Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C[N:5]([CH3:7])C)C.C(Cl)(=[O:10])C.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][C:7]([NH2:5])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)CN(C)C
Reactant: Cc1ccccc1
Reactant: CC(=O)Cl
Product: NC(=O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3.37 parts of N,N,N',N'-tetramethyldiaminomethane in 44 parts of methylbenzene was added dropwise a solution of 2.59 parts of acetylchloride in 26 parts of methylbenzene during 30 minutes at 20°-25° C. under nitrogen atmosphere. Upon completion, the reaction mixture was further stirred for 20 minutes. 10.21 Parts of compound 15 and 78 parts of methylbenzene were added to the previous mixture and stirred for 5 hours at 80° C. The reaction mixture was allowed to cool to 20° C., the precipitated product was filtered off and dried in vacuo at 40° C., yielding 11.66 parts (97.8%) of N-[(dimethylamino)methyl]2,6-dichloro-α-[2-nitrophenyl)amino]benzeneacetamide.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:20])[CH:10]=[CH:11][C:12]=3[N+:17]([O-])=O)[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1N>CC(N(C)C)=O>[CH3:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:17][C:12]1[CH:11]=[CH:10][C:9]([OH:20])=[C:8]2[C:13]=1[C:14](=[O:16])[C:15]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([N+:22]([O-:24])=[O:23])[C:6]=1[C:7]2=[O:21]
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c(O)ccc([N+](=O)[O-])c21
Reactant: Cc1ccccc1N
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1Nc1ccc(O)c2c1C(=O)c1c(O)ccc([N+](=O)[O-])c1C2=O
Yield: 32.8 %

Procedure:
A 25 g of 1,5-dihydroxy-4,8-dinitroanthraquinone and a 25 g of 2-methylaniline were dissolved in 250 ml of dimethylacetamide. The solution was heated and allowed to react at an inner temperature of 140 degrees Celsius for 4 hours. The reaction solution was cooled, and then extracted with adequate amounts of ethyl acetate and 1N-hydrochrolic acid to separate into two layers. The extracted organic layer was dried with magnesium sulfate and then concentrated. The concentrated solution was purified by silica gel chromatography to give a 9.7 g of 8-(2′-methylanilino)-1,5-dihydroxy-4-nitroanthraquinone in a 33% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[K+]>CN(C=O)C.O.CO>[Cl:15][C:3]1[C:2]([O:1][CH2:23][C:24]([OH:26])=[O:25])=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[C:4]=1[Cl:14]
Reactant: O=C1CCCCc2cc(O)c(Cl)c(Cl)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)CCCC2

Procedure:
2-Hydroxy-3,4-dichloro-6,7,8,9-tetrahydro-5H- benzocyclohepten- 5-one (10 g., 0.04 mole), anhydrous potassium carbonate (7 g., 0.05 mole) and ethyl bromoacetate (8.35 g., 0.05 mole) in DMF (75 ml.) are stirred at 60° C. for 1 hour. Then potassium hydroxide (5 g.) dissolved in water (5 ml.) and methanol (100 ml.) is added. The mixture is refluxed for one hour. The methanol is distilled, the residue is poured into water, and the solution is filtered. Upon acidification with 12 N NCl, (3,4-dichloro-5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten- 2-yloxy)acetic acid separates and is collected by filtration.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:25](Cl)=[CH:24][C:22]([NH2:23])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[C:25]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[CH:24][C:22]([NH2:23])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2cccc3cnccc23)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 15 ml, potassium carbonate 830 mg (6.0 mmol) and 4,5-dichloro-2-nitroaniline 620 mg (3.0 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and the resulting precipitates were collected and washed with water to give 4-chloro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 980 mg (98.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCBr
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCCBr)CC1

Procedure:
In analogy to examples 1.4 and 1.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester was reacted with 1,5-dibromopentane to yield trans-[4-(5-Bromo-pentyloxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester which was reacted with N-allylmethylamine to yield trans-(4-[5-(Allyl-methyl-amino)-pentyloxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as white oil, MS: 369 (MH+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[Cl:12][C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([CH3:22])[CH:14]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[Cl:12][C:13]1[N:18]=[C:17]([C:19]([O:21][C:1]([CH3:11])([CH3:6])[CH3:2])=[O:20])[CH:16]=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(Cl)nc(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: Cc1cc(Cl)nc(C(=O)OC(C)(C)C)c1
Reaction time: 22 h
Yield: 38.1 %

Procedure:
p-Toluenesulfonyl chloride (1.11 g, 5.83 mmol) was added to a solution of 6-chloro-4-methylpyridine-2-carboxylic acid (0.50 g, 27.6 mmol) as a known compound in tert-butyl alcohol (16.5 ml) and pyridine (2.4 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 22 hours. Thereafter, a solution of sodium hydrogen carbonate (1.22 g, 14.6 mmol) in water (33 ml) was added to the resulting solution, and the mixture thus obtained was then stirred. The solvent was distilled away from the reaction solution under reduced pressure. Water was added to the residue thus obtained, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure to obtain the title compound (0.506 g, yield: 76%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([CH:24]=[CH2:25])[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]=1[N+:20]([O-:22])=[O:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (3.06 g) in toluene (120 mL) were added vinyltri(n-butyl)tin (2.4 mL) and tetrakis-(triphenylphosphine)palladium(0) (0.87 g), and the reaction mixture was heated at reflux under an argon atmosphere overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue were added tetrahydrofuran (30 mL), water (30 mL) and 0.5 mol/L aqueous potassium fluoride solution (30 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residual crystals were suspended in a mixed solvent (n-hexane/ethyl acetate=5/1), and collected by filtration. The collected crystals were dried under reduced pressure to give 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitro-4-vinylbenzene (2.32 g). This material was dissolved in tetrahydrofuran (65 mL). To the solution was added borane-tetrahydrofuran complex (1.2 mol/L tetrahydrofuran solution, 9 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature overnight. To the reaction mixture were added 1 mol/L aqueous sodium hydroxide solution (30 mL) and 30% aqueous hydrogen peroxide solution (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, and then stirred at 90° C. for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.38 g).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:9](Cl)(Cl)[CH:10]([OH:12])O.Cl.[Cl:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].Cl.[NH2:27][OH:28]>O>[Cl:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:10](=[O:12])[CH:9]=[N:27][OH:28]
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: COc1cccc(N)c1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(NC(=O)C=NO)c1Cl

Procedure:
To a stirred solution of sodium sulfate (58.5 g, 412 mmol) in water (100 mL) was added a solution of chloralhydrate (9.36 g, 56.6 mmol) in water (120 mL). Chloroanisidine 39d (10 g, 51.5 mmol) was added followed by 37% HCl (20 mL). A solution of hydroxylamine (50% in water, 4.7 mL, 154.5 mmol) in 50 mL was then added and the reaction mixture was refluxed for 90 min. The suspended solid was filtered off, and washed with water and ether. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 102d as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](SCC)[CH:5]=[CH:4][C:3]=1[F:11].[CH:12]1C=C(Cl)C=C(C(OO)=O)[CH:13]=1.[O-:23][S:24]([O-:27])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([S:24]([CH2:12][CH3:13])(=[O:27])=[O:23])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To 2-bromo-4-ethylsulfanyl-1-fluorobenzene (2.2 g, 9.36 mmol) in DCM (20 mL) was added m-CPBA (6.47 g, 37.4 mmol). The mixture was stirred at room temperature for 12 h. Aqueous saturated Na2S2O3 (100 mL) was added, and extractive work up with CH2Cl2 gave the title compound (1.5 g, 50%) as a yellow solid which was carried on without purification. 1H NMR (CDCl3, 400 MHz) δ 8.15 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H), 7.88-7.85 (m, 1H), 7.32 (t, J=8.4 Hz, 1H), 3.14 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([N:27]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:56])(=[O:55])[NH2:54])=[CH:43][CH:42]=1)[C:28]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1>>[CH2:23]([N:27]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:55])(=[O:56])[NH:54][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:45][CH:46]=1)[C:28]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 2-chlorobenzoic acid (2.5 equivalents), CDI (2.5 equiv), 1-[N-butyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step B) (1.0 equiv), and DBU (2.5 equiv), according to the procedure of Example 3, Step C, to give an 83% of the desired material after flash chromatography as an off-white solid, mp 80°-82° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; FAB-MS m/e 616 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20]Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CS(C)=O.O>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(CCl)nn(Cc2ccccc2)c2cccc(Cl)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To 0.170 g (0.53 mmol) of 1-benzyl-5-chloro-3-chloromethylcinnolin-4(1H)-one in 6 mL of dimethylsulfoxide was added 0.050 g (1.3 mmol) of sodium borohydride. The reaction was stirred at room temperature for 3 h and diluted with water. The resulting precipitate was collected and dried to give 0.140 g (92%) of the title compound as a fluffy cream colored solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)COCCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH:15]=1)[C:7](=[N:18][NH2:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1ccccc1)c1cc(F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-fluoro-2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 5-fluoro-2-aminobenzophenone hydrazone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]([O:18]C)=[O:17])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]([OH:18])=[O:17])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 72.5 %

Procedure:
A mixture of 4-(1-methoxycarbonylethyl)-piperidine-1-carboxylic acid tert-butyl ester (40 g crude from last step, about 0.15 mol), LiOH (12.6 g, 0.3 mol) in water (200 mL) and THF (400 mL) was heated to reflux for 4 hours. The cooled mixture was diluted with water (200 mL) and washed with Et2O (200 mL×2). The aqueous layer was acidified with HCl (10%) at 0° C. to pH3-4. The mixture was extracted with Et2O (200 mL×3) and the combined extracts were washed with brine, dried and concentrated to give the product as a white solid (28 g, 73% from N-benzyl-4-piperidone). 1HNMR (CDCl3) δ 4.11 (m, 2H), 2.69-2.63 (m, 2H), 2.30 (p, 1H, J=7.2 Hz), 1.72-1.62 (m, 3H), 1.44 (s, 9H), 1.27-1.18 (m, 2H), 1.16 (d, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].Cl.Cl.[N:38]1([CH2:43][CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:27]([N:47]2[CH2:48][CH2:49][CH:44]([CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:45][CH2:46]2)=[O:28])[CH:6]=1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (160 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, and then triethylamine (0.268 ml) and phenyl chloroformate (0.242 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, and N,N-dimethylformamide (7 ml) was added thereto. And then 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (619 mg) and triethylamine (0.716 ml) were added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing a target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (290 mg) as pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[O:12]C2C=CC=CC=2N=1.C[O-].[Na+]>CN(C=O)C.[Cu]Br>[CH3:11][O:12][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: c1ccc2ocnc2c1
Reactant: Brc1nc2ccccc2o1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2ccccc2o1

Procedure:
In Scheme VIII, bromobenzoxazole 35 (R=CH3) was first treated with copper(I) cyanide in DMF to produce the corresponding aryl-nitrile, which upon treatment with boron tribromide afforded benzoxazole 36. Benzoxazole 36 was also prepared from a second synthetic Route, where the bromo-benzoxazole 35 was treated with zinc cyanide in the presence of a palladium catalyst [i.e. tetrakis(triphenylphosphine)palladium(0)] to afford the corresponding aryl-nitrile, which upon demethylation with boron tribromide produced benzoxazole 36. Benzoxazole 35 (R=H) was treated with copper (I) bromide, and freshly prepared sodium methoxide in DMF to produce methoxy-benzoxazole 37. Bromination of 37 with N-bromosuccinimide in acetonitrile afforded the monobromo benzoxazole 38 (major product) and the dibromobenzoxazole 39 (minor product).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:15]([O-])=O.[Na+].[Br:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28].C([O-])(=O)C.[Na+]>O.CO>[Br:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](=[O:30])[C:26](=[N:15][NH:4][C:3]1[CH:5]=[CH:6][C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:8][C:2]=1[F:1])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)CC(=O)c1occc1Br
Reactant: Nc1ccc(-n2cccn2)cc1F
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)C(=NNc1ccc(-n2cccn2)cc1F)C(=O)c1occc1Br
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a mixture of 2-fluoro-4-(1H-pyrazol-1-yl)aniline (2.3 g) and 6M hydrochloric acid (13 mL) was added dropwise a solution of sodium nitrite (1.0 g) in water (3 mL) at 0° C., and the mixture was stirred for 15 min. The obtained aqueous solution was added to a suspension, which was cooled to 0° C., of 1-(3-bromofuran-2-yl)butane-1,3-dione (3 g) and sodium acetate (6.4 g) in methanol (30 mL). The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (5.3 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C@@H:13](OC)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.C([Li])CCC.CN([CH:33]=[O:34])C.C1C[O:38][CH2:37]C1>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([CH:33]=[O:34])=[CH:20][CH:21]=1)[O:38][CH3:37]
Reactant: CO[C@@H](CCc1ccc(Br)cc1)c1nc(-c2ccccc2)oc1C
Reactant: C1CCOC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=O)cc1
Temperature: -78 °C
Yield: 62 %

Procedure:
(S)-4-[3-(5-Methyl-2-phenyl-4-oxazolyl)-3-methoxypropyl]bromobenzene (1.1 g, 2.8 mmol, prepared as described in Example 15) was dissolved in THF (30 mL), cooled to −78° C. and treated with n-butyllithium (2.5 M in THF, 1.2 mL, 3.0 mmol) dropwise via syringe. Following addition, the reaction mixture was stirred at −78° C. for an additional hour and treated with dry DMF (220 mg, 30 mmol). The reaction mixture was stirred at −78° C. for 90 minutes and at ambient temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (50 mL), 10% aqueous hydrochloric acid (50 mL), water (50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (3/1), to afford a viscous oil (580 mg, 62%). 1HNMR (300 MHz, CDCl3): δ2.0 (m, 2H), 2.3 (s, 3H), 2.5 (t, 2H), 3.2 (s, 3H), 4.15 (dd, 1H), 7.3 (m, 3H), 7.4 (d, 2H), 7.8 (d, 2H), 7.9 (m, 2H), 9.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+].CO.O>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(F)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-chloro-5-fluorobenzoate (23, 35.0 g, 185.6 mmol) in dry THF (150 mL) was added NaBH4 (21.2 g, 557 mmol). Methanol (40 mL) was added dropwise at RT. After the addition, the mixture was stirred at RT for 1 h. Water (300 mL) was slowly added. The mixture was extracted with CH2Cl2 (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give (2-chloro-5-fluorophenyl)methanol (24).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Nc1c(F)cccc1F
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2c(F)cccc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,6-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (s, 3H), 2.33 (s, 3H), 4.50 (bs, 2H), 5.88 (bs, 2H), 6.80-7.01 (m, 2H), 7.03-7.21 (m, 3H), 7.53 (bs, 1H), 8.47 (bs, 1H); MS (ESI) m/z 342.6 (M+1)+.