Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[Cl:22][C:23]1[C:28](O)=[CH:27][C:26]([C:30]2[C:34]([CH3:35])=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[N:31]=2)=[C:25]([F:39])[CH:24]=1>O1CCOCC1>[Cl:22][C:23]1[C:28]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:27][C:26]([C:30]2[C:34]([CH3:35])=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[N:31]=2)=[C:25]([F:39])[CH:24]=1
Reactant: CSc1c(C)c(-c2cc(O)c(Cl)cc2F)nn1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSc1c(C)c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)cc2F)nn1C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
65 ml (0.8 mol) of pyridine and then 80 ml (0.48 mol) of trifluoromethanesulfonic acid anhydride are added dropwise at 0-5° C. to a solution of 129 g (0.3 mol) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-(methylthio)-1-methyl-[1H]-pyrazole (approx. 70%) (Example P9) in 1.2 liters of 1,4-dioxane. After being stirred for 30 minutes at 0-5° C. and then at 22° C. overnight, the reaction mixture is concentrated to approximately 1/3 of its original volume by evaporation, poured into a mixture of ice, water and hydrochloric acid, extracted with MTBE, washed with water and concentrated by evaporation. After purification of the crude product by silica gel chromatography, 87.7 g (70% of the theoretical yield) of the desired compound are isolated in the form of crystals having a melting point of 54-56° C.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])(O)=[O:10].C([N:40](CC)CC)C.O.N>O1CCCC1.O>[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)=[O:26])(=[O:10])[NH2:40]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of isobutyl chloroformate (0.60 g) in tetrahydrofuran (1 ml) was dropwise added to a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.28 g) and triethylamine (0.82 ml) in tetrahydrofuran (13 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (10 ml) at 0°-5° C. and the solution was stirred at the same temperature for 1 hour. The mixture was poured into water (50 ml) and extracted with chloroform (50 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatogaraphy on silica gel (25 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.00 g).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[O:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>O.C1COCC1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[O:7][C:8]([CH3:9])=[C:4]([CH2:1][CH2:2][CH2:3][OH:27])[N:5]=2)=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: C=CCc1nc(-c2ccc(OC)cc2)oc1C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(CCCO)c(C)o2)cc1
Reaction time: 2 h

Procedure:
The above prepared 4-allyl-2-(4-methoxy-phenyl)-5-methyl-oxazole (4.51 g, 19.7 mmol) was dissolved in 60 ml of abs. THF and and treated at 0° with 100 ml of 9-BBN-solution (0.5 M hexane). Hydroboration was allowed to proceed for 2 h at RT. Afterwards, 56 ml of 3N NaOH and 114.5 ml of 30% H2O2 was added simultaneously, whereby the internal temperature rose to 45°. After 1 h, the heterogeneous mixture was diluted with ice and water, extracted twice with AcOEt, washed water, and dried over natrium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=1/3) yielded 4.54 g of the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][O:26][CH:27]1[CH2:30][CH:29]([C:31](O)=[O:32])[CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:31]([CH:29]3[CH2:30][CH:27]([O:26][CH3:25])[CH2:28]3)=[O:32])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: COC1CC(C(=O)O)C1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: COC1CC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(3-methoxy-cyclobutanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 3-methoxycyclobutanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light brown oil. MS m/e: 461.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:14]([CH3:31])=[C:13]([CH3:32])[N:12]=1>COCCOCCOC.C(OCC)(=O)C>[CH3:32][C:13]1[C:14]([CH3:31])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
Under a nitrogen atmosphere, diglyme (25 mL) was added to sodium hydride (1.81 g, 45.2 mmol), which is available as a 60% dispersion in mineral oil, and the mixture was cooled to 5° C. A solution of phenol (4.54 g, 48.2 mmol) in diglyme (50 mL) was added dropwise over a period of 15 minutes. The reaction became homogeneous after 15 minutes. A solution of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine (10.15 g, 30.14 mmol) was added, and the reaction was heated at 160° C. for 13 hours. An analysis by HPLC indicated the presence of starting material. Additional phenol (3.12 g, 33.2 mmol) was added to 60% sodium hydride (1.24 g, 31.1 mmol) in diglyme, and the mixture was stirred until it became homogeneous. This solution was added to the cooled reaction flask, and the reaction was heated at 160° C. for 9.5 hours. The reaction was allowed to cool to room temperature, and the volatiles were removed under reduced pressure to provide a black oil. The oil was dissolved in ethyl acetate, and the solution was washed with 1 N potassium hydroxide (3×) and brine (3×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 80:20 ethyl acetate:hexane) to provide 2.47 g of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine.
Reaction SMILES: [Cl:1][O-].[Na+].[CH2:4]([C:6]1[NH:7][C:8]([CH2:13][OH:14])=[C:9](CO)[N:10]=1)[CH3:5].C(=O)=O>O>[CH2:4]([C:6]1[NH:7][C:8]([CH2:13][OH:14])=[C:9]([Cl:1])[N:10]=1)[CH3:5]
Reactant: CCc1nc(CO)c(CO)[nH]1
Reactant: [O-]Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: CCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
11.5 Grams (15 mmol) of an aqueous solution containing 9.7% of sodium hypochlorite was dropwisely added to a solution consisting of 2.53 g (16.2 mmol) of the 2-ethyl-4,5-bis(hydroxymethyl) imidazole and 50 ml of water. After the dropwise addition has been finished, the mixture was stirred at room temperature for one hour, followed by neutralization by the addition of dry ice and further followed by evaporation to dryness under reduced pressure. The resulting solid was extracted with ethanol, the extract was evaporated under reduced pressure, and the resulting solid product was extracted with acetone. 1.48 Grams of the starting 2-ethyl-4,5-bis(hydroxymethyl) imidazole was recovered as an extraction residue, the extract was concentrated under reduced pressure, and was subjected to the column chromatography (silica gel-acetone) to obtain a 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.46 g (yield 43.0% with respect to the starting material consumed). The TLC and spectra were measured to be the same as those of Example 3.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[Br-].Br[C:54]1[CH:55]=[C:56]([NH:60][S:61]([CH:64]2[CH2:66][CH2:65]2)(=[O:63])=[O:62])[CH:57]=[N:58][CH:59]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([N:15]1[CH2:14][CH2:13][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:54]2[CH:55]=[C:56]([NH:60][S:61]([CH:64]4[CH2:66][CH2:65]4)(=[O:62])=[O:63])[CH:57]=[N:58][CH:59]=2)=[CH:3][CH:4]=3)[CH2:17][CH2:16]1)(=[O:19])=[O:20]
Reactant: COc1ccccc1S(=O)(=O)N1CCN(c2cnc3ccc(Br)cc3n2)CC1
Reactant: O=S(=O)(Nc1cncc(Br)c1)C1CC1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1S(=O)(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)C5CC5)c4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A slurry of 7-bromo-2-(4-{[2-(methyloxy)phenyl]sulfonyl}-1-piperazinyl)quinoxaline (0.96 mmol), bis(pinacolato)diboron (0.54 mmol), potassium acetate (1.16 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.05 mmol) in 1,4-dioxane (4 ml) was heated at 100° C. After the reaction stirred for 1 hour, a bromide such as N-(5-bromo-3-pyridinyl)cyclopropanesulfonamide (0.54 mmol) and 2M solution potassium carbonate (4 ml) was added and continued to stir for 1 hour. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (80% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (44 mg, 14% yield) as a pale yellow solid. MS(ES)+ m/e 581.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][N:10]([CH:17]([CH3:19])[CH3:18])[C:9]2=[O:20])=O)C.[Li+].[BH4-].[NH4+].[Cl-]>O1CCCC1>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([CH2:4][OH:3])=[CH:15][CH:14]=2)[C:9](=[O:20])[N:10]([CH:17]([CH3:19])[CH3:18])[N:11]=1
Reactant: CCOC(=O)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nc(Br)c2ccc(CO)cc2c1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
Bromo-3-isopropyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid ethyl ester (2.3 g, 6.8 mmol) was suspended in tetrahydrofuran (THF) (50 ml) and cooled to 0° C. To the suspension was added LiBH4 (5.1 ml of a 2M solution in THF, 10.2 mmol) dropwise, the suspension was allowed to warm to room temperature and stirred for 24 hours. After this time, LC-MS showed 50% starting material remained. To this was added LiBH4 (1.7 ml of a 2M solution in THF, 3.4 mmol) and the reaction mixture was stirred for a further 3 hours. The reaction was cooled to 0° C., saturated NH4Cl (40 ml) was added and the reaction mixture was then partitioned between water (50 ml) and dichloromethane (DCM) (150 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was then purified by flash column chromatography (elution: 50% toluene, 30% ethyl acetate, 20% DCM) to give the title compound (0.9 g, 43% yield) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:16]=1
Reactant: NC(N)=S
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Solvent: CCO
Product: Nc1nc(-c2ccc3c(c2)CCC(=O)N3)cs1
Reaction time: 0.5 h

Procedure:
6-(Chloroacetyl)-3,4-dihydrocarbostyril (7 g), thiourea (2.6 g) and absolute ethanol (250 ml) is stirred under reflux for two hours, cooled in an ice bath, filtered, and the filtered solid washed with ether and dried. The solid is suspended in aqueous sodium bicarbonate and stirred for 30 minutes, filtered, washed with isopropanol, dried and refluxed in methanol (300 ml) overnight. The resulting solid is filtered, suspended in boiling methanol (300 ml) and methane sulfonic acid (2.8 ml) added, resulting in the formation of a precipitate which is filtered, twice recrystallized from ethanol/DMF affording the desired product as the methane sulfonic acid salt, M.P. >250° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[N:36]=[CH:37][C:30]=12)[C:24]([O:26]C)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[CH3:46][C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[C:30]2[CH:37]=[N:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[C:31]=2[N:32]=[CH:33][N:34]=1)[C:24]([NH:53][C:50]1[CH:49]=[CH:48][C:47]([CH3:46])=[CH:52][N:51]=1)=[O:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:8])[CH3:2]
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(F)c2C)nc1

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE1 using (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AF4) and 5-methylpyridin-2-amine. 1H NMR (400 MHz, DMSO) d 0.88 (9H, s), 1.96 (3H, d), 2.24 (3H, s), 3.75 (4H, m), 4.08-4.02 (1H, m), 4.14 (1H, m), 5.99 (1H, m), 7.50-7.29 (9H, m), 7.63-7.54 (5H, m), 7.89 (1H, d), 8.17 (1H, s), 8.51 (1H, s), 8.55 (1H, s), 10.94 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH2:31][CH3:32]>>[CH2:31]([N:30]([CH3:29])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:32]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C20H23ClN6O2, 414.9
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11].FF.O.NC1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.C(Cl)(Cl)Cl.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[NH2:15]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(F)c1
Agent: [Fe]
Agent: FF
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(F)(F)C(F)F)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
6.97 Grams of 3-fluoro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene [i.e. the nitro compound (X) containing fluorine as the substituted X] was dissolved in a mixed solvent of 25 ml of ethyl acetate and 25 ml of acetic acid. The resulting solution was slowly added dropwise to a suspension of 9.0 g of iron powders in a mixed solution of 5 ml of acetic acid and 30 ml of water while maintaining the temperature at 40° C. Thereafter, stirring was continued for 30 minutes at 40° C. to 70° C. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and then with water, dried over anhydrous magnesium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with chloroform as an eluent to obtain 5.35 g of 3-fluoro-4-(1',1',2',2'-tetrafluoroethoxy)aniline [i.e. the aniline compound (IX) containing fluorine as the substituted X]. 1H-NMR (CDCl3): δ(ppm) 6.90-7.30(1H, m), 6.30-6.60(2H), 5.95(1H, tt, J=53, 3 Hz), 3.75(2H, broad)
Reaction SMILES: [C:1]([N:5]([CH2:9]Cl)[C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[S:14]>C1(C)C=CC=CC=1>[CH3:11][N:12]=[C:13]1[N:15]([CH3:16])[C:6](=[O:7])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][S:14]1
Reactant: CNC(=S)NC
Reactant: CC(C)(C)N(CCl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CN=C1SCN(C(C)(C)C)C(=O)N1C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
In 50 ml of toluene, were dissolved 3.7 g (0.02 mole) of N-t-butyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea. The solution was heated under reflux with stirring for one hour. After cooling, the precipitated crystals (m.p. >220° C. decomp.) were collected by filtration, washed with a small quantity of acetone, dissolved again in 100 ml of water, admixed with 10 ml of a 20% sodium hydroxide solution, and extracted with 50 ml of benzene. The benzene layer was dried and concentrated under reduced pressure to obtain 3.5 g (83% yield) of crystals melting at 51°-52° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]1)=[C:8]2[C:38]([OH:40])=O)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[F:50][C:51]([F:61])([F:60])[C@H:52]([NH2:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CO.CS(C)=O.CC#N.O.ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH2:28][CH2:27]1)=[C:8]2[C:38]([NH:59][C@H:52]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:51]([F:50])([F:60])[F:61])=[O:40])(=[O:3])=[O:4]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
6-(Methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (100 mg, 0.162 mmol), dichloromethane (1621 μL), DIEA (31.2 μL, 0.178 mmol), and [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (37.7 mg, 0.178 mmol) were combined in a round bottom flask. The mixture was cooled to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (145 μL, 0.243 mmol) (50% in EtOAc) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The next day 0.1 mL of water and 2 mL of CH3CN were added, and the solution was concentrated to afford a yellow residue. The residue was dissolved in MeOH/DMSO and purified by reverse phase HPLC to afford the title compound as a white solid (32 mg, 27%). MS (m/z) 735.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:33])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:16](CC4C=CC(OC)=CC=4)[N:15]=3)[N:11]=2)[C:7]=1[CH3:8]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:33])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:16][N:15]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: COc1ccc(Cn2nc(CCc3nc4c(Cl)cc(Cl)c(C)n4n3)nc2N2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cc(Cl)c2nc(CCc3n[nH]c(N4CCCC4)n3)nn12
Yield: 99.9 %

Procedure:
6,8-Dichloro-2-(2-(1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl)ethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (17 mg, 35.0 μmol, Eq: 1.00) in trifluoroacetic acid (539 μl) was heated 3 h under reflux. The product (12.8 mg, 100%) was obtained as a white solid by preparative HPLC. MS: m/z=366.2 (M+H+)
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH:15]([N:16]([CH3:18])[CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.N#N>CO.[Pd]>[CH3:17][N:16]([CH3:18])[CH:15]1[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][NH:8][CH2:14]2
Reactant: CN(C)C1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CN(C)C1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
3-benzyl-N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine (80 mg, 0.45 mmol) was dissolved in MeOH (10 ml) and the atmosphere was replaced with N2 (3×). 10% Pd/C (cat.) was added and the atmosphere was replaced with H2 (3×). The resulting reaction mixture was stirred at RT at balloon pressure overnight. When TLC showed no more UV active spot the Pd/C was filtered off (always keeping wet with MeOH) and the filtrate was concentrated which gave N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine (44 mg) in 87% yield. 1H NMR (400 MHz, MeOD) δ ppm 3.45 (d, J=12.13 Hz, 2H) 2.88 (dd, J=12.38, 2.78 Hz, 2H) 2.35 (d, J=2.02 Hz, 2H) 2.31-2.23 (m, 6H) 2.11 (t, J=4.80 Hz, 1H) 2.06-1.92 (m, 2H) 1.89-1.79 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Product: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Yield: 98 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-(4-benzyloxyphenyl)propanol was allowed to react with methanesulfonyl chloride to give 3-(4-benzyloxyphenyl)propyl methanesulfonate. The yield was 98%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 74-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[CH:5][CH:4]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(Nc2ncccc2C=O)cn1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(-c2ccc(OC)nc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
6.4 g (28 mmol) of 2-(6-methoxy-3-pyridinylamino)nicotinaldehyde was dissolved in ethanol (50 mL), and 6.7 g (42 mmol) of diethyl malonate and 0.95 g (11 mmol) of piperidine were added thereto. The resulting mixture was stirred for 4 hours at 100° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was washed with a mixed solution of ethyl acetate and diisopropyl ether. Thus, 4.1 g of the title compound was obtained as a pale yellow solid (yield: 45%).