:6]#[C:7][C:8]([CH3:17])([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])[CH3:2].C1(C2C[S:31][C:30](=[S:33])[S:29]2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C:5]([C:6]1[S:31][C:30](=[S:29])[S:33][C:7]=1[C:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([CH3:17])[CH3:9])=[O:18])[CH3:2]
Reactant: S=C1SCC(c2ccccc2)S1
Reactant: CCOC(OCC)C(=O)C#CC(C)(C)OC1CCCCO1
Solvent: ClCCl
Product: CCOC(OCC)C(=O)c1sc(=S)sc1C(C)(C)OC1CCCCO1
Temperature: 130 °C

Procedure:
A mixture of 1,1-diethoxy-5-methyl-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-yn-2-one 3 (1.5 g, 5.0 mmol) and 4-phenyl-1,3-dithiolane-thione (5.3 g, 25.0 mmol) was heated under N2 at 130° C. for 1 hour. The reaction was monitored by thin layer chromatography using silica gel as the stationary phase and dichloromethane as the mobile phase. The color of the reaction mixture changed from yellow to dark orange. After completion of the reaction, as evidenced by TLC, the reaction was stopped, cooled, and the target compound 4 was purified by radial chromatography using silica gel as the stationary phase. The target compound 4 eluted as the third fraction with a mixture of dichloromethane and hexanes (60:40). The first band was the excess 4-phenyl-1,3-dithiolane-thione, and the second band yielded 2,2-diethoxy-1-(5-(2-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl)-2-thioxo-1,3-dithiol-4-yl)ethanone 5 which was further converted to 4-(diethoxymethyl)-4-hydroxy-6,6-dimethyl-4,6-dihydro-[1,3]dithiolo[4,5-c]furan-2-thione 4.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(#N)C>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][N:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc2c(s1)CCN=C2CCc1ccc(C(F)(F)F)cc1
Yield: 102.6 %

Procedure:
To a suspension of 762 mg (2.23 mmol) N-[2-(5-methyl-thiophen-2-yl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide in 10 mL acetonitrile was added 460 uL (4.91 mmol) POCl3. The mixture was heated to reflux for 1 h and the solvent was removed in vacuo. The residue was taken up in toluene and concentrated again in vacuo. The oil was dissolved in dichloromethane and was basified with sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. 740 mg of the title compound was isolated which was used without further purification in the consecutive step.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15]C=1C.S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>O>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:29]=1[C:28]([OH:31])=[O:30]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 53 %

Procedure:
[25] To a solution of sodium dichromate (3.87 g, 13 mmol) in acetic acid (20 mL) was added 2-fluoro-4-nitrotoluene (1.55 g, 10 mmol) in portions, followed by dropwise addition of concentrated sulfuric acid (10 g). A strong exotherm was observed (100° C.) and the color changed from orange to green. The reaction was heated at 90° C. for 1 hour and cooled to 25° C. The reaction mixture was dissolved in water (30 ml) and white crystals formed upon cooling at 0° C. The white solid was collected by filtration washed with cold water and dried to give 2-fluoro4-nitrobenzoic acid (0.99 g, 53%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[N+:2]=[N-:3].C1N=CN(C(N2C=NC=C2)=O)C=1.N#N.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCCCCC(=O)O
Reactant: NCc1ccccc1
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCCCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-azido-N-(phenylmethyl)heptanamide (65) was synthesized from 7-zidoheptanoic acid (64) as shown above. To 120 mg crude 7-azidoheptanoic acid (64) (0.7 mmol, 1.0 eq) was added 1 mL anhydrous THF. To the stirring solution was added 120 mg CDI (0.74 mmol, 1.06 eq) at room temperature. N2 was rapidly evolved from the yellowish slurry. The resulting transparent solution stirred at room temperature for 0.5 h. To the solution was then added 82.5 mg benzylamine (0.77 mmol, 1.1 eq). The solution was stirred 2 h at room temperature followed by solvent removal in vacuo and silica gel chromatography (2:2:1; petroleum ether:Et2O:EtOAc) to render 65 in as a waxy solid (108 mg, 60%). Lyophilization from 50% aqueous CH3CN afforded a fluffy white powder. m.p. slightly above ambient temperature.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[C:26]([CH3:32])=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=2[CH3:32])=[N:3][CH:4]=1
Reactant: Cc1c(O)cccc1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, dd, J=2.6, 0.7 Hz), 8.18–7.99 (4H, m), 7.44–7.34 (3H, m), 7.23 (1H, d, J=8.1 Hz), 7.02 (1H, d, J=8.1 Hz), 5.45–5.35 (1H, m), 3.90 (3H, s), 2.19 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]Br.[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(O)c1cccc(N)c1
Reactant: BrCc1ccc2ccccc2n1
Product: CCCCCC(O)c1cccc(NCc2ccc3ccccc3n2)c1

Procedure:
For compounds in which X is --NR2 --(CHR1)n --, the corresponding amino starting compounds are employed to form the desired amino coppound. Thus, 2-aminopyridine is condensed with 3-(1-hydroxyhexyl)benzyloromide to form 2-[3-(1-hydroxyhexyl)benzylamino]pyridine. Alternatively, 2-quinolylmethylbromide is condensed with 3-(1-hydroxyhexyl)aniline to form 2-[3-(1-hydoxyhexyl) anilinomethyl]quinoline.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH3:10][O:11]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:10]=[O:11])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCc1ccccc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(C=O)ccc1O

Procedure:
45.5 g of titanium tetrachloride was dropwise added, under stirring with ice, to a solution obtained by dissolving 14.64 g of 2-ethylphenol in 200 ml of dichloromethane. After the completion of the dropwise addition, 22.76 g of α,α-dichloromethyl methyl ether was dropwise added thereto. The ice bath was removed, and the reaction solution was stirred at room temperature for 2 hours. Then, the reaction solution was poured into a 10% hydrochloric acid aqueous solution, and the mixture was stirred for 2 hours. The reaction mixture was extracted with chloroform. The chloroform layer was washed with water, and then extracted with a 10% sodium hydoxide aqueous solution. The alkali extract layer was washed twice with chloroform, and then acidified to a pH of about 2 by gradually adding concentrated hydrochloric acid. Then, the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a dark reddish purple oily substance. This product was purified by silica gel column chromatography by using benzene-ethyl acetate (16 : 1, v/v) as the developer, whereby 6.90 g of the above identified compound was obtained as a pale red oily substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:37])([F:36])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=3)=[O:24])[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:37])([F:36])[C@:12]([C:15]2[N:16]=[C:17]([NH:22][C:23]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:27][N:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[F:21])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)C(F)(F)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F
Reaction time: 1 h

Procedure:
To a solution of ((R)-4-{6-[(3-chloro-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (180 mg, 0.317 mmol) in DCM (1.5 ml) was added TFA (0.5 ml) and the mixture was stirred at it for 1 h. The reaction mixture was poured on 10% aq. Na2CO3, more DCM was added and the layers were separated. The aq. phase was extracted with DCM (3×), the combined DCM phases were dried with K2CO3 and evaporated to provide the title compound as colorless solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[C:14]2[S:15][C:7]([CH2:6][N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=4)[CH2:25][CH2:24]3)=[CH:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: Oc1ccc(N2CCN(Cc3cc4ncc(C(F)(F)F)cc4s3)CC2)cc1
Reaction time: 72 h

Procedure:
The solution from Example 25C (2 mL) was treated with 4-(1-piperazinyl)phenol (178 mg) in DMSO (1 mL). After 72 hours, the mixture was concentrated under a stream of nitrogen gas and the residue recrystallized from DMSO:methanol (1:1) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.81 (4H, t, J=4.8 Hz), 3.18 (4H, J=4.8 Hz), 3.95 (s, 2H), 6.78 (2H, d, J=9 Hz), 6.90 (2H, J=9 Hz), 7.48 (1H, s), 8.38 (1H, m), 8.80 (1H, m). MS (DCI/NH3) m/z 394 (M+H)+. Anal. Calcd for C19H18N3F3OS: C, 56.72; H, 4.76; N, 10.44. Found: C, 56.43; H, 4.50; N, 10.35.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][C@@H:9]([OH:30])[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:16]3)[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][N:15]1[CH2:16][CH:17]2[O:19][CH:13]([CH2:12][N:11]([CH2:10][C@H:9]([OH:30])[CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][CH:31]=3)[CH2:18]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OC[C@@H](O)CN2CC3CN(CCN)CC(C2)O3)cc1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
tert-Butyl 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-di-azabicyclo[3.3.1]non-3-yl}ethylcarbamate (2.9 g, 6.56 mmol; see WO 01/28992) was dissolved in DCM (30 mL). Trifluoroacetic acid (22.2 g, 194.7 mmol) was added and the solution was stirred for 2 h. The mixture was concentrated under reduced pressure, redissolved in toluene and acetonitrile and concentrated in vacuo again. The product mixture was dissolved in acetonitrile (50 mL) and solid K2CO3 (9.7 g, 10.2 mmol) was added. The mixture was filtered and concentrated under reduced pressure. The mixture was then redissolved in a mixture of EtOAc and a saturated solution of NaHCO3. The mixture was extracted twice with DCM, the combined organic extracts dried (Na2SO4) and evaporated to afford 1.6 g (68.7%) of the title compound.