Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.[Cl-:28].[Li+].N(OCCC(C)C)=O>C(#N)C.[Cu](Cl)Cl>[Cl:28][C:2]1[CH:6]=[C:5]([C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: [Cl-]
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [Li+]
Solvent: CC#N
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
A mixture of N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5- yl]phenoxy}ethyl)urea 111 mg, lithium chloride 64 mg, and copper (II) chloride 81.2 mg in acetonitrile 2 ml was stirred at ambient temperature for 10 minutes. To this mixture was added isoamyl nitrite 62.3 mg, and the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution, H2O, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHCl3=10%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt/IPE to give N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea 31.1 mg as a white powder.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>CC#N>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([NH:27][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][O:17][CH2:18][CH2:19]3)=[CH:29][CH:28]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC#N
Product: CN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
4-Chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (70 mg, 0.27 mmol) and 4-morpholinoaniline (97 mg, 0.54 mmol) in MeCN (2 ml) was heated in a microwave reactor at 140° C. for 15 mins, then at 140° C. for 15 mins. The mixture was purified by preparative HPLC (Kromasil-column C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (46 mg, 42%); 1H NMR (400 MHz, CDCl3): δ 7.10-7.23 (m, 6H), 6.58-6.63 (m, 2H), 6.49-6.55 (m, 2H), 3.77-3.83 (m, 4H), 3.27 (s, 3H), 2.96-3.01 (m, 4H); Mass Spectrum: M+H+ 400.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[NH2:29].[OH-].[Na+]>O1CCCC1>[NH2:29][C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:19]=1[O:18][C:5]1[CH:6]=[CH:7][C:8]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][C:4]=1[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1Oc1ccc(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)O)c1
Temperature: 0 °C

Procedure:
Methyl-2-(2-amino-4-trifluoromethylphenoxy)-5-(1,1,3,3-tetramethylbutyl)benzoate (330 mg, 0.0008 mol) was mixed in tetrahyrofuran (15 mL) and cooled to 0° C. 1N Sodium hydroxide was added and stirring was continued, allowing the mixture to warm to room temperature. After 16 h the tetrahydrofuran was evaporated and the residue mixed in water. 3N Hydrochloric acid was added, bringing the pH to 4.0. The aqueous phase was extracted with ethyl acetate. The organic phase was dried (MgSO4) and the solvent was evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CD3OD) δ7.97 (d, 1H), 7.54 (dd, 1H), 7.09 (d, 1H), 6.71-6.98 (m, 2H), 6.60 (d, 1H), 3.83 (s, 1H), 1.79 (s, 6H), 0.73 (s, 9H).
Reaction SMILES: [ClH:1].[CH:2]([N:5]([CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[CH3:21][S:22]([O:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=3)[S:31][C:30]=2[CH:45]=1)(=[O:24])=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>C(O)C>[ClH:1].[CH:18]([N:5]([CH:2]([CH3:3])[CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([C:33]2[C:29]3[CH:28]=[CH:27][C:26]([O:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:45][C:30]=3[S:31][C:32]=2[C:34]2[CH:35]=[CH:36][C:37]([O:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:38][CH:39]=2)=[O:15])=[CH:16][CH:17]=1)([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: CC(C)N(CCOc1ccc(C(=O)O)cc1)C(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)N(CCOc1ccc(C(=O)c2c(-c3ccc(OS(C)(=O)=O)cc3)sc3cc(OS(C)(=O)=O)ccc23)cc1)C(C)C

Procedure:
A 7.6 g. portion of 4-(2-diisopropylaminoethoxy)benzoic acid, hydrochloride, was converted to the acid chloride as described in Example 1 above, and was used to acylate 5 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene in the presence of 20 g. of aluminum chloride. Work up according to Example 4 gave 7.4 g. of crystalline product after trituration of the isolated oil with denatured ethanol. The product was recrystallized from denatured ethanol to obtain 6.5 g. of purified product, and a 1.5 g. portion was further purified by chromatography over silica gel, eluting with 1:3 methanol:chloroform to obtain 1.15 g. of analytical sample, m.p. 198°-201°.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([O:24][CH3:25])[CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1C(OCC)=O.[OH-].[Na+]>O1CCOCC1>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([O:24][CH3:25])[CH:12]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)c(OC)c3)cnn2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(-c2cnn3c(O)ccnc23)ccc1Sc1ccccc1

Procedure:
To 340 mg of 7-hydroxy-6-ethoxycarbonyl-3-(3-methoxy-4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine, 15 ml of dioxane and 2 ml of aqueous solution of 2N sodium hydroxide were added, and heated and refluxed for 1 hour. The reaction mixture was concentrated in vacuo, and 30 ml of water was added to the residue, which was neutralized with acetic acid. The precipitate was filtered, washed with water and dried, and the title compound was obtained (260 mg)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 49.2 %

Procedure:
A suspension of 0.47 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine in 7 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 15 minutes. The reaction mixture is poured into 25 cm3 of water and 9 cm3 of N hydrochloric acid are added. The solid obtained is drained and washed with 3 times 5 cm3 of water. After recrystallizing once from a mixture of 4.5 cm3 of ethanol and of 4.5 cm3 of dimethylformamide, 0.29 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C..
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][Si:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][O:17][C:18](ON1C(=O)CCC1=O)=[O:19].C(N(CC)CC)C>ClCCl>[CH3:13][Si:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][O:17][C:18]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:19]
Reactant: COC(=O)CCCCCCN
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCCNC(=O)OCC[Si](C)(C)C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Methyl 7-amino-heptanoate hydrochloride (7.0 g, 35.9 mmol) was dissolved in dichloromethane (75.4 mL), and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (10.0 g, 38.6 mmol) and triethylamine (10 mL, 71.7 mmol) were then added at room temperature. The mixture was stirred for 5 hours, and then quenched with water (100 mL), and separated. The aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain 8.89 g (29.3 mmol, 82% yield) of methyl 7-(2-trimethylsilanyl-ethoxycarbonylamino)-heptanoate.
Reaction SMILES: [CH3:1][C@H:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)OC(=O)[NH:3]1.[H][H]>CO.CC(O)=O.[Pd]>[NH2:3][C@@H:2]([CH3:1])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A suspension of (S)-4-methyl-5,5-diphenyl-2-oxazolidinone (11) (3.52 g, 13.90 mmol) in MeOH/AcOH and a 10% Pd (148 mg, 1.39 mmol) on activated carbon was shaken for 45 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl (2M, 100 ml), stirred overnight at room temperature, made basic with NaOH pellets, and saturated with K2CO3. The organics were then extracted into diethyl ether (3×100 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Impurities were washed with AcOEt over silica gel by means of dry-flash column chromatography, and then further elution with a mixture of MeOH and AcOEt, ranging from 5% up to 30%, gave the title compound (12) (1.90 g, 65%) as a white solid. m.p. 76–77° C. [α]D25=−19.32 (c, 0.10765 in CHCl3). δH 1.04 (3H, d, 3J=6.30 Hz, CH3), 1.31 (2H, broad s, NH2), 3.55 (1H, d, J=9.90 Hz, CH—Ph2), 3.73 (1H, dq, 3J=6.30 and 10.20 Hz, CH—NH2), 7.10–7.40 (10H, m, Ar—H). δC 22.4 (CH3), 50.3 (CH—NH2), 62.4 (CH—Ph2), 126.5, 126.8, 128.2, 128.5, 128.7 and 129.0 (o-, m- and p-Ar), 143.3 and 143.7 (α-Ar). Anal. Calcld for C15H17NO: C 85.26; H 8.11; N 6.63. Found: C 85.10; H 8.08; N 6.36. ir 3343 (NH2). m/e (CI—NH3) 212 (MH+, 100%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:28])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCCC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCCC1

Procedure:
Using 1 g of N-(trans-4-methylcyclohexyl)-4-[2-(1-pyrrolidinyl)ethoxy]-3-methoxycinnamamide (Example 143), 0.05 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 0.88 g of N-(trans-4-methylcyclohexyl)-3-{4-[2-(1-pyrrolidinyl) ethoxy]-3-methoxyphenyl}propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cc1ccc(NCc2nnn(C)n2)c(C)c1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(C)cc2C)[C@H]1O
Yield: 57 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (250 mg, 0.89 mmol) obtained in step 1 of example 2 and N-(2,4-dimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (256 mg, yield: 57%).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1)[CH2:2][CH3:3]>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:4]1[S:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncc(CO)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCCc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
100 g of manganese dioxide were added to 21 g of 2-propyl-5-thiazole-methanol in 1000 ml of benzene and the mixture was stirred for 3 hours at room temperature. 40 g of manganese dioxide were added and the mixture was stirred at room temperature for 2 hours after which another 20 g of managanese dioxide was added. The mixture was stirred for 16 hours at room temperature and was filtered and the filter was washed with methylene chloride. The filtrate was evaporated to dryness under reduced pressure to obtain 18.5 g of 2-propyl-5-thiazolecarboxaldehyde.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:27]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(OC)c(OC)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-dimethoxybenzoyl chloride, there is obtained ethyl N-(3,4-dimethoxybenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 430 (12), 401 (5), 194 (100), 165 (42);
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:9][C:10](ON1C(=O)CCC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:47][CH2:48][CH2:49][CH2:50][N:51]([CH2:78][C:79]1[N:80]([CH2:84][C:85]([N:87]([CH2:96][C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:86])[CH:81]=[CH:82][N:83]=1)[CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:77])[N:60]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH2:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH:55]=[CH:56][N:57]=1)[C:44]([OH:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:100]([O:99][C:97](=[O:98])[CH2:96][N:87]([CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])[C:85](=[O:86])[CH2:84][N:80]1[CH:81]=[CH:82][N:83]=[C:79]1[CH2:78][N:51]([CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:77])[N:60]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH2:61][C:62](=[O:68])[O:63][C:64]([CH3:65])([CH3:67])[CH3:66])[CH:55]=[CH:56][N:57]=1)[CH2:50][CH2:49][CH2:48][CH2:47][C@H:43]([NH:42][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[NH:20][C:21](=[O:40])[NH:22][C@H:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:31][CH2:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:44]([OH:46])=[O:45])([CH3:103])([CH3:102])[CH3:101]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 84.3 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-5-(2,5-dioxopyrrolidin-1-yloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (82 mg, 0.14 mmol), ((S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (98 mg, 0.11 mmol) and DIPEA (0.50 mL) in DMF (2.0 mL) was stirred at rt for overnight. The Solvent was removed under reduced pressure to give a residue, which was purified by biotage eluting with 1% to 40% MeOH in DCM to afford (2S,7S,11S)-2-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-16,16-dimethyl-4,9,14-trioxo-15-oxa-3,8,10-triazaheptadecan-1-oic acid (125 mg, 84%) as a white solid. MS (ESI), 674.6 (M/2+H)+.
Reaction SMILES: [BrH:1].C(O)(=O)C.[C:6]([C:8]1[CH:9]=[C:10]([C:14](=O)[CH2:15][S:16][C:17]#[N:18])[CH:11]=[CH:12][CH:13]=1)#[N:7].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]#[N:7])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(C#N)c1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (10 ml) solution was added to a solution of 2-(3-cyanophenyl)-2-oxoethyl thiocyanate (1.0 g, 4.94 mmol) in acetic acid (10 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 990 mg (75.6%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]Cl.[I-].[Na+].C(N(CC)CC)C>C(#N)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CN(C)CCCCl
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(CCCN(C)C)CC2)cc1
Yield: 25.2 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.29 g, 0.793 mmole) in 25 mL of acetonitrile was added 3-(dimethylamino)propyl chloride hydrochloride (0.013 g, 0.793 mmol), sodium iodide (0.02 g, 0.119 mmol), and triethylamine (0.32 g, 3.18 mmol). The reaction mixture was refluxed for 20 hours under Argon and then was cooled and concentrated in vacuo. To the residue was added, aqueous sodium hydroxide (1 N) solution (30 mL), and the resulting solution was extracted three times with chloroform (25 mL). The organic extracts were combined, washed with sodium carbonate solution, dried (Na2SO4), and concentrated to provide a brown oil. This material was purified on a flash silica gel column (10% methanol-chloroform to 17.5% methanol-chloroform) to provide 0.09 g (25%) of N,N-diethyl-4-[benzyl(1-(3-dimethylaminopropyl)piperidin-4-yl)amino]benzamide as a pale rose glass. MS (ES), m/z 451 (MH+). 300 MHz 1H NMR (CDCl3) δ1.17 (t, J=7.0 Hz, 6H), 1.69-1.89 (m, 4H), 2.14 (br t, 2H), 2.18-2.38 (br m, 2H), 2.42 (s, 4H), 2.47 (t, J=7.1 Hz, 2H), 2.59 (t, J=6.9 Hz, 2H), 3.06 (br d, J=11.6 Hz, 2H), 3.30-3.49 (m, 4H), 3.72-3.90 (br m, 1H), 4.52 (s, 2H), 6.65 (d, J=8.7 Hz, 2H), 7.10-7.30 (m, 7H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Si]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)(C(C)(C)C)(C)C>>[F:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
In a manner similar to that of Example 4, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazin- 6-carboxylic acid (II, X: fluoro) is reacted with 4-(t-butyldimethylsilyl)-1-methylpiperazine (III, R2, R3 and R4 : methyl; R5 : t-butyl) to obtain a solid compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[I-].[Na+].CCOCC>COCCOC>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)=[C:6]([O:27][CH3:28])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:26]=2)[CH:22]=[N:23]1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCN(C)CC1
Temperature: 135 °C
Yield: 51.5 %

Procedure:
A reaction mixture of 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 500.9 mg (5 mmol) of 1-methylpiperazine and 74.5 mg (0.5 mmol) of sodium iodide in 10 mL of DME was heated at 135° C. for 15 hr under N2 in a sealed tube. After cooling, the solvent was removed and the residue was taken into 15 mL of brine. The aqueous solution was extracted with 15% methanol/methylene chloride. The organic solvent was dried over Na2SO4 and filtered. Removal of the solvent gave the crude product solid. Purification of the crude product on preparative TLC (developing solvent: 15% methanol/methylene chloride) to give a yellow foam solid. Trituration of the foam solid with ether yielded 117.9 mg (51.6%) of the product as a yellow solid, m.p. 179° C. (dec.), mass (electrospray, m/e): M+H 458.0.