Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:10]1=[O:25])C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:10]1=[O:25]
Reactant: C[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1O
Yield: 98.4 %

Procedure:
The O-benzyl derivative (51) (23.08 g) was taken up in THF (250 ml) and hydrogenolysed in the presence of 10% Pd/C until no starting material remained. The solution was filtered through Kieselguhr and the filtrate evaporated to give a white solid (52) (16.63 g), m.p. 94°-96° C. (from EtoAc-hexane), νmax (KBr) 3400, 1795, 1770, 1720, and 1400 cm-1, δ(CDCl3) 1.45 (d, J 6.5 Hz, 3H) (irradiation at 4.18 caused this signal to collapse to a s), 4.18 (dq, j 6.5 and 2 Hz, 1H), 4.70 (d, J 2 Hz, 1H) (irradiation at 4.18 caused this signal to collapse to a s), 7.3-8.0 (m, 4H), and 7.7-8.7 br (1H, exch.), m/e 246 (M+) and 187 (base peak). (Found: C, 58.28; H, 4.11; N, 11.46; M+ 246.0647. C12H10N2O4 requires C, 58.54; H, 4.09; N, 11.38%, M, 246.0681).
Reaction SMILES: [C:1]1([N:7]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:8](=[O:50])[CH2:9][C@@H:10]2[O:15]C(C)(C)O[C@H:12]([CH2:18][CH2:19][N:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:22]([C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:39])=[C:21]3[CH:47]([CH3:49])[CH3:48])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[OH:59]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:20]([CH2:19][CH2:18][CH2:12][CH:11]([OH:59])[CH:10]([OH:15])[CH2:9][C:8]([N:7]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:50])[C:21]([CH:47]([CH3:49])[CH3:48])=[C:22]([C:38]([NH:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:39])[C:23]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][CH:27]=1
Reactant: CO
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Agent: Cl
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCCC(O)C(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol (300 mL) and reacted by adding 1.0N hydrochloric acid (100 mL) and stirring for 12 hours at room temperature. The white crystalline solid [R-(R*,R*)]-5-(4-fluorophenyl)-β,γ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide is isolated by filtration (mp 228.5°-232.9° C., uncorrected). FTIR (KBr) 3400 (broad), 2850, 1640 cm-1 ;
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2.[BH4-].[Na+].[CH3:21][C:22](OC(C)=O)=[O:23].[CH3:28][CH:29]([OH:31])C>>[C:22]([O:11][C:10]1[C:2]([O:1][C:29](=[O:31])[CH3:28])=[C:3]2[C:7](=[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=13)[NH:6][C:5](=[O:16])[C:4]2([CH3:18])[CH3:17])(=[O:23])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)O
Reactant: CC1(C)C(=O)N=C2C1=C(O)C(=O)c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)Oc1c2c(c3ccccc3c1OC(C)=O)NC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (0.030 g, 0.124 mmol) in i-PrOH (0.5 mL) was added NaBH4 (0.020 g, 0.52 mmol) while stirring at RT. After 5 minutes, Ac2O (100 μL, 0.1 g, 0,98 mmol) was added via a syringe and the mixture was allowed to stir for 1 h followed by addition of more NaBH4 (0.020 g, 0.52 mmol) and stirring over night. The solvent was removed in vacuum and the solid was dissolved in CHCl3, filtered and purified by prep. HPLC (RP). Yield: 0.016 mg (40%). 1H NMR (400 MHz, CDCl3) δ 1.50 (brs, 6 H), 2.35 (appd, 6 H), 7.47 (m, 2 H), 7.68 (d, 1 H), 7.85 (d, 1 H), 10.05 (brs, 1 H). MS (CI) m/z: 328.36 (M+1).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:21]([N:26]=[C:27]=[O:28])(=[O:25])[C:22]([CH3:24])=[CH2:23]>ClCCCl>[C:21]([NH:26][C:27](=[O:28])[O:8][CH:7]([C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)N=C=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Yield: 102.1 %

Procedure:
Into a three-necked flask purged with nitrogen gas, benzoin (2.12 g; 10 mmol) was charged, and chloroform (30 ml) was added thereto. To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (7 g) was dropwise added in 5 minutes under nitrogen stream while stirring. Chloroform and 1,2-dichloroethane were removed by evaporation under reduced pressure to give benzoylbenzyl N-methacryloylcarbamate (3.3 g), which was recrystallized from a mixture of benzene and chloroform to give colorless transparent plates. M.P., 161°-163° C.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:28])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=S)Nc2ccccc2)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isothiocyanate (0.44 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.74 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(4-(3-phenylthioureido)butyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].C(N(C(C)C)C(C)C)C>O1CCCC1>[CH2:28]([N:30]([CH2:31][CH3:32])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:29]
Reactant: CCNCC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), diethylamine (250 ul, 2.42 mmole), N-ethyldiisopropylamine (282 ul, 1.62 mmole) and propylphosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (5 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4,N4-diethyl-1-methyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (140 mg, 81.3%) as a white solid. Mp.: 165-7° C. MS: m/z=427.4 (M+H+).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH:12]C(=O)C)([O-:5])=[O:4].C(O)C>O>[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH2:12])([O-:5])=[O:4]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of potassium hydroxide (2.5 g), 3-nitro-4-acetamido-1,1′-biphenyl (23.5 g), prepared in (A) above, water (6 mL) and ethanol (12 mL) is heated at reflux for one hour. The reaction mixture is cooled to room temperature and then poured into 300 mL of a mixture of water and ice. The solid is collected by filtration and the crude product is recrystallized from methanol (800 mL) to give 14.1 g of the title compound as an orange solid melting at 170-172° C.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1>O>[NH2:3][C:4]1[C:12]([Br:1])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: BrBr
Solvent: O
Product: Nc1ncc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Bromine (2.3 mL, 44.6 mmol) was added dropwise to a suspension of the 6-aminonicotinic acid Compound 112a (5.08 g, 36.8 mmol) in water (20 mL) at 4° C. After the completion of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4.5 h. Saturated Na2S2O5 was added slowly to the stirred mixture. The solid was collected through filtration, washed with water, and dried under vacuum overnight to give 9.30 g of 6-amino-5-bromonicotinic acid along with 3,5-dibromo-2-aminopyridine in ˜1:1 ration as a greenish solid; MS (ES) m/z: 217 (M+H+). A mixture of the solid (4.00 g) containing 6-amino-5-bromonicotinic acid, DPPA (6.08 g, 22.1 mmol), triethylamine (2.80 g, 27.7 mmol), benzyl alcohol (3.8 mL, 36.8 mmol), and toluene (50 mL) was heated at 70° C. for 1 h, then 100° C. for 1 h. After concentration, the reaction mixture was purified by flash chromatography (EtOAc/hexane as solvent) to give 1.31 g (26% in 2 steps) of Compound 112b as a yellow solid; 1H NMR (300 MHz, CDCl3) δ7.99 (brs, 1H), 7.91(d, J=2.3 Hz, 1H), 7.39-7.34 (m, 5H), 6.50 (brs, 1H), 5.19 (s, 2H), 4.79 (brs, 2H); MS (ES) m/z: 324 (M+H+). Anal. Calcd. For C13H12BrN3O2.0.1H2O : C, 48.20; H, 3.80; N, 12.97. Found: C, 48.40; H, 3.90; N, 12.64.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].N1C=CC=CC=1.CCN(C(C)C)C(C)C.[C:28](Cl)(Cl)=[O:29].CS([O-])(=O)=O.[O:37]=[C:38]1[CH:43]([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([CH2:53][NH3+:54])[CH:50]=3)[C:45]2=[O:55])[CH2:42][CH2:41][C:40](=[O:56])[NH:39]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:28]([NH:54][CH2:53][C:49]2[CH:50]=[C:51]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:55])[N:44]([CH:43]2[CH2:42][CH2:41][C:40](=[O:56])[NH:39][C:38]2=[O:37])[CH2:52]3)=[O:29])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: [NH3+]Cc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: CS(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(C(F)(F)F)c(Cl)c4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethyl)aniline (0.60 g, 3.07 mmol), pyridine (0.24 g, 3.07 mmol), and DIEA (1.10 ml, 6.14 mmol) in acetonitrile (5 mL) was added phosgene (1.54 mL, 2.91 mmol, 20% in toluene) via syringe at 0° C. After 30 min, (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methanaminium methanesulfonate (0.84 g, 2.27 mmol) was added in one portion followed by additional DIEA (1.1 ml, 6.14 mmol). The resulting suspension was stirred for 1.5 h and allowed to warm to room temperature. After 1.5 h, the reaction was quenched by the addition of 1 N HCl (20 ml) and the precipitated solid was filtered, washed with water and air-dried. The crude product was purified further by reslurrying with acetonitrile (10 mL) followed by precipitation from DMF (5 mL) water. The product was isolated by filtration, washed with Et2O and dried in vacuo to give 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea as an off-white solid (420 mg, 40%). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 45/55, CH3CN/0.1% H3PO4, 4.76 min (98.7%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.90-2.16 (m, 1H), 2.26-2.45 (m, 1H), 2.59 (d, J=19.6 Hz, 1H), 2.82-3.00 (m, 1H), 4.25-4.52 (m, 4H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 7.05 (t, J=5.9 Hz, 1H), 7.39-7.49 (m, 2H), 7.53 (s, 1H), 7.69 (dd, J=4.2, 8.2 Hz, 2H), 7.91 (s, 1H), 9.32 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.20, 42.83, 47.12, 51.58, 115.58, 118.19, 118.60, 118.98, 121.44, 121.94, 122.96, 125.05, 126.93, 128.31, 128.38, 130.38, 131.14, 142.41, 144.32, 145.28, 154.66, 167.92, 171.00, 172.85. LCMS: MH=495; Anal Calcd for C22H18ClF3N4O4+0.28H2O: C, 52.86%; H, 3.74%; N, 11.21%; Cl, 7.09%; F; 11.40%. Found: C, 52.60%; H, 3.41% ; N, 11.01%; Cl, 7.23%; F, 11.63%.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH3:12]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCC(CC)CO
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn](CCCC)(OCC(CC)CC)O[Sn](CCCC)(CCCC)OCC(CC)CC
Reaction time: 0.67 h
Yield: 99 %

Procedure:
672 g (2.7 mol) of dibutyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1700 g (16.7 mol) of 2-ethyl-1-butanol (made by Chisso Corporation, Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to approximately 157° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational agitation and heating were carried out for approximately 40 minutes at normal pressure, and then the purge valve was closed, and the pressure in the system was gradually reduced, and then with the pressure in the system at from 80 to 65 kPa, reaction was continued for approximately 5 hours while distilling off water-containing 2-ethyl-1-butanol. Then, the pressure in the system was further reduced and the distillation was continued, and then once distillate stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 928 g of reaction liquid was obtained in the flask. According to 119Sn-, 1H-, and 13C-NMR analysis results, the product 1,1,3,3-tetrabutyl-1,3-bis(2-ethylbutyloxy)-distannoxane was obtained at a yield of 99% based on the dibutyltin oxide. The same procedure was repeated twelve times, thus obtaining a total of 11200 g of 1,1,3,3-tetrabutyl-1,3-bis(2-ethylbutyloxy)-distannoxane.
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([O:8][C:9]2[C:44]([F:45])=[C:43]([F:46])[C:12]([C:13]([C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([O:33]CC5C=CC=CC=5)[CH:25]=4)=[C:17]([F:41])[C:16]=3[F:42])=[O:14])=[C:11]([F:47])[C:10]=2[F:48])=[CH:6][C:5]=1[O:51]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:18]2[C:17]([F:41])=[C:16]([F:42])[C:15]([C:13]([C:12]3[C:11]([F:47])=[C:10]([F:48])[C:9]([O:8][C:7]4[CH:49]=[CH:50][C:4]([NH2:1])=[C:5]([OH:51])[CH:6]=4)=[C:44]([F:45])[C:43]=3[F:46])=[O:14])=[C:20]([F:21])[C:19]=2[F:22])=[CH:25][C:26]=1[OH:33]
Reactant: O=C(c1c(F)c(F)c(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c(F)c1F)c1c(F)c(F)c(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(C(=O)c3c(F)c(F)c(Oc4ccc(N)c(O)c4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 72 h
Yield: 95 %

Procedure:
32.5 g of 4,4'-bis(4-nitro-3-benzyloxyphenoxy)octafluorobenzophenone prepared as described in Example 3 (0.04 mol) are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 3 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and 100 ml n-hexane is added, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH2:14][CH:15]([CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[OH:16].[C-:24]#[N:25].[K+]>CO.O1CCCC1.O>[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH2:14][CH:15]([CH:17]1[CH2:22][CH2:21][C:20]([N:2]([CH3:3])[CH3:1])([C:24]#[N:25])[CH2:19][CH2:18]1)[OH:16]
Reactant: [C-]#N
Reactant: O=C1CCC(C(O)CN2Cc3ccccc3C2)CC1
Reactant: CNC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1(C#N)CCC(C(O)CN2Cc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40% aqueous dimethylamine solution (1.72 ml, 12.5 mmol) was added to 4 M hydrochloric acid (706 μl), cooled to 0, in methanol (785 μl). A solution of 4-[2-(1,3-dihydroisoindol-2-yl)-1-hydroxyethyl]cyclohexanone (732 mg, 2.82 mmol) in methanol (4 ml) and tetrahydrofuran (6 ml) was then added. Potassium cyanide (445 mg, 6.67 mmol) was then added to the mixture and the mixture was stirred at room temperature overnight. Thereafter, water (80 ml) was added to the reaction mixture and the mixture was extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)CCCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-dimethylbutane-1,4-diamine according to general procedure 1 providing the intermediate (300 mg, 74%) as a yellow oil: Rf=0.40 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=9.6 Hz, 1H), 7.45 (s, 1H), 6.38 (d, J=9.6 Hz, 1H), 6.07 (brs, 1H), 3.40 (quart, J=5.2 Hz, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.25 (s, 6H), 1.76 (quin, J=6.6 Hz, 2H), 1.64 (quin, J=6.8 Hz, 2H); ES-MS: (M+H)=312, 314 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)OC(C)(C)C)=[C:6]([CH:16]=O)[CH:5]=[CH:4][N:3]=1.[C:18]1([CH2:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[N:8]=[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]3([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41])[CH2:34][CH2:35][CH2:36]3)=[CH:29][CH:28]=1)[C:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:16]2
Reactant: CC(C)(C)OC(=O)Nc1c(C=O)ccnc1Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Cl)nccc4cc3-c3ccccc3)cc2)CCC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl (2-chloro-4-formylpyridin-3-yl)carbamate (7-3) (300 mg, 1.17 mmol), tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (4-1) (427 mg, 1.17 mmol) and potassium carbonate (485 mg, 3.51 mmol) in DMF (10 mL) was stirred at 120° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane-EtOAc) to give tert-butyl {1-[4-(8-chloro-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-4) as a pale yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([O:18][CH3:19])=[CH:11][CH:12]=3)[C@:7]3([CH2:23][O:22][C:21]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[N:20]3)[C:6]=2[CH:5]=1)=[N+]=[N-].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C(O)C.C1COCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([O:18][CH3:19])=[CH:11][CH:12]=3)[C@:7]3([CH2:23][O:22][C:21]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])=[N:20]3)[C:6]=2[CH:5]=1
Reactant: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(N=[N+]=[N-])ccc1O2
Agent: [Pd+2]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(N)ccc1O2

Procedure:
A solution of (S)—N-(2′-azido-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide (0.410 g, 0.978 mmol) in ethanol (12 mL) and THF (8 mL) was stirred with palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (0.136 g, 0.978 mmol) under hydrogen at atmospheric pressure and RT for 2 hours. The catalyst was removed by filtration over a celite-pad, washed with ethanol (15 mL). The combined filtrates were concentrated to yield the crude product (104584-37-2). The product (S)—N-(2′-amino-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide was obtained as an off-white solid. MS (ESI pos. ion) m/z: 394 (M+1).
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.N>[Cl-].[Zn+2].[Cl-].CO.O>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of sulfolane were added 2.72 g of 7-ACA, 9.0 g of zinc chloride and 1.40 g of methanol. The mixture was heated at 60° C. for 100 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 10 ml of water and 20 ml of methanol. Then, the mixture was adjusted to pH 7.7 with aqueous ammonia at a temperature of from -2° C. to 2° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.02 g. The yield of the desired product was 42 %.