Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][O:80][CH2:79][CH2:78]5)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCOCC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0203 g (0.201 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0511 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-N-(tetrahydro-pyran-4-yl)-benzamide (I-235).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([CH3:16])=[CH:11][C:12](=O)[NH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CC1C(C2C=CC=C(C#N)C=2)=NNC(=O)C1.[Cl:33]C1C=C(C2C(C)CC(=O)NN=2)C=CC=1.P(Cl)(Cl)(Cl)=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([Cl:33])=[CH:11][C:10]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(=O)[nH]nc1-c1cccc(C#N)c1
Reactant: CC1CC(=O)NN=C1c1cccc(Cl)c1
Agent: CC1CC(=O)NN=C1c1cccc(C#N)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1cccc(C#N)c1

Procedure:
A 2.95 g. portion of 6-(m-cyanophenyl)-5-methyl-3(2H)-pyridazinone [prepared as described in Example 8 but employing 4,5-dihydro-5-methyl-6-(m-cyanophenyl)-3(2H)-pyridazinone (which in turn is prepared by employing 6-(m-chlorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in Example 44 of U.S. Pat. No. 3,824,271)] and 35 ml. of phosphorus oxychloride are heated on a steam bath for 5 hours. The mixture is concentrated free of excess phosphorus oxychloride and the concentrate is diluted with ice water. The resulting product, a tan solid, is recovered by filtration, washed with water and dried, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11].CO>O1CCCC1>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:4][C:10]([CH3:11])=[O:12])[CH:5]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)ccc1C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
2,5-Dimethylaniline 16 (5.0 gm, 0.041 moles) was dissolved in 30 ml tetrahydrofuran (THF) at room temperature under argon. Acetic anhydride (5.9 ml, 0.062 moles) was added. Within 15 minutes, solids formed and the mixture became a solid white mass after 1 hour. Methanol was added which dissolved the mass. The mixture was evaporated under reduced pressure, dissolved in hot DCM and purified by flash chromatography on silica gel, eluting with a mixture of methanol and DCM. 2,5-Dimethylacetanilide 17 (6.67 gm, 99% yield) was isolated after removing the solvent. NMR (CDCl3) δ 7.53, 1H, br s; 6.89-7.06, 3H, m; 2.30, 3H, s; 2.19, 3H, s; 2.17, 3H, s.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31]>>[NH2:22][C:20]1[S:21][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:24]3[C:25]([S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:7][C:2]=2[F:1])=[N:18][N:19]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3nnc(N)s3)c(F)c2)OC1(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2nnc(N)s2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amine and 2-bromo-N-(tert-butyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19FN4O2S2, 406.09; m/z found, 407.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.20-8.10 (m, 2H), 7.69-7.56 (m, 2H), 7.46-7.36 (m, 3H), 1.08 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](O)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 70 °C
Yield: 278.2 %

Procedure:
To a solution of 0.65 g (2.2 mmol) of 4-fluoro-2,6-dinitrophenol in 30 mL dimethylformamide was added 1.4 mL (15 mmol) of phosphorous oxychloride. The mixture was heated to 70° C. overnight, cooled to room temperature and quenched with ice. The mixture was diluted with water and the precipitate was collected giving 1.35 g (82%) of the title compound as a cream colored solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1)#[N:2].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Solvent: O
Product: N#Cc1ccc(Cn2cc(C#N)nn2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 4-cyanobenzyl azide (0.8 g) and 2-chloroacrylonitrile (0.88 9) in water (5 ml) is stirred at about 80° C. for 20 hours. Excess 2-chloroacrylonitrile is distilled off in vacuo, the mixture is cooled to room temperature and the precipitated product is isolated by filtration and washed with water. The product (yield 0.92 g; 88% of theory) of m.p. 93.5-94° C. (recrystallization from ethyl acetate/toluene) is obtained after drying.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:33][S:34]([O:23][CH:21]([CH3:22])[CH2:20][O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:25]=[CH:24][C:9]=3[CH:10]=2)[CH2:14][CH2:15]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)propan-2-ol (555 mg), triethylamine (0.34 mL) and methanesulfonyl chloride (0.19 mL) in THF (5 mL) was stirred at room temperature for 1 hr and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (624 mg).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:29]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:30]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccc4c(c3)CCO4)ccc12

Procedure:
Prepared in analogy to example 31h from 1-cyano-6-(2,3-dihydro-benzofuran-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine. ESI MS (m/z): 404 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[OH:14][CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.[BH4-].[Na+]>>[C:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([N:17]([CH2:16][CH2:15][OH:14])[CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:32])=[CH:21][CH:22]=1)([O:30][CH3:31])=[O:29]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)COc1ccc(CC(C)N(CCO)CC(O)c2csc(C(F)(F)F)n2)cc1
Reaction time: 3 h

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole and N-(2-hydroxyethyl)- 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine. Before the reduction with sodium borohydride, the mixture is heated to boiling for 3 hours to complete the reaction. The base is then purified on a silica gel column using ethyl acetate as mobile phase.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:17]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[NH2:17])[CH2:13][O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (1.13 g, 5.2 mmol) in anhydrous THF (20 mL) at −15° C. was added N-methylmorpholine (0.57 mL, 5.2 mmol) and isobutylchloroformate (0.67 mL, 5.2 mmol) under a nitrogen atmosphere. After 2 minutes, 33% aqueous ammonia (0.45 mL, 7.8 mmol) was added and the resulting mixture was stirred at −15° C. for 2 h. The reaction mixture was allowed to warm to RT and was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, then dried (MgSO4) and concentrated in vacuo. The resulting pink oil was used without further purification (1.03 g, 91%). 1H NMR (CDCl3, 300 MHz): δ 6.42 (1H, br s), 5.48 (2H, br s), 4.25 (1H, br s), 3.83-3.74 (1H, m), 3.52-3.41 (1H, m), 3.40 (3H, s), 1.42 (9H, s).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11](CO)[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O>[C:1]([O:9][CH2:10][CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC(O)CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Product: O=CCOC(=O)c1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
This known intermediate was prepared by portionwise addition of NaIO4 (80 g) to a mixture of 1-benzoyl glycerol (50 g), CH2Cl2 (500 ml), and H2O (25 ml) under vigorous stirring at room temperature. The resulting solution was stirred for 2 hours, MgSO4 (100 g) was added and the solution stirred for an additional 30 minutes. The mixture was filtered, the filtrate evaporated in vacuo and the residue distilled in vacuo to yield 26 g of pure product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]1=[O:34].S([O-])(O[O-])(=O)=[O:36].[K+].[K+].OOS([O-])=O.[K+]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:36])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:3]1=[O:34]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccccn3)n(Cc3cccc4ccccc34)cc21
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)c3ccccn3)n(Cc3cccc4ccccc34)cc21

Procedure:
Prepared from the compound of Example 20, 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") following the method of Example 8 c).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (6.02 g, 49 mmol), 4-phenyl-benzylchloride (10 g, 49 mmol) and potassium carbonate (20 g, 148 mmol) in N,N'-dimethylformamide (100 ml) was stirred at room temperature for 16 h. The mixture was poured into water (500 ml) and stirred for 1 h. The solid formed was filtered off, washed with water (2×200 ml) and heptane (2×75 ml) and dried in vacuo at 50° C. for 16 h affording 12.3 g (87%) of 3-(biphenyl-4-ylmetoxy)benzaldehyde as a solid. TLC showed presence of unchanged 4-phenylbenzylchloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:22])C(=O)C1>CN(C=O)C.ClCCl>[Br:22][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(Br)ccc2[nH]c(=O)oc(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.1 %

Procedure:
A solution of Example 385A (10.5 g, 54.4 mmol) in DMF (100 mL) and dichloromethane (200 mL) was cooled to 0° C., treated portionwise with NBS (14.4 g, 80.9 mmol) over 40 minutes, stirred overnight at room temperature and filtered. The filtrate was concentrated to provide the desired product (˜20 g) which was used directly in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.[N+:13]([C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:13]([C:16]1[NH:17][CH:18]=[C:19]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=2)[N:20]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: OB(O)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nc(CCc2ccc(B(O)O)cc2)c[nH]1
Reaction time: 48 h
Yield: 14.1 %

Procedure:
4-(2-Bromoethyl)phenyl boronic acid (0.525 g, 2.72 mmol) and 2-nitroimidazole (0.3 g, 2.72 mmol) were heated in dry dimethylformamide (15 ml) in presence of anhydrous potassium carbonate (1.38 g, 10 mmol) under nitrogen with stirring at 60°-70° C. for 48 hours. Dimethylformamide was removed under reduced pressure and the resulting gum was dissolved in a minimum amount of water and acidified with 2N hydrochloric acid. The precipitated solid was filtered off and washed with water. The combined aqueous portion was again extracted with ethyl acetate (5×50 ml). The organic layer was dried, concentrated and combined with the previously precipitated solid and chromatographed (silica gel). Elution with 1:1 ethyl acetate/hexane yielded some unreacted starting bromide (0.1 g); continued elution with 2:1 ethyl acetate/hexane provided the required boronic acid as a pale yellow crystalline solid. The product was recrystallized from tetrahydrofuran/hexane. Yield: 0.25 g (36%), m.p. 229°-231° C., M.S. (M+H)+ 262.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:10]=[N+:11]=[N-:12].[Na+]>C(O)C.O>[N:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7])=[N+:11]=[N-:12]
Reactant: C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NC1CCCCC1O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of cyclohexene oxide (150 g, 1.53 mol) in a mixture of ethanol (600 ml) and water (600 ml) is added ammonium chloride (168 g, 3.1 mol) followed by sodium azide (198 g, 3 mol). The resulting solution is stirred gently at 50° C. for 12 hours before being allowed to cool. The volatiles are removed in vacuo, and 6M hydrochloric acid (˜120 ml) is added to bring the reaction to pH 7. The reaction is extracted with ethyl acetate (2×750 ml), and the organic extracts are washed with brine (750 ml) and dried over sodium sulfate. Removal of the solvent in vacuo affords 2-azido-cyclohexan-1-ol as a slightly yellow oil (171.8 g, 80%), which is used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29]>>[C:23]([O:22][C:20]([NH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:3]3[CH:4]=[CH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:31])[CH:18]=[CH:17][CH:16]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3c(c2N)CCCC3)c1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1

Procedure:
1-Amino-2-(3-tert-butoxycarbonylaminophenyl)amino-5,6,7,8-tetrahydronaphthalene and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound.
Reaction SMILES: N1(C2C(C(N[C@H]3CCC[C@@H]3NC3C=NC(C(F)(F)F)=CN=3)=O)=NC=CC=2)CCCCC1.Cl.[F:33][C:34]([F:49])([F:48])[C:35]1[N:36]=[CH:37][C:38]([NH:41][C@H:42]2[CH2:46][CH2:45][CH2:44][C@@H:43]2[NH2:47])=[N:39][CH:40]=1.[F:50][C:51]1[C:52]([N:61]2[N:65]=[CH:64][CH:63]=[N:62]2)=[C:53]([CH:57]=[C:58]([F:60])[CH:59]=1)[C:54](O)=[O:55]>>[F:50][C:51]1[C:52]([N:61]2[N:65]=[CH:64][CH:63]=[N:62]2)=[C:53]([CH:57]=[C:58]([F:60])[CH:59]=1)[C:54]([NH:47][C@H:43]1[CH2:44][CH2:45][CH2:46][C@@H:42]1[NH:41][C:38]1[CH:37]=[N:36][C:35]([C:34]([F:33])([F:48])[F:49])=[CH:40][N:39]=1)=[O:55]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)cc(F)c1-n1nccn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1N1CCCCC1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)cc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 3-(piperidin-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 51) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 40a; 60 mg, 0.27 mmol) except this was purified only by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.Cl.[CH3:14][OH:15]>>[Br:1][C:2]1[C:11]([N:7]2[CH2:8][CH2:3][CH:14]([OH:15])[CH2:5][CH2:6]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: O=c1ccc2c(Br)cccc2[nH]1
Reactant: CO
Agent: Cl
Product: O=C1CCc2c(ccc(N3CCC(O)CC3)c2Br)N1

Procedure:
The above 5-bromocarbostyril was dissolved in 1 ml of hydrogen chloride-methanol solution, and mixture was refluxed for 1 hr. The reaction mixture was concentrated and purified by a silica gel column chromatography to give 24 mg of 5-bromo-6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:42]=[CH:41][C:17]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])[CH:20]=2)=[C:16]([F:43])[CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:43][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:12])[CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 0.42 h
Yield: 25 %

Procedure:
After adding a solution of 2-phenylacetyl isothiocyanate in toluene (0.2 M, 2.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (85 mg) and (+)-10-camphorsulfonic acid (92 mg) in ethanol (2.0 ml) at room temperature, the mixture was stirred for 25 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 95:5) to provide the title compound (30.5 mg, 25%) as white powder.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1)[CH3:26]>C1COCC1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:33][CH:32]=1)[CH3:26]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CCOC(=O)COc1ccc(CCCCN)cc1
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.74 g, 1.9 mmol) and triethylamine (0.5 mL) were sequentially added into a solution of 48 (0.62 g, 2.47 mmol) in THF (10 mL). The reaction mixture was stirred in the boiling solvent for 4 h and at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 49 (0.5 g, 57%) as a yellow solid. The purity of the product was confirmed by HPLC. m/z (APCI)=464 [C20H26ClN7O4+H]+.