Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:21]=3)[C:17]([Cl:35])=[CH:16][N:15]=2)[CH2:9][CH2:8]1)(=O)=O.[CH3:36][NH2:37]>CO>[Cl:35][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[N:21]=2)=[CH:19][C:14]([NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][NH:37][CH3:36])[CH2:8][CH2:9]2)=[N:15][CH:16]=1
Reactant: CN
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Solvent: CO
Product: CNC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 70 °C

Procedure:
To a scintillation vial containing (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methyl methanesulfonate (15 mg, 0.029 mmol) was added MeOH (1 ml) and a solution of methyl amine (0.14 ml, 0.289 mmol) in MeOH. The reaction mixture was capped and heated to 70° C. in a oil bath for 16 hr. The resulting solution was concentrated and purified by reverse phase preparative HPLC to yield 5′-chloro-N6-(3-fluorobenzyl)-N2′-(trans-4-((methylamino) methyl)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (8.6 mg, 52%), LCMS (m/z): 454.2 (MH+), retention time=0.64 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.15-1.29 (m, 2H) 1.29-1.42 (m, 2H) 1.67-1.80 (m, 1H) 1.86-1.96 (m, 2H) 2.09-2.21 (m, 2H) 2.71 (s, 3H) 2.90 (d, J=7.04 Hz, 2H) 3.58-3.70 (m, 1H) 4.63 (s, 2H) 6.88 (s, 2H) 6.94 (d, J=7.43 Hz, 1H) 6.96-7.03 (m, 1H) 7.07-7.13 (m, 1H) 7.15-7.21 (m, 1H) 7.29-7.39 (m, 1H) 7.69-7.78 (m, 1H) 8.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:18]([NH:19]C(=O)C)=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[N:7]=[N:8][C:4]=2[CH:3]=1.Cl.[OH-].[Na+].O>C(O)C.C(Cl)Cl.C(OCC)(=O)C>[NH2:19][C:18]1[C:2]([F:1])=[CH:3][C:4]2[N:8]=[N:7][N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:5]=2[CH:17]=1
Reactant: COc1ccccc1-n1nnc2cc(F)c(NC(C)=O)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nnc2cc(F)c(N)cc21
Temperature: 25 °C

Procedure:
A mixture of N-[5-fluoro-1-(o-methoxyphenyl)-1H -benzotriazol-6-yl]acetamide (7.14 g, 0.024 g) and concentrated hydrochloric acid (18 mL) in ethanol is refluxed for 2 hours, cooled to room temperature, brought to about pH 5.5 with 3M sodium hydroxide solution and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark, brown oil. Flash column chromatography of the oil using silica gel and 5% to 10% ethyl acetate in methylene chloride solutions gives the title product as an orange solid, mp 128°-129° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:28]#[N:29])[C:14](=[O:27])[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CO>CN(C=O)C>[O:27]=[C:14]1[C:13]([C:28]#[N:29])=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:10]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[NH:15]1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(-c2ccnc(Nc3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
To 5-(2-methylsulfonylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (160 mg, 0.35 mmol) in DMF, under argon, was added a prepared mixture of aniline (129 μL, 1.30 mmole) and potassium bis(trimethylsilyl)amide (0.5M in toluene) (2.6 mL, 1.30 mmole) under argon. The reaction was stirred for 15 minutes and then quenched into ethyl acetate and water. The pH was adjusted to 5.4 with aqueous potassium hydrogen sulfate solution and the ethyl acetate layer removed and concentrated to give a solid. Trituration of the solid from methanol (4 mL) gave 80 mg of a solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:40]([CH3:39])(=[O:42])=[O:41])[C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a cooled solution (0°-5° C.) of 4.0 g of 1-[(4-butylphenyl)methyl]-1-(6-hydroxyhexyl)-3-(2,4,6-trichlorophenyl)urea and 2.6 ml of triethylamine in 90 ml of dichloromethane was added dropwise a solution of 0.8 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The resulting solution was allowed to come to room temperature and was stirred for 16 hours. The procedure of Example 515 was continued and gave 4.5 g of the desired product as a light yellow oil in 97% yield
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(OCC)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1Cl
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (5.18 g, 32.3 mmol) was slowly added dropwise to a solution of 1-[2-chlorophenyl]ethanone (5.00 g, 32.3 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 2-bromo-1-(2-chlorophenyl)ethanone as an oil quantitatively.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCSCCCC(F)(F)C(F)(F)F)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=2)[C:3]1=[O:41].CS(OCCCCC[CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:65])([F:64])[F:63])(=O)=O>>[CH3:1][C:2]1([CH3:42])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:63])([F:65])[F:64])[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:39])([F:40])[F:38])[CH:29]=2)[C:3]1=[O:41]
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Yield: 43 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, 10-[(4,4,5,5,5-pentafluoropentypthio]undecyl methanesulphonate (prepared according to an experimental protocol similar to that described in WO 2005077968) replacing 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate. The expected compound is obtained in the form of a pale yellow oil with a yield of 43% (328 mg).
Reaction SMILES: [Cl-:1].[C:2]([N:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:7]=[N+:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:5])([CH3:4])[CH3:3].[C:25]12(N([Si](C)(C)C)C3C=CC=CC=3)[CH2:34][CH:29]3CC(C[CH:27]([CH2:28]3)[CH2:26]1)C2>>[Cl-:1].[C:15]12([N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:7]=[N+:6]([C:2]34[CH2:3][CH:11]5[CH2:12][CH:13]([CH2:14][CH:9]([CH2:10]5)[CH2:5]3)[CH2:4]4)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH:27]3[CH2:28][CH:29]([CH2:34][CH:25]([CH2:26]3)[CH2:17]1)[CH2:16]2
Reactant: CC(C)(C)N(C=[N+](c1ccccc1)C(C)(C)C)c1ccccc1
Reactant: C[Si](C)(C)N(c1ccccc1)C12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Product: C(N(c1ccccc1)C12CC3CC(CC(C3)C1)C2)=[N+](c1ccccc1)C12CC3CC(CC(C3)C1)C2
Yield: 71.5 %

Procedure:
With the same method used in the synthesis of 4a except for adding 3b (2 equiv), 4b (71.5%) was obtained as a white solid. 1H NMR (300 MHz, CD2Cl2) δ=8.71 (s, 1H), 7.24-6.90 (m, 6H), 6.78 (d, J=7.4 Hz, 4H), 2.21 (br. s, 6H), 2.07-1.99 (m, 12H), 1.66 (br. s, 12H); 13C NMR (75 MHz, CD2Cl2) δ 152.7, 135.0, 130.3, 129.0, 128.9, 66.6, 41.8, 35.4, 30.5. HRMS-DART (m/z): [M]+ calcd for C33H41ClN2, 465.3264. found, 465.3249.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BrH:13]>>[BrH:13].[Br:13][CH2:2][CH2:3][NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](NCCO)c1ccccc1
Agent: Br
Product: C[C@H](NCCBr)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
22.1 g (133.16 mmole) of (S)-(−)-N-(2-hydroxyethyl)-α-methylbezylamine produced in Example 11(1) above was suspended in 105 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 95 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112 mg of acetone, and 100 ml of ethyl acetate and 150 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 70 ml of ethyl acetate and then dried to obtain 20 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 130 ml of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 ml of acetone, diluted with 143 ml of ether, and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected and washed with 75 ml of ethyl acetate to obtain 6.7 g of the second crop of the title compound.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[Cl:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[NH2:11]>C(#N)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[Cl:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[N+:11]#[N:6]
Reactant: N#[O+]
Reactant: Nc1cc(F)ccc1Cl
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: N#[N+]c1cc(F)ccc1Cl
Reaction time: 1 h

Procedure:
Nitrosonium tetrafluoroborate (802 mg, 6.87 mmol) was added to a solution of 2-chloro-5-fluoroaniline (1.00 g, 6.87 mmol) in acetonitrile (50 mL) at 0° C. The resulting mixture was stirred for 1 hour, then diluted with ethyl ether (150 mL). The precipitate was filtered and air-dried to give 2-chloro-5-fluorobenzenediazonium tetrafluoroborate (1-1) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.66 (ddd, 1H, J=6.7, 2.1, 1.0 Hz), 8.16 (m, 2H).
Reaction SMILES: [Na].S([C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1C(O)=O)(O)(=O)=O.S(C1C=C(C(O)=O)C(=CC=1)C(O)=O)(O)(=O)=[O:19].[OH-].[Na+]>[Ni]>[OH:19][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1C(=O)O
Agent: [Ni]
Agent: [Na+]
Agent: [Na]
Product: O=C(O)c1cccc(O)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
403.9 g (91.4%), corresponding to 369 g (100%), (1.5 mols), of the dry monosodium salt of a mixture of 3-sulphophthalic acid and 4-sulphophthalic acid are added to 960 g of 50% strength sodium hydroxide solution (12 mols of NaOH), which have been initially introduced into a nickel autoclave with a capacity of 1.3 l. The autoclave is closed and kept at a temperature of 260° C. for a period of 10 hours, during which time a maximum pressure of 28 bars is set up. After the reaction has ended, the contents of the autoclave are allowed to cool, the suspension is removed and the reactor is rinsed with about 1000 ml of water. The suspension is warmed to 80° C. and introduced carefully, in the course of 1 hour, into a mixture of 1500 ml of crude concentrated hydrochloric acid and 300 g of ice, whilst stirring vigorously. Vigorous evolution of gas due to the carbon dioxide and sulphur dioxide liberated is observed. After all of the mixture has run in, residues of sulphur dioxide are driven off by warming for two hours at 90° C., and the mixture is then cooled slowly to room temperature. The crystal slurry which is filtered off is dried in a vacuum drying cabinet at 90° C. and 20 mm Hg and gives a yield of 201 g (97% of theory) of 3-hydroxybenzoic acid with a purity of 99.9%. The water content is 0.01% and the sodium chloride content is 0.1%. No other impurities are detectable.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:30]Br>C(Cl)Cl.O>[Br:30][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[NH:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1]
Reactant: BrBr
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)ncn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(NCC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.45 g, 1.37 mmol) in methylene chloride (10 mL), was added sat. aq. sodium bicarbonate (2 mL) and bromine (0.07 mL, 1.37 mmol). The resulting mixture was stirred at room temperature for 18 hours, and the reaction was then diluted with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in DCM as eluent to afford the product (314 mg, yield 56%). MS (m/z): 406 (M+H).
Reaction SMILES: CN(C)C=O.CS(O[CH2:11][CH2:12][CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+].O>C(OCC)(=O)C>[O:20]1[C:16]2([CH2:21][CH2:22][CH:13]([CH2:12][CH2:11][N:23]=[N+:24]=[N-:25])[CH2:14][CH2:15]2)[O:17][CH2:18][CH2:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CCC2(CC1)OCCO2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCC1CCC2(CC1)OCCO2
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To 10 mL of an N,N-dimethylformamide solution containing 1.4 g of 2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl methanesulfonate, 0.45 g of sodium azide was added at room temperature, and the mixture was stirred at 45 to 50° C. for 1 hour and 30 minutes. Thereto was further added 70 mg of sodium azide, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:1] to obtain 1.0 g of a colorless oily substance, 2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl azide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][NH:37][CH2:36][C:35]2([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][N:37]([C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=1)=[O:27])[CH2:36][C:35]2([CH3:43])[CH3:42]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CNCc2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5ccc(F)cc5C(C)(C)C4)ncn3)CC1)C(=O)N2

Procedure:
60 mg (0.15 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 33 mg (0.15 mmol) 6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 66 μL (0.47 mmol) TEA and 54 mg (0.17 mmol) TBTU were stirred in 1.5 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3].C([O-])([O-])=O.[K+].[K+].[I-].C[N+]1(C)[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)C>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[CH:2]([N:1]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[CH3:3]
Reactant: C[N+]1(C)CCC(=O)CC1
Reactant: CC(N)c1cnccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(c1cnccn1)N1CCC(=O)CC1
Yield: 80 %

Procedure:
To a stirred mixture of 2-(1-aminoethyl)pyrazine (225 mg), ethanol (10 mL) and K2CO3 (72 mg) heated to reflux was added dropwise over 30 min, a solution of 4 g of 1,1-dimethyl-4-oxopiperidinium iodide (2.1 g) in water (36 mL). When the addition was complete, the mixture was heated under reflux for an additional 2 h, cooled, basified to pH 10 with Na2CO3 and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Column chromatography over silica gel, eluting with a gradient of ethyl acetate; 0-5% methanol gave 300 mg of 1-(1-(2-pyrazinyl)-ethyl)-4-oxopiperidine as an oil: 1H NMR (400 MHz, CDCl3) 8.74 (d, 1H), 8.54 (dd, 1H), 8.48 (d, 1H), 3.94 (q, 1H), 2.89-2.75 (m, 4H), 2.46 (t, 4H), 1.50 (d, 3H).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.C(COC)OC.O>CCOCC>[CH3:24][C:20]1[CH:19]=[C:18]([N:17]=[CH:4][N:5]2[CH2:9][CH2:8][NH:7][C:6]2=[N:10][N+:11]([O-:13])=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Cc1cccc(N)c1
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1cccc(N=CN2CCNC2=N[N+](=O)[O-])c1
Yield: 51.8 %

Procedure:
A mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 0.92 g of m-toluidine, 5 ml of dimethoxyethane and 0.12 g of a boron trifluoride ether complex was heated under reflux for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and condensed. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 1.1 g of 1-(3-methylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: FC1C=C2C(=CC=1)N=C(C(NC(=O)OC(C)(C)C)C)C(C1C=CC=CN=1)=C2C1C(C)=CC=CN=1.FC(F)(F)C(O)=O.NC1C(C#N)=C(Cl)N=CN=1.C(N(C(C)C)CC)(C)C.[NH2:61][C:62]1[C:67]([C:68]#[N:69])=[C:66]([NH:70][C@H:71]([C:73]2[C:82]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][N:84]=3)=[C:81]([C:89]3[C:94]([CH3:95])=[CH:93][CH:92]=[CH:91][N:90]=3)[C:80]3[C:75](=[CH:76][CH:77]=[C:78]([F:96])[CH:79]=3)[N:74]=2)[CH3:72])[N:65]=[CH:64][N:63]=1>C(Cl)Cl>[NH2:61][C:62]1[C:67]([C:68]#[N:69])=[C:66]([NH:70][CH:71]([C:73]2[C:82]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][N:84]=3)=[C:81]([C:89]3[C:94]([CH3:95])=[CH:93][CH:92]=[CH:91][N:90]=3)[C:80]3[C:75](=[CH:76][CH:77]=[C:78]([F:96])[CH:79]=3)[N:74]=2)[CH3:72])[N:65]=[CH:64][N:63]=1
Reactant: Cc1cccnc1-c1c(-c2ccccn2)c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)cc12
Agent: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Agent: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)Nc2ncnc(N)c2C#N)nc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)-quinolin-2-yl)ethylcarbamate (0.23 g, 0.50 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.97 mL, 12.5 mmol) and the resulting solution was stirred at room temperature for one hour. The solution was concentrated under reduced pressure then diluted with 1-butanol (2.5 mL) followed by the addition of 4-amino-6-chloropyrimidine-5-carbonitrile (0.082 g, 0.53 mmol) and diisopropylethylamine (0.26 mL, 1.51 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (0.082 g, 0.53 mmol). The solution was stirred at 120° C. for 3 h then purification was attempted by silica gel column chromatography eluting with 0-100% (1:10:90 NH4OH:MeOH:DCM) in DCM). The resulting crude solid was repurified by silica gel column chromatography eluting with a gradient of 0-7% MeOH in DCM to afford a mixture of (R) and (S)-4-amino-6-(1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylamino)pyrimidine-5-carbonitrile as a yellow glass: LC-MS (ESI) m/z 477.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:11]O)=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: ON=C1CCc2cc(N3CCOCC3)c(F)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 27.2 %

Procedure:
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-1-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-1-one oxime (218 mg) in ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are as follows.