Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([OH:41])=[C:36]([CH3:42])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:43]=[CH:44][CH:45]=[CH:46][C:4]=2[NH:3]1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:41][C:47](=[O:49])[CH3:48])=[C:36]([CH3:42])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:43]=[CH:44][CH:45]=[CH:46][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C

Procedure:
A solution of 42 mg (0.07 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 7i) in 5 mL acetic anhydride was heated to 50° C. for 2 h. The mixture was evaporated down i.vac. and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OC)c(N)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of methyl 3-amino-4-methoxybenzoate (0.509 g, 2.81 mmol) in pyridine (10 ml), methanesulfonyl chloride (0.285 ml, 3.65 mmol) was added drop wise and the mixture was stirred at RT for 2 hours. The solvent was removed under vacuum, and the crude was portioned between EtOAc and HCl 1N. The organic phase was dried over Na2SO4 and the solvent was removed. The crude was purified by filtration through a silica gel cartridge (DCM:EtOAc=90:10) to give methyl 4-methoxy-3-(methylsulfonamido)benzoate (0.673 g, 2.60 mmol, 92% yield, MS/ESI+ 259.9 [MH]+).
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[C:3]1=[O:18].[CH3:19][Li].O>C(OCC)C>[OH:18][C:3]1([CH3:19])[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:2]1[CH3:1]
Reactant: [Li]C
Reactant: CC1C(=O)c2ccccc2C=Cc2ccccc21
Solvent: O
Solvent: CCOCC
Product: CC1c2ccccc2C=Cc2ccccc2C1(C)O

Procedure:
To a stirred solution of 5-methyl-6-oxo-dibenzo[a,e]cyclooctene (0.1 g) in anhydrous diethyl ether (10 ml) under nitrogen at 0° C. was added methyl lithium (0.43 ml of a 1.4 M solution in diethyl ether). After stirring for approximately 30 minutes water (10 ml) was added. The phases were separated and the ethereal layer was washed with water (2×10 ml), dried (Na2SO4) and the solvent removed in vacuo to give the title compound as a colourless solid (0.104 g), mP 86°-87° C. δ1.43 (CDCl3 360 MHz,) (3H, s, C--CH3), 1.44 (3H, d, J=7.0 Hz, --CH--CH3), 2.03 (1H, s, --OH), 4.07 (1H, q, J=7.0 Hz, --CH--CH3), 6.75 (1H, d, J=11.8 Hz, CHA =CHB), 6.96-7.21 (8H, m, ArH and CHA =CHB), 7.41 (1H, d J=7.5 Hz, ArH), 7.85 (1H, d J=7.9 Hz, ArH) m/e 250 (M+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([C:17](Cl)=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:22]([O:24][C:25](=[O:27])[NH2:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:27])[NH:26][C:17]([CH:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:18])[CH3:23]
Reactant: O=C(Cl)C1c2ccccc2Oc2c1cccc2C(F)(F)F
Reactant: CCOC(N)=O
Product: CCOC(=O)NC(=O)C1c2ccccc2Oc2c1cccc2C(F)(F)F

Procedure:
The title compound, white solid, m.p.=196-198° C., MS: m/e=365 (M+) was prepared in accordance with the general method of example 36 from 4-trifluoromethyl-9H-xanthene-9-carbonyl chloride and carbamic acid ethyl ester.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3\[O:11][C:12]([CH3:14])([CH3:13])[C:8]([C:30]4[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=4)=[CH:9]\3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Temperature: 88 °C

Procedure:
To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (200 mg, 0.62 mmol), 6-fluoropyridin-3-ylboronic acid (104 mg, 0.74 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (2.5 mL, 2.5 mmol). The mixture was heated at 88° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-5% MeOH/CHCl3 afforded (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 100 mg, 47%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([OH:26])[C@@H:21]1[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([O:26][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)[C@@H:21]1[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](F)C[C@@H]1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a stirring solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-2-((tert-butyldiphenylsilyloxy)methyl)-3-fluoro-5-hydroxycyclopentyl)hept-5-enoate (prepared in Step D, 28.6 g, 52.8 mmol) in anhydrous DCM (500 mL) was added dihydropyran (6.69 g, 79.3 mmol). The reaction mixture was cooled to 0° C. and p-toluenesulfonic acid (25 mg) was subsequently added and the reaction was stirred for 2 hours at 0° C. The reaction mixture was then allowed to warm to room temperature and stirring was continued for another 2 hours. The crude reaction mixture was transferred to a separatory funnel, washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic phase was dried over sodium sulfate, filtered, and the solvents were removed by evaporation to afford the crude title intermediate (32.7 g). The crude intermediate was carried on with no further purification.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[N+:21]([O-])=O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C>[Fe].O1CCOCC1>[C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[NH2:21])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1COCCO1
Product: Nc1ccc(OC(=O)C=Cc2ccccc2)c(N)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
62.8 g (200 milimole) of 2,4-dinitrophenyl cinnamate, 15 g of carbon black with 5% Pt and 2% iron (product with water content of about 50%), and 500 ml of 1,4-dioxane were placed in a reaction vessel (hydrogenating apparatus), and then the reaction mixtures were heated at 60° C. with stirring under a hydrogen atmosphere. In approximately 20 hours, 14.50 L of hydrogen was absorbed, and the reaction was completed when the absorption of hydrogen stopped. Then the reacted solution was separated by filtration to remove the catalyst. The filtrate was concentrated, and 50.8 g of 2,4-diaminophenyl cinnamate was yielded. The exothermic peak temperature was 230° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30]I)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(#N)C.C(O)C>[N+:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][N:2]([CH2:3][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:1])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CNCc1cnc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1cnc2ccccc2n1
Temperature: 85 °C
Yield: 83.1 %

Procedure:
To a stirred suspension of 2-(methylaminomethyl)quinoxaline (1.10 g, 6.35 mmol) and potassium carbonate (0.88 g, 6.35 mmol) in 2:1 acetonitrile/ethanol (40 mL) was added 1-(4-nitrophenoxy)-3-iodopropane (1.95 g, 6.35 mmol). The resulting mixture was heated at 85° C. overnight, concentrated, and partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic phase was dried (MgSO4), decolorized (charcoal), and concentrated to afford 1.86 g (83%) of product as a yellow semi-solid which was of sufficient purity to use in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([Cl:22])=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([N:15]=1)=[CH:13][C:12]([C:10]([C:4]1[C:3]([F:23])=[C:2]([NH:1][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:7]=[C:6]([F:8])[C:5]=1[F:9])=[O:11])=[CH:21][CH:20]=2
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Yield: 15.1 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (40 mg, 0.119 mmol, 1.0 eq.) in DCM (5 mL) was added propane-1-sulfonyl chloride (84.6 mg, 0.593 mmol, 5.0 eq.) and pyridine (94 mg, 1.19 mmol, 10.0 eq.). The mixture was heated under reflux overnight, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) and Prep-TLC to afford N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide (8 mg, 15.2%). LRMS (M−H−) m/z calculated 442.0, found 442.0. 1H NMR (CDCl3, 400 MHz) δ 8.91 (s, 1 H), 8.27-8.41 (m, 3 H), 7.71-7.77 (m, 1 H), 6.63 (s, 1 H), 3.13-3.17 (t, 2 H), 1.86-1.94 (q, 2 H), 1.07-1.11 (t, 3 H).
Reaction SMILES: [C:1]([S:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[OH-].[K+].Cl[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][C@H:31]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:32]([N:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:35])=[O:33])[CH:27]=CC=1.Cl>C(O)C>[C:47]([O:46][C:45]([NH:44][C@H:31]([C:32]([N:34]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])=[O:33])[CH2:30][C:26]1[CH:27]=[C:2]([CH:23]=[CH:24][CH:25]=1)[CH2:1][S:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:51])([CH3:49])([CH3:50])[CH3:48]
Reactant: CCOC(=O)Cc1c(SC(C)=O)[nH]c2ccccc12
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCl)c2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(SCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)[nH]c2ccccc12
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution ethyl 2-(2-(acetylthio)-1H-indol-3-yl)acetate (380 mg, 1.4 mmol) in ethanol (5 ml) was added potassium hydroxide (84 mg, 1.5 mmol). After 10 minutes, (5)-tert-butyl 3-(3-(chloromethyl)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (I-5, 605 mg, 1.4 mmol) was added to the solution. The reaction was stirred for 2 hours and then neutralized with 1N (aq) HCl and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (1-5% MeOH/DCM) to provide the desired product (796 mg, 1.26 mmol), 90%. MS (m/z) 632 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]([O-])=[O:10].[Na+]>>[Cl:1][C:2]1[C:3](=[O:8])[CH:4]=[CH:5][C:6](=[N:9][OH:10])[CH:7]=1
Reactant: O=N[O-]
Reactant: Oc1ccccc1Cl
Agent: [Na+]
Product: O=C1C=CC(=NO)C=C1Cl

Procedure:
2-Chloro-1,4-benzoquinone-4-oxime was prepared by reaction of 2-chlorophenol with sodium nitrite under acidic conditions by the method described by T. Ishikawa et al. in J. Org. Chem. 1996, 61, page 2778.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.C(N(CC)CC)C.[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[Cl:21][C:22]1[C:30]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:25]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1.06 g, 5.55 mmol, Intermediate 4) and triethylamine (0.850 ml, 6.10 mmol) were dissolved in dichloromethane (DCM) (25 ml). 2-chloro-3-(trifluoromethyl)benzoyl chloride (1.348 g, 5.55 mmol) was added and the mixture stirred at room temperature for 24 h. The solvents were removed in vacuo and the solid partitioned between dichloromethane (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with dichloromethane (3×50 ml), the combine organic extracts were dried over anhydrous sodium sulfate and then concentrated to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (2.22 g, 5.58 mmol, 101% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].C(O)C>>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Product: CCNc1ncccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 92 %

Procedure:
2-Chloro-3-nitropyridine (20.00 g, 126 mmol) was added to ethylamine in ethanol (40 mL, 80 mmol) at room temperature and kept overnight. The solution was evaporated, the residue was diluted with 150 mL of EtOAc, washed with aqueous NaHCO3 and purified by column chromatography on silica gel (hexane/ethyl acetate 4/1) to give yellow solid (19.5 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: Oc1ccccc1F
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1ccccc1OCCCBr
Reaction time: 24 h
Yield: 26.2 %

Procedure:
To a solution of 2-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed by Cs2CO3 (0.232 g, 0.713 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0274 g, 26.2%). ELMS Rt (2.24 min).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1>ClC1C=CC=CC=1>[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 47.3 %

Procedure:
304.2 g (3.53 mol) of piperazine, 7.5 g of chlorobenzene, 39.8 g (0.235 mol) of 3-chloro-1,2-benzisothiazole were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, which was heated to stir at about 120° C. for 20 hours. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 24.4 g (m.p. 89° to 90 ° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 3-chloro-1,2-benzisothiazole was 47.4%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH2:15][CH3:16])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:17]1([C:23]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]3)[O:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:1][C:2]1[C:3]([O:14][CH2:15][CH3:16])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:36][CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:26]2[O:25][N:24]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:27]=2)[CH2:34][CH2:33]1)=[O:9]
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOc1nc(OCC)c(C(=O)O)cc1N
Product: CCOc1nc(OCC)c(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1N

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 298 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C1C=CC2N(O)N=NC=2C=1.[CH2:24]([O:42][CH:43]1[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH2:46][CH:45]([C:87](O)=[O:88])[CH2:44]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][C:87]([CH:45]1[CH2:46][CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:43]([O:42][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:44]1)=[O:88]
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2cc(C(=O)OC)ccc2OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Methyl 3-amino-4-methoxybenzoate (81 mg, 0.44 mmol) was dissolved in chloroform (1 ml), HOBt (7 mg, 0.05 mmol) and 3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (199 mg, 0.22 mmol) were added. EDC.HCl (45 mg, 0.23 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (10 ml) to give N-(2-methoxy-5-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (225 mg, 0.21 mmol, yield 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[C:19]([F:18])([F:28])[F:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2-trifluoromethyl-benzylbromide (95.6 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (75.0 mg, 48.1%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].O1CCCC1.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])=[O:14])[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To a 20 mL volume two-necked flask, 0.50 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 10 ml of tetrahydrofuran (anhydrous), 0.27 g of acetophenone and 130 mg of acetic acid were added under a nitrogen atmosphere, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (60 ml) was added to the residue and the resultant was extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure and subjected to silica gel column, chromatography (ethyl acetate:chloroform=3:1) to give 0.32 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-phenyl-1-ethylidene)hydrazine ((40-b)-(15)-6).