Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[CH:60]=[CH:59][C:58]([C:61](Cl)=[O:62])=[N:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:58]2[CH:59]=[CH:60][N:56]([CH3:55])[N:57]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1ccc(C(=O)Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)n1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-3-carbonyl chloride as starting materials in 36% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.41 (s, 2H), 9.02 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.47 (s, 1H), 4.52 (m, 2H), 3.83 (s, 3H), 3.12 (m, 1H), 2.98 (m, 4H), 2.77 (m, 1H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7]Br.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCNCC1.CCN(CC)CC.I([O-])(=O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7][N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)C(CCCBr)(c1ccc(Br)cc1)C(C)C
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C1CNCCN1
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(CCCN1CCN(c2ccccc2)CC1)(c1ccc(Br)cc1)C(C)C

Procedure:
After the 5-bromo-2-(4-bromophenyl)-2-isopropylpentanoic acid methyl ester (200 mg, 1 eq) was dissolved in acetonitrile, 4-phenylpiperazine (70 mg, 1 eq) as a piperazine derivative, Et3N (0.06 ml, 1.2 eq), and sodium iodate were added into the solution and heated and refluxed for 3 hours. When the reaction was completed, the precipitate was filtrated and the mixture was vacuum distilled and extracted with ethyl acetate and water. After the organic layer was washed with 1N HCl and saturated NaHCO3, the target compound 2-(4-bromophenyl)-2-isopropyl-5-(4-phenylpiperazine-1-yl)pentanoic acid methyl ester was obtained by drying the mixture with anhydrous sodium sulfate and removing the solvent at low pressures (69 mg, 42%).
Reaction SMILES: CN(C)CCN.[CH:7]([O:10][N:11]1[C:15](=O)[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2C1=O)([CH3:9])[CH3:8].C(O)(=O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:29](C(C2CCCCC2)=O)[CH:28]=1>CCO>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35])=[C:31]([C:15]([CH:14]2[CH2:13][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][O:10][CH:7]([CH3:8])[CH3:9])[CH:32]=1
Reactant: O=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Reactant: CC(C)ON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)ON=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H; 7.61, d, J=8.8 Hz, 1H; 7.49, d, J=8.8 Hz, 1H; 7.46, d, J=2.4 Hz, 1H; 7.42, dd, J=2.4 and 8.8 Hz, 1H; 7.30, dd, J=2.4 and 8.8 Hz, 1H; 7.24, d, J=2.4 Hz, 1H; 4.49, m, 1H; 4.39, m, 1H; 2.97, m, 1H; 2.45, m, 1H; 1.97-1.71, m, 14H; 1.34-1.24, m, 18H. HRMS (M+) 426.0983.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Cl>C1(C)C=CC=CC=1.Cl[Ni](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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:3]1[CH:2]=[CH:11][CH:10]=[CH:9][C:4]=1[CH3:5]
Reactant: Brc1ccc2ccccc2c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc2ccccc2c1
Yield: 172 %

Procedure:
The Grignard solution was subsequently added dropwise to a solution of 120 g (0.57 mol) of 2-bromonaphthalene and 3.5 g of bis(triphenylphosphine)nickel chloride in 800 cm3 of toluene at such a rate that the internal temperature did not exceed 50° C. Subsequently, the mixture was heated under reflux for a further 3 hours, admixed with 500 ml of 10% strength aqueous HCl, the phases were separated and the organic phase was freed of solvent under reduced pressure. Filtration through silica gel (hexane) gave 107 g (87%) of 13 as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(=O)NCC1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2cc(F)c(N3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
The N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (1.00 g, 2.20 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. with an ice bath. Trifluoroacetic acid (20 mL) was added, the cooling bath removed, and the reaction mixture allowed to warm to ambient temperature over 1 h. The reaction mixture was then concentrated in vacuo and the residue dissolved in H2O (15 mL). The resultant solution was added to Bio Rad AG-1-X8 ion exchange resin (12 mL; OH- form, washed with H2O until neutral), additional H2O (5 mL) was added, and the mixture stirred for 10 min. The mixture was then filtered and the resin washed with additional H2O (3×5 mL). The aqueous filtrate was lyophilized to give 0.559 g (72%) of the title compound as a white solid with mp 108°-112° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:16][CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:19][C:20]#[N:21].C(NC(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:16][CH3:17])[C:10]([O:12][CH2:19][C:20]#[N:21])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CCCl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 8 h
Yield: 63 %

Procedure:
Boc-L-Hcm-OH (43 mg, 153 μmol) was dissolved in THF (1 mL). To the solution were added chloroacetonitrile (484 μL, 7.65 mmol) and diisopropylamine (53 μL, 306 μmol). The mixture was stirred overnight under N2 atmosphere. After 18 h, additional chloroacetonitrile (484 L, 7.65 mmol) was added. Concentration under reduced pressure followed by flash chromatography over silica gel with AcOEt-Hexane (3:1) gave the titled compound in (31.3 mg, 63% yield): 1H NMR (360 MHz, CDCl3) δ 5.02 (s, 1H), 4.73 (dd, J=31.3 Hz, 2H) 4.49 (s, 1H), 2.77-2.73 (m, 2H), 2.37 (m, 3H), 2.37-2.27 (m, 1H), 2.13-2.02 (m, 1H), 1.46 (s, 9H); LRMS (ESI) m/z calcd for C12H21N2O4S2 (M+H)+ 321.1. found 321.0.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13](C(O)(C)C)[CH:14]=[CH:15][CH:16]=1)[CH3:9].S(Cl)(Cl)=O.N1C=C[CH:30]=[CH:29][CH:28]=1>>[CH3:22][C:2]([CH3:1])([CH3:21])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:29]([CH3:30])=[CH2:28])[CH3:9]
Reactant: c1ccncc1
Reactant: CN(CC=CC#CC(C)(C)C)Cc1cccc(C(C)(C)O)c1
Solvent: O=S(Cl)Cl
Product: C=C(C)c1ccccc1CN(C)C/C=C/C#CC(C)(C)C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
A mixture of pyridine (10 ml), Compound 37 (940 mg; 3.1 mmol), and thionyl chloride (1.12 g; 9.4 mmol) was stirred for 15 minutes while being cooled with ice, and then stirred for 15 minutes at room temperature. Subsequently, unreacted pyridine and thionyl chloride were evaporated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added thereto. The mixture was extracted with ether twice (70 ml and 50 ml), and the combined organic layer was washed with saturated brine, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 360 mg of the target compound (yield: 40.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[H-].[Na+].[CH3:22]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:22])[C:10]2[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[CH3:19]
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C)c2nc(C)nc(Cl)c2C)c(C)c1
Reaction time: 0.03 h

Procedure:
A solution of (6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (276 mg, 1 mmol) in dry THF (2 ml) was treated with sodium hydride (60% in oil, 60 mg, 1.5 mmol) at room temperature. After stirring for 2 minutes, an excess of methyl iodide (0.5 ml) was added and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a pale yellow solid (255 mg). 1H NMR (CDCl3) δ 6.85 (s, 2H), 3.26 (s, 3H), 2.50 (s, 3H), 2.27 (s, 3H), 2.03 (s, 6H), 1.39 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=1.O>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccn1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Trimethylacetyl chloride (4.22 g, 35.0 mmol) was added dropwise to a solution of 2-amino-4-chloropyridine (3.00 g, 23.3 mmol) in pyridine (11 mL) at 0° C. The resulting solution was stirred for 12 h at r.t. Water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4). The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate and hexane (2/8), to give the title compound as a colourless solid (4.9 g, 99%).
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([N:12]([CH3:21])[C@H:13]([C:17]([O:19]C)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>O1CCOCC1.[OH-].[Na+]>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:10]([N:12]([CH3:21])[C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of Z-Phe-N-Me-Val-OMe (3.39 g) in dioxane (40 ml), 2N NaOH (4 ml) was added, followed by stirring for 2 hours at 50° C. The reaction mixture was mixed with water and washed with methylene chloride. The aqueous layer was adjusted to pH3 by the addition of 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=95:5) to give the titled compound (3.03 g, 92%).
Reaction SMILES: [F:1][C:2]([F:15])([C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])[CH:3]=[CH2:4].[Cl:16][SiH:17]([Cl:19])[Cl:18]>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:15])([C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([F:9])([F:8])[F:10])[CH2:3][CH2:4][Si:17]([Cl:19])([Cl:18])[Cl:16]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1C
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CC[Si](Cl)(Cl)Cl
Temperature: 140 °C
Reaction time: 0.13 h
Yield: 92 %

Procedure:
123 g (0.5 mol) of 3,3,4,4,5,5,6,6,6-nonafluorohexene and 76 g (0.5 mol) of trichlorosilane together with 0.34 g of CPC 072 (Pt(0)-divinyltetramethyldisiloxane in xylene; concentration Pt:3,3,4,4,5,5,6,6,6-nonafluorohexene=1:20,000) are charged to a 250 ml laboratory steel autoclave. The autoclave is closed and heated to 140° C. in an oil bath over 70 minutes. The exothermic reaction begins after about 8 minutes, the reaction mixture rising to 165° C. It is subsequently cooled, the reactor is emptied, and short-path distillation gives 176 g (0.46 mol) of 3,3,4,4,5,5,6,6,6-nonafluorohexyltrichlorosilane (yield: 90%, purity: >98 area % GC-TCD).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:3][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[N:9]=1)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(N3CCOCC3)cc(C(C)(C)S(C)(=O)=O)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
Tert-butyl (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)carbamate (2.6 g, 5.46 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:17]([O:19]CC)=O)=[C:5]([C:12](OCC)=[O:13])[NH:6]2.O.[NH2:23][NH2:24]>C(O)C>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]2[C:4]3[C:17](=[O:19])[N:24]=[N:23][C:12](=[O:13])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2c1[nH]c1cc(Cl)cc(Cl)c21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of diethyl 4,6-dichloroindole-2,3-dicarboxylate (3.22 g, 9.8 mM) in ethanol (20 mL) was added hydrazine hydrate (14.2 mL, 294 mM). The solution was refluxed for 3 hours during which time a precipitate formed. The reaction mixture was then cooled to room temperature, the solid was filtered and heated to reflux in 3N HCl. After several minutes, the mixture was cooled to room temperature and the solid was filtered, washed with ethanol, and dried. This afforded the titled product as a white solid (2.6 g, 90%), mp >300° C. NMR (d6 -DMSO): 13.02 (br s, 1H), 11.72 (br s, 2H), 7.54 (s, 1H), 7.40 (s, 1H). MS(CI): 271(M+1).
Reaction SMILES: Br.[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][O:15]C(=O)C)=[CH:12][N:11]=[CH:10]2)=[CH:6][C:5]=1[F:21])#[N:3].O.[OH-].[Li+]>C1COCC1.O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:6][C:5]=1[F:21])#[N:3]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CO)cc1F
Reaction time: 2 h

Procedure:
To a solution of 1-(4-cyano-3-fluorobenzyl)-5-(acetoxymethyl)imidazole hydrobromide (as described in Example 14, Step C) (31.87 g, 89.77 mmol) in 300 mL of 2:1 THF/water at 0° C. was added lithium hydroxide monohydrate (7.53 g, 179 mmol). After two hours, the reaction was concentrated in vacuo to a 100 mL volume, stored at 0° C. for 30 minutes, then filtered and washed with 700 mL of cold water to provide a brown solid. This material was dried in vacuo over P2O5 to provide the titled product as a pale brown powder which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [C:1]1([C@H:7]2[N:10](CC3C=CC(OC)=CC=3OC)[C:9](=[O:22])[C@H:8]2[N:23]=[N+:24]=[N-:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C.O>[C:1]1([C@H:7]2[NH:10][C:9](=[O:22])[C@H:8]2[N:23]=[N+:24]=[N-:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](N=[N+]=[N-])[C@H]2c2ccccc2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1c1ccccc1
Yield: 65.1 %

Procedure:
(±)-(cis)-4-Phenyl-1-(2,4-dimethoxybenzyl)-2-oxo-3-azidoazetidine (737 mg) is dissolved in 25 ml of acetonitrile and heated to 80°-83° C. under nitrogen. To the resulting solution are added over a 1 hour period 943 mg of potassium persulfate and 570 mg of potassium monohydrogen phosphate, both dissolved in 25 ml of water. After the addition, the mixture is further heated at 80°-83° C. for 7 hours. The mixture is cooled and the pH is adjusted to 6-7 by adding solid potassium monohydrogen phosphate. Most of the acetonitrile is removed under reduced pressure and the resulting mixture is extracted with 60 ml of chloroform. The chloroform layer is washed with water (60 ml), dried over anhydrous sodium sulfate and stripped of solvent to give a crude product as an oil. The crude product is chromatographed on 40 g of silica gel eluting with 1:1 petroleum ether-ethyl acetate. The combined fractions yield crystals and the product is recrystallized from petroleum ether-ethyl acetate to give 267 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:34](=[O:35])[CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2c(C)cccc2C)CC1

Procedure:
To a stirred solution of 8 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 4 parts of pyridine and 80 parts of benzene are added dropwise 7.7 parts of benzeneacetyl chloride in 40 parts of benzene. After the addition is complete, the whole is heated to reflux and stirred at reflux temperature for 3 h. 45. The reaction mixture is cooled and filtered. The benzene-phase is washed with water and then with sodium hydrogen carbonate solution and with water. After evaporation, an oily residue is obtained, which solidifies on triturating in 1,1'-oxybisethane, to yield 5 parts of ethyl 4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate; mp. 106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[Br:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([NH:1][S:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20])=[CH:11]2
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2c(Br)cccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
3-Amino-8-bromoquinoline (300 mg, Production Example 5b) was dissolved in pyridine (5 ml), to which was then added 3-pyridinesulfonyl chloride (254 mg), followed by stirring at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title compound (270 mg).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O>[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(C(=O)NNC(=O)c2ccccc2)c1C
Reaction time: 24 h
Yield: 91 %

Procedure:
First, 9.4 g (69.0 mmol) of benzoylhydrazine and 50 mL of N-methyl-2-pyrrolidinone (NMP) were put into a 300-mL three-neck flask and stiffed under nitrogen flow while being cooled with ice. To this mixed solution, a mixed solution of 13.0 g (77.1 mmol) of 2,3-dimethylbenzoyl chloride and 10 mL of NMP was slowly added dropwise, and the mixture was stiffed at room temperature for 24 hours. After reaction for the predetermined time, this reacted solution was slowly added to 500 mL of water, so that a white solid was precipitated. The precipitated solid was washed by repeating twice ultrasonic cleaning in which water and then 1M hydrochloric acid were used. Then, ultrasonic cleaning using hexane was performed, so that 16.9 g of a white solid of 1-(2,3-dimethylbenzoyl)-2-benzoylhydrazine was obtained in a yield of 91%. A synthesis scheme of Step 1 is shown in (d-1).