Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[C:25](=O)[CH3:26])=[O:15])=[O:6])#[N:2].C([O-])(=O)C.[K+].Cl.[NH2:34][NH:35][C:36]([NH2:38])=[O:37]>CO>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[C:25](=[N:34][NH:35][C:36](=[O:37])[NH2:38])[CH3:26])=[O:15])=[O:6])#[N:2]
Reactant: NNC(N)=O
Reactant: CC(=O)c1cccc2cc(C(=O)N[C@H]3CCCC[C@H]3C(=O)NCC#N)[nH]c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC(=NNC(N)=O)c1cccc2cc(C(=O)N[C@H]3CCCC[C@H]3C(=O)NCC#N)[nH]c12

Procedure:
7-Acetyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethylcarbamoyl)-cyclohexyl]-amide was reacted with potassium acetate and semicarbazide hydrochloride in methanol and purified by preparative TLC plate to yield 7-[1-(carbamoyl-hydrazono)-ethyl]-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethylcarbamoyl)cyclohexyl]-amide MS: 367 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.IC.[CH2:11](Cl)[Cl:12]>>[Cl-:12].[CH3:8][N+:4]1([CH3:11])[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1
Reactant: CN1CCCC(O)C1
Reactant: ClCCl
Solvent: CI
Product: C[N+]1(C)CCCC(O)C1
Product: [Cl-]

Procedure:
3-hydroxy-1-methylpiperidine (21.7 g, 0.188 mol), iodomethane (40.0 g, 0.280 mol) and methylene chloride (50 ml).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)([O-:3])=[O:2].[NH2:14]O.[BH4-].[Na+]>>[NH2:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[CH:8][CH:9]=[N:10]2.[NH2:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=[C:11]2[C:6]=1[NH:7][CH2:8][CH2:9][NH:10]2
Reactant: O=[N+]([O-])c1ccc2nccnc2c1
Reactant: NO
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c([N+](=O)[O-])ccc2c1NCCN2
Product: Nc1c([N+](=O)[O-])ccc2nccnc12

Procedure:
5-Amino-6-nitroquinoxaline was synthesized by reaction of 6-nitroquinoxaline with hydroxylamine in an alkaline medium in accordance with J. Chem. Soc., Perkin I, 1975, 1229. The product was reacted With sodium borohydride as in Example 1). The 1,2,3,4-tetrahydro-5-amino-6-nitroquinoxaline obtained in the form of brown crystals in a yield of 11.5% of the theoretical had a melting point of 213° C.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:37]C1N(C2N=C(N)NC(=O)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[C:27]2[Br:37])[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1nc2c(nc(Br)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2c(Br)nc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for Palmitoyl-2′-deoxyguanosine, substituting the appropriate amount of 8-bromoguanosine for 2′-deoxyguanosine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.CO.[OH-].[Na+].Cl>O>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Compound 39b (1.0 g) was added to methanol (10 mL), and 4M aqueous sodium hydroxide (650 μL) and water (400 μL) were further added thereto, followed by stirring at room temperature for 2 hours. After completion of reaction, 6N aqueous hydrochloric acid was added to the reaction mixture, to thereby adjust the pH to 3, and the precipitate was filtrated, whereby compound 39c was yielded (862 mg, yield: 90%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.CO>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)cc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 4-fluorobenzoyl chloride (0.45 g, 2.8 mmol). The mixture was stirred at room temperature overnight followed by addition of MeOH (1 mL). After filtration, the resulting solid was washed with CH2Cl2 then recrystallized in CH3OH to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-fluoro-benzamide as a white solid (0.5 g, 59%): mp, 233-235° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.6 (96%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.86-2.98 (m, 1H), 4.95 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.30-7.38 (m, 2H), 7.72-7.86 (m, 3H), 7.96-8.03 (m2H), 9.18 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.35, 48.86, 115.15, 115.44, 121.87, 127.12, 129.91, 130.03, 130.37, 131.52, 133.05, 134.80, 139.21, 162.35, 165.54, 165.64, 166.95, 167.52, 169.82, 172.74. Anal Calcd for C21H16FN3O5: C, 66.61; H, 3.94; N, 10.26; F, 4.64. Found: C, 61.53; H, 3.82; N, 10.20; F, 4.72.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[NH2:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:31][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][N:22]=[C:21]3[NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[C:3]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cc1ccc(F)c(S(C)(=O)=O)c1
Reactant: Cn1ccc(N)n1
Product: Cc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(S(C)(=O)=O)c1

Procedure:
The compound of Example 147 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1-fluoro-4-methyl-2-(methylsulfonyl)benzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([CH3:37])[C:31]=1[CH3:38].C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[C:32]([CH3:37])[C:31]=1[CH3:38]
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (62 mg, yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20]C)C.C[N:25]([CH3:28])C=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:25][C:28]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:23][CH2:22][N:19]([CH3:17])[CH3:20])=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CCN(CC)CC
Product: CN(C)CCCc1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 75 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (50 mg, 0.18 mmol) 4-(3-dimethylamino-propyl)-phenylamine hydrochloride (0.40 mmol) were stirred in dimethylformamide (1 mL) and triethylamine (140 μL) at 78° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with water, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[3-(dimethylamino)propyl]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (58 mg, 75%) as a golden solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>S(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([O:14][CH3:15])[CH:4]=1)([CH3:13])[CH3:12])[CH3:17]
Reactant: CCNCC
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1I
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(C)(C)c1ccc(I)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 2-(4-iodo-3-methoxy-phenyl)-2-methyl-propionic acid (326 mg, 0.976 mmol, prepared by saponification of ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate, example 4) in thionyl chloride (5 mL) was heated at reflux for 1 h. It was concentrated to dryness then taken in 5 mL of tetrahydrofuran. Diethylamine (1 mL, 2 mmol, 2M solution in tetrahydrofuran) was added. The reaction mixture was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, IntelliFlash 280, eluting with a gradient of 5-95% ethyl acetate in hexanes) gave N,N-diethyl-2-(4-iodo-3-methoxy-phenyl)-isobutyramide (361.4 mg, 95%) as clear oil.
Reaction SMILES: F[C:2](F)(F)C1C=CC=CC=1.[CH2:11]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH:19]N1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)S1(=O)=O>>[C:11]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:30]1([OH:31])[CH2:29][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:2]1
Reactant: FC(F)(F)c1ccccc1
Reactant: C1CCCCCCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1O
Product: O=C1CCCCCCC1
Product: OC1CCCCCCC1
Yield: 16.5 %
Yield: 6.5 %

Procedure:
To 9 ml of trifluorotoluene was added 336 mg (3.0 mmol) of cyclooctane, 60 mg (0.3 mmol) of N-hydroxysaccharin and 5.3 mg (0.015 mmol) of acetylacetonatocobalt Co(acac)3. The resultant mixture was stirred under an oxygen atmosphere at a temperature of 100° C. for 1.5 hours. The products in the reaction mixture were analysed by gas chromatography, with cyclooctane being transformed, with a conversion of 30%, into cyclooctanone (selectivity 54.5%, yield 16.5%), cyclooctanol (selectivity 22%, yield 6.5%) and octanediacid (selectivity 22%, yield 6.5%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.O1CCCNCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:28][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNCCOC1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCCOCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1,4-oxazepane hydrochloride and isolated as white gum (12.0 mg, 63%). MS(m/e): 401.5 (MH+).
Reaction SMILES: [F:1][C:2]1[C:16]([N:17]([CH3:37])[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[C:21]=2[C:33]([F:36])([F:35])[F:34])=[O:19])=[CH:15][CH:14]=[C:13]([F:38])[C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.[ClH:39]>O1CCOCC1>[Cl-:39].[F:1][C:2]1[C:16]([N:17]([CH3:37])[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:32])([F:31])[C:27]([F:30])([F:28])[F:29])[C:21]=2[C:33]([F:34])([F:35])[F:36])=[O:19])=[CH:15][CH:14]=[C:13]([F:38])[C:3]=1[CH2:4][NH3+:5]
Reactant: Cl
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1C)c1ccc(F)c(CNC(=O)OC(C)(C)C)c1F
Solvent: C1COCCO1
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1C)c1ccc(F)c(C[NH3+])c1F
Product: [Cl-]

Procedure:
A solution of tert-butyl [2,6-difluoro-3-(methyl{[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzyl]carbamate (1.2 g, 21 mmol) in HCl (21 ml of a 4N solution in 1,4-dioxane, 40 eq.) was stirred at room temperature for 6.5 h and then concentrated under reduced pressure. This gave [2,6-difluoro-3-(methyl{[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (954 mg, 89%) which was reacted further without additional purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C1([NH:39][CH2:40][C:41]([NH2:43])=[O:42])C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.ON1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2N=N1.C(N(CC)CC)C>ClCCl>[C:41]([CH:40]([NH:39][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)(=[O:42])[NH2:43]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC(=O)CNc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylglycinamide (34 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 56 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]=[C:20]4[NH:30][CH:31]=[C:32]([CH3:33])[C:19]=34)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:34][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][N:21]=[C:20]3[NH:30][CH:31]=[C:32]([CH3:33])[C:19]=23)[CH2:14][CH2:13]1)=[O:11]
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.029 g, 0.051 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, and the resulting residue was dissolved in minimal DCM. The solution was added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propan-1-one (0.020 g, 72% yield) as the dihydrochloride salt. MS APCI (+) m/z 475 detected.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]1([CH3:16])[CH:11]=[CH:10]C(S(O)(=O)=O)=CC=1.[CH:17](=[O:21])[CH2:18][CH2:19][CH3:20].[OH-].[Na+]>O.C1CCCCC1>[CH2:1]([O:5][CH:17]([O:21][CH2:10][CH2:11][CH2:6][CH3:16])[CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CCCC=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Product: CCCCOC(CCC)OCCCC
Reaction time: 0.08 h

Procedure:
889.5 g of n-butanol, 1500 g of cyclohexane, and 5.7 g of p-toluenesulfonic acid are placed in a 4 liter three-necked flask fitted with a stirrer, dropping funnel, reflux condenser, and internal thermometer. 432.7 g of n-butyraldehyde is added with stirring over a period of 5 minutes. Owing to the acetal formation which starts spontaneously, the internal temperature rises to about 35° C. The mixture is allowed to react at 35° C. to 40° C. for 30 minutes, a Ph of 7.0 is then established in the reaction mixture, which is composed of a lower water phase and an upper organic phase, by addition of sodium hydroxide solution (20% aqueous solution), and the water phase is separated. To remove the low-boiling components, the organic phase is subjected to initial distillation at 200 mbar and a bottom temperature up to 160° C.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C=O>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1OC
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 83.6 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole), 1.87 g (0.01 mole) 9f 3,4-dimethoxybenzyl chloride, 0.5 g (0.005 mole) of triethylamine, 1.4 g (0.01 mole) of potassium carbonate, and 2 ml of dimethylformamide were mixed with 20 ml of toluene, and the resulting mixture was heated at the refluxing temperature for 2 hours. The reaction liquid was left to cool, washed by shaking with water, and the organic solvent layer was concentrated under reduced pressure to obtain 3.6 g (83.6% yield) of oily 1-(3,3-diphenylpropyl)-4-(3,4-dimethoxybenzyl)piperazine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]([C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=O)=[C:23](O)[N:24]=2)=[N:11]1.[NH3:38]>C(#N)C>[F:6][C:7]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]3[C:26]([CH3:32])([CH3:31])[C:27](=[O:29])[NH:38][C:23]=3[N:24]=2)=[N:11]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccc(F)cc3F)c3ncccc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 ml of phosphoryl chloride were added to 2.74 g (6.221 mmol) of the compound from Example 77A, and the mixture was stirred at RT overnight. The reaction mixture was then taken up in 430 ml of acetonitrile and, with ice cooling, stirred into 260 ml of concentrated ammonia solution (33% in water). The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The residue was stirred with ethyl acetate and diethyl ether. A solid was filtered off with suction and then washed with diethyl ether and ethyl acetate. Drying under high vacuum gave 2.13 g of the title compound in a purity of 94% (79% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:34]1[N:38]=[CH:37][S:36][N:35]=1)[C:19]([NH:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:34]1[N:38]=[CH:37][S:36][N:35]=1)[C:19]([NH:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1ncsn1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1ncsn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Trifluoroacetic acid (3.6 ml) was added to a suspension of 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.2 g) in anisole (1.2 ml), and the mixture was stirred for 2 hours at ambient temperature. The resultant solution was added dropwise to diisopropyl ether (100 ml) and the precipitates were collected by filtration. The precipitates were added to a mixture of water (50 ml) and ethyl acetate (50 ml) and adjusted to pH 6.5 with 5% aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to give 7-[2-carboxymethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (0.5 g).