Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:15][O:16][CH2:17][C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[C:20]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]2[CH3:35])[C:19]=1[CH3:36]>CN(C)C=O>[ClH:24].[CH3:15][O:16][CH2:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:21]=[C:20]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]2[CH3:35])[C:19]=1[CH3:36]
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc(Nc2ccccc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 45.4 %

Procedure:
After aniline (2.41 ml, 26.4 mmol) and triethylamine(3.68 ml, 26.4 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(7 g, 22 mmol) in dimethylformamide (20 ml), 4.1 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[C:57]([CH3:63])=[N:58][C:59](Cl)=[CH:60][CH:61]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>>[CH3:1][O:2][C:3](=[O:64])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[C:57]([CH3:63])=[N:58][C:59]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[CH:60][CH:61]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(Cl)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: C1COCCN1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(N2CCOCC2)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(6-Chloro-2-methyl-pyridine-3-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was treated with morpholine according to General Procedure U to give (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methyl-6-morpholin-4-yl-pyridine-3-sulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (24 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][C:27]1([CH2:39][NH2:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28]1>C(#N)C>[CH3:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:11]([NH:40][CH2:39][C:27]1([CH3:26])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28]1)=[O:13]
Reactant: CC1(CN)CCN(Cc2ccccc2)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCC1(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 14.1 g (75 mmole) of t-butoxycarbonyl-L-alanine in 135 ml of dry acetonitrile was treated with 12.5 g (77 mmol) of 1,1'-carbonyldiimidazole. After stirring at room temperature for one hour and gas evolution had ceased, the reaction mixture was heated at 60° for one hour cooled to room temperature and treated with 14.2 g (70 mmol) of 3-methyl-1-(phenylmethyl)-3-pyrrolidinemethanamine. The reaction mixture was stirred at room temperature for 18 hours and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate/water and the organic layer was separated, washed with water, dried (MgSO4), and evaporated in vacuo to give 23.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.CS[C:18]1[S:22][C:21](B(O)O)=[CH:20][CH:19]=1.Cl.[CH3:27]C(O)C>>[ClH:1].[CH3:27][C:18]1[S:22][C:21]([C:2]2[N:7]=[N:6][C:5]([C:8]34[CH2:15][N:12]([CH2:13][CH2:14]3)[CH2:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(B(O)O)s1
Reactant: Clc1ccc(C23CCCN(CC2)C3)nn1
Reactant: CC(C)O
Agent: Cl
Product: Cc1ccc(-c2ccc(C34CCCN(CC3)C4)nn2)s1

Procedure:
This compound is obtained according to the method described in stage 1.6 of Example 1, using 5-(6-chloropyridazin-3-yl)-1-azabicyclo[3.2.1]octane, prepared according to stage 1.5 of Example 1, and 5-methylsulfanyl-2-thienylboronic acid. The hydrochloride thereof is prepared by treatment of the base with a solution of hydrochloric acid in propan-2-ol, and the crystals obtained are collected by filtration and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]([F:13])[F:12].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:3]([CH:11]([F:12])[F:13])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(F)F)c1Cl

Procedure:
A solution of 2-chloro-1-(difluoromethyl)-3-nitrobenzene (0.43 mmol) and SnCl2 dihydrate (0.86 mmol) in 1 mL EtOH was heated to 110° C. for 6 min in a closed vial. At RT, the mixture was diluted with water, basified with 1M NaOH solution to pH 13-14 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as brown oil;
Reaction SMILES: [CH2:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](Cl)[CH:12]=C.[CH2:15](Br)C=C.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH2:9]([C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:10])[CH3:15])[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: C=CCCl
Reactant: CC(O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: C=CCC(C)(O)Cc1ccccc1
Reaction time: 8 h

Procedure:
A 2-liter autoclave was charged with benzyl ethanol hydrogenated-tallow amine (632.2 gm.; 1.5 mol), 133.9 gm. allyl chloride, 18.1 gm. allyl bromide, 160 gm. sodium bicarbonate, and 175 ml isopropyl alcohol. The mixture was allowed to react at 100° C. overnight. An aliquot was removed and found to contain 61.2% amine. The apparent slow reaction rate was due to a leak in the autoclave. When the problem was corrected, an additional 133.9 gm. of allyl chloride and 18.1 gm. allyl bromide was added. The reaction as allowed to go overnight. An aliquot was removed and analyzed. It contained 16.1% amine and 0.4% amine HCl. An additional 36 gm. of allyl bromide was added. The following day, a sample was removed, analyzed, and found to contain 7% amine and 0.5% amine HCl. Allyl bromide (15 gm.) and 25 gm. of sodium bicarbonate were added and the reaction was continued overnight. Analyses of an aliquot showed there to be 0.0% amine HCl and 5.2% amine. The autoclave was charged with methyl chloride to finish the quaternization reaction. Final analysis showed an Effective gram molecular weight of 780.7.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[CH:12]=[N:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2]1.CC(C)([O-])C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1>O1CCCC1.O>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:13][CH:12]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=2)[C:11]2[CH:27]=[CH:28][CH:29]=[CH:30][C:10]=2[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CC(N=C(c2ccccc2)c2ccccc2)c2ccccc2-c2noc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to −65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystallised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>CCCCCCC.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][N:13]([C:33](=[O:34])[C:32]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:30]([C:29]([F:28])([F:43])[F:44])[CH:31]=1)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCNc1cnccc1-c1ccccc1Cl)OCc1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(NCCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl)OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from {2-[4-(2-chloro-phenyl)-pyridin-3-ylamino]ethyl}-carbamic acid benzyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (36%). MS (ESI): m/z=622.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]=[N:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[C:24]([O-])(=O)[CH3:25].[K+]>BrC1C=CC=CC=1.C(Cl)Cl.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]([C:25]4[CH:24]=[CH:6][CH:23]=[CH:2][CH:3]=4)[NH:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CC(=O)[O-]
Reactant: O=c1cc2nnc(=O)n-2c2ccc(Cl)cc2n1-c1ccccc1
Agent: [Cu]
Agent: [K+]
Solvent: ClCCl
Solvent: Brc1ccccc1
Product: O=C1N(c2ccccc2)NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N12

Procedure:
A mixture of 8.2 g of 8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione, 5 g of copper powder and 2.5 g of potassium acetate in 100 ml of bromobenzene are refluxed for 6 hours with stirring. The reaction is diluted with methylene chloride, filtered through a short Florisil column and the filtrate washed with dilute aqueous ammonium hydroxide. The organic phase is washed with water, dried and the solvent evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12].[CH2:18](O)C>>[CH2:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)[CH2:12][CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCO
Reactant: NC(=O)c1nccnc1N
Product: CCCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 4.6 g (0.033 mole) of 3-amino-2-pyrazinecarboxamide, 29.3 g (0.133 mole) of triethyl orthopropoxyacetate and 30 ml of acetic anhydride. Yld: 2.6 g (36%), m.p. 158°-160° C. (ethanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[C:9](Br)[C:8]1=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C([O-])=O)C=CO1)#[N:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:9]1[C:8](=[O:20])[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=1)#[N:22]
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccn1
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccn2)c1=O

Procedure:
A mixture of 0.05 g of 1-(2-pyridyl)-5-(2-pyridyl)-3-bromo-1,2-dihydropyridin-2-one, 0.04 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 0.02 g of tetrakistriphenylphosphine palladium and 0.1 g of cesium carbonate was stirred at 120° C. in a nitrogen atmosphere for 2 hours in dimethylformamide. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then saturated saline water, and dried by magnesium sulfate anhydride. The solvent was concentrated under a vacuum, and the residue was refined by silica gel chromatography (ethyl acetate/hexane=3:1), to obtain 0.04 g of the white, powdery subject compound.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC(C)C)=O.C([N:27](CC)CC)C.N>ClCCl.CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-nitrophenoxy)isobutyric acid (50) (5 g), isobutyl chloroformate (4.36 mL) and triethylamine (8 mL) in dichloromethane (20 mL) was stirred at room temperature for 1 hour. Then 2.0 M ammonia in methanol (20 mL) was added to the solution. The resulting solution was stirred at room temperature for 2 hours and then solvent was removed under reduced pressure. The mixture was purified by recrystallization from EtOAc and hexanes to give 2-(4-nitrophenoxy)-2-methylpropanamide (51).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:13]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][N:14]=2)=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:23][N:24]([CH3:28])[C:25](=[O:26])[O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:13]([CH:8]3[CH2:9][NH:10][CH2:11][CH2:12][N:7]3[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:14][O:15][C:16]=2[CH:21]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Temperature: 85 °C
Yield: 80.7 %

Procedure:
To a stirred solution of 3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazol-6-ol (0.80 g) in pyridine (10 ml) was added dimethylcarbamyl chloride (0.70 g) under N2. The reaction was heated to 85° C. for 2 hours. TLC (silica gel 30% MeOH/CH2Cl2) showed no starting material was present. The solvent was removed in vacuo and the residue was flash chromatographed (silica gel) eluting with 7% MeOH/CH2Cl2 to afford 0.80 g of material. The material was further purified through recrystallization from CH2Cl2 /pet. ether to afford 0.70 g of the product, m.p. 171-172° C.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43]([OH:45])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[N:53]1([C:59]2[C:60]3[CH:68]=[CH:67][CH:66]=[N:65][C:61]=3[N:62]=[CH:63][N:64]=2)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C1COCC1.CCOC(C)=O>[C:34]([O:38][C:39](=[O:40])[NH:41][CH:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43](=[O:45])[N:56]1[CH2:57][CH2:58][N:53]([C:59]2[C:60]3[CH:68]=[CH:67][CH:66]=[N:65][C:61]=3[N:62]=[CH:63][N:64]=2)[CH2:54][CH2:55]1)([CH3:35])([CH3:36])[CH3:37]
Reactant: c1cnc2ncnc(N3CCNCC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ncnc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
DIEA (0.74 mL) and HBTU (1.3 g) was added to the solution of (2R)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (0.092 g) in THF (5 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes, and then 4-piperazin-1-yl-pyrido[2,3-d]pyrimidine (0.31 g) was added. The reaction was stirred at room temperature for 1 hour. 20 mL of EtOAc was added and the organic layer was separated. The aqueous layer extracted with EtOAc (20 mL). The combined organic layer was washed with saturated sodium bicarbonate (20 mL) and dried over sodium sulfate. After removal of solvent, the residue was purified by flash chromatography (10:1=DCM:MeOH) to give [1-benzyl-2-oxo-2-(4-pyrido[2,3-d]pyrimidin-4-yl-piperazin-yl)-ethyl-carbamic acid tert-butyl ester as white foam solid (0.392 g, 58.9%). 1H NMR (CDCl3, 400 MHz) δ 9.11 (br, 1H), 8.92 (s, 1H), 8.15 (d, 1H), 7.40 (m, 1H), 7.20-7.33 (m, 5H), 5.42 (m, 1H), 4.85 (m, 1H), 3.78-3.82 (m, 2H), 3.61-3.70 (m, 2H), 3.50-3.58 (m, 2H), 3.15-3.20 (m, 1H), 3.08-3.12 (m, 2H), 1.42 (s, 9H). Rt 2.23 min. MS (ESI+) [M+H]+463.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][NH:18][C:10](=[O:12])[C@@H:9]1[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1C[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Yield: 82 %

Procedure:
A solution of Boc-Mop-OH (0.42 g, 1.71 mmol), H-Gly-OBn.TsOH (0.64 g, 1.88 mmol), DCC (0.35 g, 1.71 mmol), HOBt.H2O (0.26 g, 1.71 mmol) and DIEA (0.89 mL, 5.13 mmol) in DMF (30 mL) was stirred at room temperature under Ar(g) for 20 h. The mixture was filtered to remove insoluble DCU and concentrated by rotary evaporation under high vacuum. The product was isolated by flash chromatography (two columns were needed; the first was run in 8:2 EtOAc/hexanes and the second in 7:3 EtOAc/hexanes) affording Boc-Mop-Gly-OBn (0.55 g, 82%) as a clear oil. 1H NMR (500 MHz, CDCl3, ˜3:2 ratio of 2 rotamers): δ7.41-7.32 (m, 5 H), 6.53 (app bs, 0.4 H), 5.22-5.15 (m, 2 H), 4.44 (dd, J=7.9, 5.6 Hz, 0.6 H); 4.31 (t, J=7.8 Hz, 0.4 H), 4.16-3.97 (m, 2.6 H), 3.93 (app bs, 0.4 H), 3.81-3.72 (m, 0.6 H), 3.53-3.43 (m, 1.4 H), 3.32 and 3.31 (overlapping s, 3 H), 2.49-2.42 (m, 0.6 H), 2.41-2.33 (m, 0.4 H), 2.16-2.05 (m, 1 H), 1.89 (bs, 0.6 H), 1.47 (s, 5 H), 1.42 (s, 4 H);
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][CH2:15][N:16]([C:18]2[CH:19]=[CH:20][C:21](OS(C(F)(F)F)(=O)=O)=[N:22][CH:23]=2)[CH3:17])=[CH:9][N:8]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1B(O)O.[C:48](=[O:51])([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O>[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][CH2:15][N:16]([C:18]2[CH:19]=[CH:20][C:21]([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=3[O:51][CH3:48])=[N:22][CH:23]=2)[CH3:17])=[CH:9][N:8]=1
Reactant: CN(CCN(C)c1ccc(OS(=O)(=O)C(F)(F)F)nc1)c1ccc(OS(=O)(=O)C(F)(F)F)nc1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(N(C)CCN(C)c3ccc(-c4ccc(OC)cc4OC)nc3)cn2)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-bis(2-trifluoromethanesulfonyloxy-5-pyridyl)-N,N′-dimethylethylenediamine (108.0 mg, 0.200 mmol) synthesized in Reference Example 1 in ethanol-toluene (1:6, 3.5 mL) were added 2,4-dimethoxyphenylboronic acid (108.0 mg, 0.200 mmol), tetrakis-(triphenylphosphine)palladium (46.0 mg, 0.040 mmol) and a 2.0 M aqueous sodium carbonate solution (0.20 mL, 0.40 mmol). After stirring at 80° C. for 2 hours, brine was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified column chromatography on silica gel to provide N,N′-bis[2-(2,4-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine as a colorless amorphous powder (109.0 mg; quantitative).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C>[CH2:3]([N:9]1[CH2:14][CH2:13][N:12]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:11](=[O:15])[C:10]1=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCN1CCNC(=O)C1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(Cc2ccc([N+](=O)[O-])cc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
With 1.1 g of sodium hydride (50% purity) was mixed 50 ml of DMF, and 4.6 g of 1-n-hexyl-2,3-dioxopiperazine was added thereto with stirring at room temperature over a period of 10 minutes. Subsequently, the resulting mixture was subjected to reaction at 50° to 60° C. for 30 minutes, and 5.5 g of p-nitrobenzyl bromide was added to the reaction mixture over a period of 10 minutes, after which the mixture thus obtained was further subjected to reaction at 50° to 60° C. for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was extracted with 70 ml of ethyl acetate, and the ethyl acetate layer was washed with water and then a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The crystals thus obtained wre recrystallized from isopropyl alcohol to obtain 4.0 g (51.9% yield) of 1-n-hexyl-4-(4-nitrobenzyl)-2,3-dioxopiperazine having a melting point of 115° to 117° C.