Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C@@H:9]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of benzyl (2S)-2-[N-(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionate (5.0 g) in dimethylformamide (50 ml) was added dropwise to a stirred mixture of 60% sodium hydride (0.6 g) and dimethylformamide (50 ml) at ice-bath temperature. After the addition was completed, the reaction mixture was stirred at the same temperature for 30 minutes. Benzyl bromide (1.76 ml) was added and then the whole mixture was stirred for 3.5 hours. Additional benzyl bromide (0.4 ml) was added and then stirred for 2.5 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and ethyl acetate (4:1) to give benzyl (2S)-2-[N-(tert-butoxycarbonyl)-N-benzylamino]-3-(2-naphthyl)propionate (3.53 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15]OCC2)=[C:4]([NH:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][NH:18][CH3:19].[CH2:20]([OH:22])[CH3:21]>>[CH3:17][N:18]([CH3:19])[C:9]([NH2:10])=[N:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:11]1[CH2:16][CH2:15][O:22][CH2:20][CH2:21]1
Reactant: CCO
Reactant: CNC
Reactant: Cc1cccc(NC#N)c1N1CCOCC1
Product: Cc1cccc(N=C(N)N(C)C)c1N1CCOCC1

Procedure:
In a similar manner to that described in Example 286, N-(3-methyl-2-morpholinophenyl)cyanamide (2.5 g) in ethanol (8 ml) and a 33% ethanolic solution of dimethylamine (3.5 ml) were heated under reflux for 1 hour. A further amount of the 33% ethanolic solution of dimethylamine (3.5 ml) was added and the mixture heated under reflux for a further hour to give 1,1-dimethyl-2-(3-methyl-2-morpholinophenyl)guanidine (m.p. 100° C.) which was recrystallised from hexane and converted into its monofumarate salt (m.p. 180° C.) which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:27](=[O:28])[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:29]#[N:30])=[CH:23][CH:24]=4)[NH:19][C:18]=3[C:17]([CH3:32])([CH3:31])[C:16]=2[CH:33]=1.[C:34]([O:38][C:39]([N-:41][S:42](N1C=CC(=[N+](C)C)C=C1)(=[O:44])=[O:43])=[O:40])([CH3:37])([CH3:36])[CH3:35].O>N1C=CC=CC=1>[C:34]([O:38][C:39]([NH:41][S:42]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:27](=[O:28])[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:29]#[N:30])=[CH:23][CH:24]=4)[NH:19][C:18]=3[C:17]([CH3:31])([CH3:32])[C:16]=2[CH:33]=1)(=[O:44])=[O:43])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC1(C)c2cc(OCCN)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
Trifluoroacetic acid salt of 8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A8-2, 20 mg, 0.044 mmol) was dissolved in pyridine (0.5 mL), added with N-(tert-butoxycarbonyl)-N-[4-(dimethyl azaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (13.5 mg, 1 eq.), and then stirred at room temperature for 14 hr. The reaction solution was added to water, and then extracted with ethyl acetate. After washing with saturated brine, the organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were separated by silica gel preparative TLC (ethyl acetate) to obtain the title compound (16.1 mg, 68%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][C:19]([C:23]([NH:25][C:26]5[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)[CH3:34])=[CH:28][CH:27]=5)=[O:24])=[CH:18][C:17]=4[CH:41]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:42][I:43]>CN(C)C=O>[I-:43].[CH3:34][N+:33]([CH3:42])([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:19]2[CH2:20][CH2:21][O:22][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=4)=[CH:41][C:17]=3[CH:18]=2)=[O:24])=[CH:27][CH:28]=1)[CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3OCC2)cc1)C1CCOCC1
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+](C)(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3OCC2)cc1)C1CCOCC1
Product: [I-]

Procedure:
A solution of 7-(4-piperidinophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.2 g) and methyl iodide (0.025 ml) in dimethylformamide (5 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-ethyl acetate to give dimethyl(N-(7-(4-piperidinophenyl)-2,3-dihydro-1-benzoxepin-4-carbonyl)-4-aminobenzyl)-4-tetrahydropyranylammonium iodide (Compound 221) (0.1 g) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[C:32]([CH:33]=O)=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:32]3[C:27]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccnc1N1CCOCC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccnc4N4CCOCC4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 42.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Morpholin-4-yl-pyridine-3-carbaldehyde (31.2 mg, 0.163 mmol) were reacted to produce 32 mg (42%) of the title compound. mp: 150° C., 1H NMR (300 MHz, DMSO-d6): 12.95 (s, 1H), 8.33 (d, J=5 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.19 (s, 1H), 7.09 (m, 1H), 6.34 (s, 1H), 6.32 (s, 1H), 5.21 (t, J=8 Hz, 1H), 3.64 (s, 4H), 3.29 (s, 1H), 3.06 (m, 4H), 2.87 (s, 1H), 2.78 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS: 510, 512 (M+H), HPLC: 2.02 min (G method).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:31][CH2:30]1
Reactant: OC1CCNCC1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: ClCCCCCCCBr
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCCN3CCC(O)CC3)cc12

Procedure:
The compound was prepared by a method similar to Example 2 from 6-hydroxyflavone, 1-bromo-7-chloroheptane and 4-hydroxypiperidine: mp 135°-136° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:10][C:3]1[C:2]([CH:19]=[O:20])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c(Cl)n1
Temperature: 25 °C

Procedure:
The 3-bromo-2-chloro-6-methoxy-pyridine (0.50 g, 2.26 mmol) obtained in (19-1) above was dissolved in toluene (dehydrated) (11 mL), and thereafter, n-butyllithium (1.46 mL, 2.3 mmol, 1.57 mmol/L hexane solution) was added dropwise to the solution at −78° C. in an argon atmosphere. The obtained mixture was stirred at the same temperature as described above for 30 minutes, and DMF (1.0 mL) was then added to the reaction solution. The obtained mixture was further stirred for 30 minutes. Thereafter, a saturated ammonium chloride water (20 mL) was slowly added to the reaction solution, and the temperature of the mixture was then increased to room temperature. The mixture was extracted with diethyl ether (20 mL) twice, and organic layers were gathered. The resultant was dried over anhydrous sodium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was purified by silica gel column chromatography (SiO2 30 g, hexane:ethyl acetate=95:5 to 80:20), so as to obtain 180 mg of 2-chloro-6-methoxy-3-pyridinecarboxaldehyde.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[C:7](C)=[O:8].[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([CH:7]=[O:8])=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CC(C)=O
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
In a nitrogen atmosphere, 51 g (0.33 mol) of phosphorus oxychloride (manufactured by Wako Pure Chemical Industries, Ltd.) were added dropwise to 88 ml of cooled dimethylformaldehyde (DMF). The dropping rate was adjusted so as to keep a temperature of 2° C. to 4° C. at the time of dropping, and stirring was further continued for 30 minutes at 2° C. after the completion of dropping. To this mixture, a 70-ml dimethylformamide solution of 54.8 g (0.33 mol) of N,N-dimethyl-3-nitroaniline (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added dropwise such that the reaction temperature does not exceed 5° C.; and the mixture was stirred for 2 hours as it was. Thereafter, temperature was gradually raised, and the mixture was stirred at 60° C. for one night. After being cooled to room temperature, the reaction liquid was poured into vigorously stirred 500 ml of ice water. The pH of the mixture was adjusted to about 8 with sodium acetate being added thereto, and the precipitated crystal was filtered out and dried, whereby 50.2 g of a crude product were obtained. This product was recrystallized from acetone/normal hexane, whereby 21 g of the aimed product were obtained (yield: 33%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH:10]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])=[CH2:11]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([CH:10]=[CH2:11])[CH:13]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: C=Cc1cccc(N)c1
Reactant: Cc1cnc(Cl)nc1Cl
Product: C=Cc1cccc(Nc2nc(Cl)ncc2C)c1
Yield: 39 %

Procedure:
This compound was prepared according to the procedure of Example A1, step A, using 2,4-dichloro-5-methylpyrimidine and 3-vinylaniline as the starting materials in 39% yield. LCMS calculated for C13H13ClN3 (M+H)+: m/z=246.1.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:19]O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[NH:26][C:25]2=[O:33])[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:26]([CH2:19][C:7]3[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:14]4[C:9]([N:8]=3)=[N:10][C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=4)[C:25]2=[O:33])[CH2:23][CH2:22]1
Reactant: CC(C)CCn1c(CO)nc2nc(C(F)(F)F)ccc21
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a suspension of (1-isopentyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 44-3 (1.0 g, 3.5 mmol (73% purity)), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (731.8 mg, 4.2 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in 24 ml dry THF was added (E)-diïsopropyl diazene-1,2-dicarboxylate (1.0 ml, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and purified by preparative column chromatography to obtain 44 as a white solid (578.0 mg, 37%). m/z=445 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (m, J=6.50 Hz, 8H) 1.13-1.24 (m, 2H) 1.48-1.64 (m, 2H) 1.73 (dquin, J=13.19, 6.49, 6.49, 6.49, 6.49 Hz, 1H) 2.92 (tt, J=6.81, 3.48 Hz, 1H) 4.35-4.52 (m, 2H) 5.41 (s, 2H) 7.13 (d, J=5.27 Hz, 1H) 7.61 (d, J=8.28 Hz, 1H) 7.79 (d, J=8.28 Hz, 1H) 8.34 (d, J=5.27 Hz, 1H) 8.68 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[OH:14])=[O:8].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([CH:9]1[CH:13]([O:14][C:1](=[O:3])[CH3:2])[CH:12]=[CH:11][S:10]1)=[O:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1sccc1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1SC=CC1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
8.6 parts of acetyl chloride are added in the course of 10 minutes to a solution, cooled to 0° C., of 16 parts of 3-hydroxy-thiophene-2-carboxylic acid methyl ester and 15.3 parts by volume of triethylamine in 100 parts by volume of chloroform. The solution is stirred for 4 hours at 0° C. After the reaction, the mixture was poured into 100 parts by volume of ice water and the organic phase is separated off, dried and concentrated. The residue is distilled. 19.4 parts (96% of theory) of 3-acetoxydihydrothiophene-2-carboxylic acid methyl ester of boiling point 82°-84° C./0.08 mbar are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)[CH:5]=[CH:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH:7]([CH2:8][N:9]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH:7]([CH2:8][N:9]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:10]3)[C:6]=2[CH:5]=1
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Yield: 94.5 %

Procedure:
Hydrogenation of 1-(4-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (2.0 g, 6.66 mmol) under a hydrogen atmosphere (40 psi, or approximately 2.7 atmospheres) and 10% Pd/C (200 mg) in methanol over 1.5 hours, filtration through Celite and concentration affords a yellow oil (1.7 g). (TLC 50% ethyl acetate/hexanes Rf 0.27). 1H NMR (400 MHz, CDCl3)6.99 (m, 1H), 6.64 (br s, 1H), 6.57 (m, 1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.17–3.07 (m, 3H), 2.35 (m, 1H), 1.90 (d, J=10.8 Hz, 1H). GCMS m/e 270 (M+).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide (97 mg, 0.430 mmol), 6-aminoquinoline (62 mg, 0.430 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg). The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg, 0.045 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (14 mg). MS 352.58 (M+H); UV 202.9, 265.2, 297.2, 357.9 nm; t 0.335 min.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([CH3:23])[CH:14]=1.N1C=CC=CC=1.Cl>ClCCl>[CH2:5]([O:4][C:2]([N:18]1[C:17]2[CH:16]=[C:15]([CH3:23])[CH:14]=[C:13]([Br:12])[C:22]=2[O:21][CH2:20][CH2:19]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(Br)c2c(c1)NCCO2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Br)c2c(c1)N(C(=O)OCc1ccccc1)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A solution of benzyl chloroformate (1.32 g, 0.008 mol) in dichloromethane (20 mL) was added dropwise under nitrogen to an ice-cold solution of 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.78 g, 0.007 mol) and pyridine (1.06 g, 0.013 mol) in dichlormethane (40 mL). After 1 hour at ambient temperature, a 10% aqueous HCl solution was added. The layers were separated and the organic phase was washed with water (50 mL×2), dried (Na2SO4) and concentrated to give 8-bromo-6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester as a colorless oil (2.34 g, 96%) which was used in the step 2 without purification.
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CBr.C([Li])CCC.[Si:27]([O:44][CH2:45][C@H:46]([CH3:49])[CH:47]=O)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Si:27]([O:44][CH2:45][C@@H:46]([CH3:49])[CH:47]=[CH2:1])([C:40]([CH3:42])([CH3:43])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@H](C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
Under argon atmosphere, Ph3P+CH3Br (2.2 g, 7.4 mmol) was suspended in 15 ml of THF, butyllithium (5.2 ml, 9.3 mmol) was added to the resultant solution at 0° C., and the mixture was stirred for 20 min. The treated mixture was added to a 15-ml THF solution of (S)-3-(t-butyldiphenylsilyloxy)-2-methylpropanal (49) (1.2 g, 3.7 mmol) at 0° C. The resultant mixture was stirred for 15 min and further for 45 min after the temperature was returned to room temperature. Then, the reaction mixture was extracted with ethyl acetate after the addition of a saturated ammonium chloride aqueous solution. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated. The crude product was purified by column chromatography (12 g, 2% AcOEt-hexane) to obtain a colorless oily product (50) (1.1 g, 92%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([S:19][C:20]1[S:21][C:22]([C:26]#[N:27])=[C:23](Cl)[N:24]=1)[CH2:16][CH2:17][CH3:18]>C(#N)C>[CH2:15]([S:19][C:20]1[S:21][C:22]([C:26]#[N:27])=[C:23]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:24]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCSc1nc(Cl)c(C#N)s1
Reactant: Sc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCSc1nc(Sc2ccccc2)c(C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.15 ml (5.55 g) of thiophenol and 7.0 ml of triethylamine are added successively while stirring to a solution of 10.93 g of 2-n-butylthio-4-chloro-5-cyanothiazole prepared according to Example V(b), in 100 ml of acetonitrile. After stirring at room temperature for another hour and leaving to stand overnight, the reaction mixture is evaporated. The residue is dissolved in methylene chloride, after which the organic solution is successively washed with water, 1N sodium hydroxide solution and water, and is then dried, filtered and evaporated. Chromatography in petroleum ether (40-60)/diethyl ether 3:1 v/v as a solvent over a 1400 ml dry silica gel column provides the desired product in a yield of 7.24 g; oil; Rf (petr.ether/diethyl ether 3:1 v/v) 0.35; identification by means of I.R. spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[C:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:12][CH:11]=1.[BH4-].[Na+]>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[OH:26])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(C=C2Cc3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccccc1NC(=O)c1ccc(CC2Cc3ccccc3C2O)cc1
Temperature: 50 °C
Yield: 73.5 %

Procedure:
To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml) and water (1 ml) was added NaBH4 (75 mg, 1.95 mmol). The reaction mixture was stirred at 50° C. 16 h and cooled down. Water was added to the solution and the precipitated was filtered and rinsed with cold water to afford the title compound 275 (224 mg, 74%) as a white solid. 1H NMR: (acetone) δ (ppm): 9.05 (bs, 1H), 8.00 (dd, J=8.2, 2.7 Hz, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.22-7.12 (m, 3H), 7.01 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.87 (dd, J=8.0, 1.1 Hz, 1H), 6.68 (dd, J=7.6, 7.6 Hz, 1H), 4.98 (t, J=5.8 Hz, 0.4H), 4.89 (t, J=6.7 Hz, 0.6H), 4.63 (bs, 2H), 4.45 (d, J=6.9 Hz, 0.6H), 4.06 (d, J=6.0 Hz, 0.4H), 3.30-3.19 (m, 1H), 2.88-2.48 (m, 3H, CH2). LRMS: 358.2 (calc.); 359.1 (found).