Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5](N)=[C:4]([I:12])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([I:12])[CH:3]=1
Reactant: Nc1c(I)cc(Br)cc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
4-bromo-2-iodo-6-nitroaniline (5 g, 0.0145 mol) was added in portions to stirred concentrated sulfuric acid (60 ml) keeping the temperature at 0-5° C. After stirring in the cold for 1 h, sodium nitrite (2.3 g, 0.0326 mol) was added and the reaction mixture stirred in the cold for a further 2 h. The reaction mixture was then poured into ice (250 ml). The resultant mixture was added, in portions, to a boiling solution of copper (II) sulfate (0.36 g, 0.00145 mol) in ethanol (150 ml) and boiled for a further 2 h. The reaction mixture was cooled to ambient temperature and extracted with ethyl acetate (300 ml) which was washed with saturated sodium hydrogen carbonate solution (250 ml) and dried (MgSO4). The solvent was removed in vacuo to give 3-Bromo-5-iodonitrobenzene as a yellow solid (4.21 g, 88%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(NC(C)C)(C)C.[CH2:38]([OH:41])[C:39]#[CH:40]>C1(C)C=CC=CC=1.[Cu]I.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:24]([N:22]([CH3:23])[C@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]([CH2:14][CH3:15])[C:4]2[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([C:40]#[C:39][CH2:38][OH:41])[CH:3]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CCN(c1cc(C#CCO)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (2 g, 4.14 mmol) in dry toluene was added CuI (0.015 g, 0.079 mmol), PPh3 (0.043 g, 0.165 mmol), PdCl2(PPh3)2 (0.058 g, 0.082 mmol), N,N-diisopropyl amine (1.08 g, 10.78 mmol) and reaction was purged with argon for 15 min. prop-2-yn-1-ol (0.46 g, 8.29 mmol) was added to it reaction was heated at 80° C. at sealed condition for 5 h. On completion, it was quenched with water and extracted with ethyl acetate. Organic layer was dried over Na2SO4. The crude compound was purified by column chromatography to afford the title compound (1.2 g, 63.2% yield).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC.C(N(CC)CC)C>O1CCOCC1.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>[CH3:20][C:12]1[C:11]([NH:10][C:9]2[C:6]([C:7]#[N:8])=[CH:5][N:4]=[CH:3][C:2]=2[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(Nc2c(C#N)cncc2-c2nccs2)ccc2[nH]ccc12

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (120 mg, 0.32 mmol), 2-(tributylstannyl)-1,3-thiazole (340 mg, 0.91 mmol), dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and triethylamine (36 mg, 0.35 mmol) in dioxane (4 mL) was heated at reflux for 24 h. 4-[(4-Methyl-1H-indol-5-yl)amino]-5-(1,3-thiazol-2-yl)nicotinonitrile was obtained following the work-up and purification procedures as described for the preparation of 5-(2-formyl-1-methyl-1H-imidazol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 541. HPLC retention time: 10.1 min.(g); MS: 332.2 (M+H); melting range: 245-247° C.; and HRMS: 332.0964.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(Cl)Cl.CO>[NH2:23][CH2:22][C@@H:7]1[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2C(=O)c3ccccc3C2=O)c(OC)c1
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN)c(OC)c1
Reaction time: 16 h

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (4.40 g, 8.31 mmol) in DCM:MeOH (5:1, 60 mL) was added hydrazine hydrate (1.50 g, 25.0 mmol). After stirring for 16 h the precipitate was filtered off and the filtrate was concentrated, affording title compound (quantitative) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([CH:16]([CH3:36])[CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:3]1.[H][H]>[Pd].COCCO>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([CH:16]([CH3:36])[CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:3][C@H:2]1[OH:1]
Reactant: [H][H]
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: COCCO
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Yield: 87.5 %

Procedure:
A mixture of 63 parts of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[(phenylmethyl)amino]-1-piperidinebutanamide and 485 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated with methylbenzene, yielding 45 parts (87.5%) of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide (interm. 9).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].C([O-])([O-])=O.[K+].[K+].Cl.Br[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: BrCCN1CCOCC1
Reactant: CCOC(=O)c1cn([C@H]2CCCNC2)c2ncc(Br)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn([C@H]2CCCN(CCN3CCOCC3)C2)c2ncc(Br)cc2c1=O
Temperature: 120 °C

Procedure:
(S)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate hydrochloride Intermediate 33, 0.400 g, 0.96 mmol) and K2CO3 (0.663 g, 4.80 mmol) were taken up in acetonitrile (3 mL) and 4-(2-bromoethyl)morpholine hydrochloride (0.221 g, 0.96 mmol) added. The reaction mixture was heated to 120° C. in the microwave for 30 min. The reaction mixture was cooled to room temperature and filtered, and the inorganics were washed with EtOAc two times. The solvent was removed in vacuo. (S)-ethyl 6-bromo-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (0.420 g, 89%) was recovered as a tan solid and will be carried on without further purification. MS (ES)(M+H)+: 494 for C22H29BrN4O4.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.II.[I:20]([O-])(=O)=O.[Na+]>C(O)(=O)C>[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: [O-][I+2]([O-])[O-]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 472.8 %

Procedure:
To a solution (S)-2-amino-3-phenylpropanoic acid 91 (4.01 g, 24.3 mmol) in acetic acid (22 mL) was added sulfuric acid (2.9 mL, 5.14 mmol), iodine (2.47 g, 4.7 mmol) and sodium iodate (1.02 g, 5.14 mmol). The mixture was heated to 70° C. and allowed to stir at this temperature for 16 h before an additional portion of sodium iodate (1.02 g, 5.14 mmol) was added. The reaction was left for a further 2 h before being concentrated, dissolved in methanol (20 mL) and treated with NaOH (60 mL). The mixture was left to precipitate out of the basic solution overnight and the resulting solid was filtered by vacuum filtration to yield the title compound (7.07 g, 24.3 mmol, 100%) as a pink solid, which had spectral data in agreement with that reported.93 [α]D21 −10.6 (c. 0.3, HCl). Mp 258-260° C. (lit. 261-262° C.)93 1H NMR (CD3OD, 300 MHz): δ 7.71 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 7.10 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 4.26 (dd, J=6.3, 7.2 Hz, H2); 3.26 (dd, J=5.4, 14.1 Hz, 1H, H3a); 3.04 (dd, J=7.2, 14.4 Hz, 1H, H3b). Mass Spectrum (CI, +ve) m/z 279 (100%), 292 (70%) [M+]. HRMS calcd for C9H11NO2 291.9834 found 291.9568.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][N:4]1[C:9](=O)[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH2:5][CH2:6][C:7]([CH3:11])([CH3:12])[CH2:8][CH2:9]1
Reactant: CC(C)CN1C(=O)CC(C)(C)CC1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(C)CN1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-(2-Methylpropyl)-3,3-dimethylglutarimide (19.5 g, 0.0984 mol) in dry ether (30 ml) was added via a dropping funnel over 30 minutes to a suspension of lithium aluminum hydride (5.36 g, 0.141 mol) in dry ether (50 ml) at 0° C. stirring under nitrogen. The mixture was then boiled for 3 hours, allowed to cool to room temperature and the excess lithium aluminium hydride was decomposed by careful addition of solid sodium sulphate decahydrate (20 g). After the suspended solid had turned white, the mixture was filtered, the solid washed twice with ether (2×50 ml), and the combined filtrate concentrated to yield a colourless liquid. Distillation gave the pure product, (1-(2-methylpropyl)-4,4-dimethylpipeidine, 13.0 g (82%), b.p. 81°-82° C./16 mmHg. 1H NMR (CDCl 3) δ2.30 (4H, t), 2.05 (2H, d), 1.80 (1H, m), 1.35 (4H, t), 0.90 (6H, s) and 0.85 (6H, d).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH:15][C:16]1[C:24]([CH:25]=[O:26])=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[C:17]=1[O:27][CH3:28]>O1CCOCC1>[OH:15][C:16]1[C:24]([CH:25]=[O:26])=[CH:23][C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]=1[O:27][CH3:28]
Reactant: COc1c(O)c(C=O)cc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1c(O)c(C=O)cc2ccoc12

Procedure:
A solution of 817 mg. (3.6 mmole) of DDQ in 10 ml. of dioxane was added to 582 mg. (3 mmole) of 2.3-Dihydro-6-hydroxy-7-methoxy-5-benzofurancarboxaldehyde in 15 ml. of dioxane and the resulting mixture was heated under reflux for 7 hours, cooled and the formed solid removed by filtration. The precipitate was thoroughly washed first with benzene, then with CHCl3. The washings were combined with the initial filtrate and the total concentrated in vacuo to a residue which was chromatographed first on a 20 ml. dry silica gel column (E. Merck 7734) with CHCl3 elution followed by conventional chromatography over 20 g. of silica (E. Merck 7734) packed in benzene-ethyl acetate (95:5) and elution with this solvent mixture provided, after workup, a yellow solid, m.p. 60°-62°.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([CH:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)O)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[H][H]>C(O)C.[Pd]>[CH2:27]([C:19]1[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10]3)[N:17]=2)=[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: OC(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: c1ccc(Cc2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 65.9 %

Procedure:
To a solution of concentrated sulfuric acid (9 mL, 169 mmol) in ethanol (25 mL) was added 10% palladium on carbon (200 mg) and a solution of {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (350 mg, 0.908 mmol) in ethanol (5 mL). The reaction mixture was stirred under 55 PSI of hydrogen for 3 days. The reaction mixture was filtered through a pad of celite. Saturated aqueous sodium bicarbonate solution was added to the filtrate until basic. The resulting mixture was concentrated on rotovap to remove the excess ethanol, then extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (29:1 dichloromethane:methanol) provided 4-(2-benzylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (221 mg, 66%) as an off-white solid. 1H NMR (CDCl3) δ 8.45 (d, 1H), 8.25 (d, 1H), 8.19 (d, 1H), 7.30–7.13 (m, 6H), 6.82 (m, 1H), 6.63 (d, 1H), 5.12 (d, 1H), 4.52 (s, 2H), 4.35 (m, 1H), 2.03 (m, 2H), 1.78–1.50 (m, 6H); MS m/z 370 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:26]2[CH2:25][CH2:24][N:23]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:22]([CH3:21])[CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2C(C)(C)C)cc1

Procedure:
71 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 2-methyl-1-m-tolylpiperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Br:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[Br:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Br)nc2n1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Br)nc3n2)cc1
Temperature: 4 °C
Yield: 46.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (10.2 g), N,N'-carbonyldiimidazole (10.8 g) and 2-amino-7-bromo-1,8-naphthyridine (11.2 g). The product produced by precipitation in water (9.8 g; m.p. 220° C.) is dissolved in boiling acetonitrile (1000 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-bromo-1,8-naphthyridin-2-yl)-4-methoxybenzamide (8.3 g) is produced, m.p. 221° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].CCN(CC)CC.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:34]([NH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:25])([F:36])[F:37])=[O:35]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.11 g, 4.68 mmol) and Et3N (720 ml, 5.17 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (707 ml, 4.68 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and washed with n-hexane to give tert-butyl 3-methoxy-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.11 g, 56%) as a white crystalline powder. mp 131–133° C.; 1H-NMR (CDCl3) δ 1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.83–6.88 (m, 3 H), 6.98 (br s, 1 H), 7.17–7.21 (m, 1 H), 7.52–7.59 (m, 2 H), 7.89–7.91 (m, 1 H), 8.04–8.06 (m, 1 H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH:14]=[C:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1.Cl.[CH3:45][NH:46][O:47][CH3:48]>CO>[CH3:48][O:47][N:46]([CH3:45])[C:16]([C:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH:14]=1)=[O:18]
Reactant: CNOC
Reactant: O=C(O)C1=CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CO
Product: CON(C)C(=O)C1=CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of Compound 260a (100 mg, 0.40 mmol) in methanol (10 mL) stirred at r.t., was added DMT-MM (4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 142 mg, 0.52 mmol), N-methylmorpholine (88.4 μL, 0.81 mmol) and N,O-dimethylhydroxylamine hydrochloride (60 mg, 0.615 mmol). The reaction mixture was stirred at r.t. for 3 h. The solvent was evaporated to dryness in vacuo. The residue was diluted with aq. 1N NaOH and dichloromethane. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 60:40) affording the title product (90 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:26][OH:27])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[C:22]([F:24])([F:23])[F:25])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Sulfur trioxide-pyridine complex (23.4 g, 147 mmol) was added to a stirred solution of {9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}methanol (8.72 g, 20.9 mmol), triethylamine (23.3 mL), and dimethyl sulfoxide (140 mL) in dichloromethane (30 mL) at room temperature, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (6.90 g, 16.7 mmol, 80%).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][C@@H:6]([OH:7])[C@H:2]([N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Trans-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.47 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 6.7 mL, 2.25 mmol) and the mixture was heated at 50° C. for 3 hour. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 hours. The residue was then dissolved in dimethyl formamide (5 mL) and potassium carbonate powder (435 mg, 3.15 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (30 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 751 mg (64% yield) of racemic trans-ethyl 1-(1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:13]([OH:15])=O.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8][CH2:7]2)=[O:15])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCO2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCO2
Yield: 25.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6-methoxychroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide (0.3 g) was obtained. melting point: 82-84° C.