Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:29][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:30]12([C:40](Cl)=[O:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C1COCC1.N1C=CC=CC=1>[C:30]12([C:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:29][C:11]5[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]67[CH2:26][CH:25]8[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]8)[CH2:20]6)[CH2:28]7)=[O:18])=[CH:15][C:10]=5[N:9]=4)=[CH:4][CH:3]=3)=[O:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C45CC6CC(CC(C6)C4)C5)ncc3[nH]2)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2cn1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of amine 14 (0.200 g, 0.50 mmol) in dry THF-Pyridine (10 ml/0.400 ml), adamantane carbonyl chloride (0.150 g, 0.75 mmol) was added and stirred at room temperature under argon overnight. The reaction was quenched with water and stirred at room temperature for 30 min. The yellow solid was filtered and passed through SiO2 gel using CH2Cl2: MeOH (95:5) as a eluent that yielded the desired product 15 (0.150 g, 50%). M.p. 265° C.; 1HNMR (DMSO-d6, 500 MHz): δ 13.02 (1H, brs, NH), 9.48 (1H, brs, NH), 9.37 (1H, brs, NH), 8.64 (1H, s), 8.24 (1H, s), 8.08 (2H, d, J=5.0 Hz), 7.88 (2H, d, J=5.0 Hz), 2.03-1.60 (30H, m). EIMS m/z: 449.6 (M+1); Anal (C34H39N5O2×0.85 H2O) C, H, N.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([N:4]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:13][CH2:14]1)[C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCNC1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CCCN(C(=O)OCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-propyl-1,4-dioxaspiro[4.5]decan-8-amine (2.97 g, 14.9 mmol) from above step A in THF is treated with TEA (2.1, 14.9 mmol) and benzyloxycarbonyl chloride (2.1 mL, 14.9 mmol). The mixture was stirred for 18 h at room temperature. THF was removed under vacuum and the residue was taken EtOAc and washed with 10% citric acid, saturated NaHCO3, and saturated NaCl. The solution was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CP(C)(=O)OCC(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 3.32 g of isobutyl P-[2(S)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.19 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours, under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(S)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =+18.6 (0.56% in ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=2[Cl:18])=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][Cl:21])=[CH:11][C:10]=2[Cl:18])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Solvent: CN(C)C=O
Product: ClCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Yield: 100 %

Procedure:
4-(4-Chlorophenylthio)-3,5-dichlorobenzyl alcohol (1.28 g, 4.00 mmol) was added to stirred thionyl chloride (5.0 ml) at ambient temperature. The solution was refluxed 15 minutes, treated with dimethylformamide (1 drop), refluxed 15 minutes, treated with more dimethylformamide (1 drop), and refluxed 1 hour. Thionyl chloride was evaporated under a stream of nitrogen, hexane (5 ml) was added and evaporated under a stream of nitrogen, and the residue was dried under vacuum. Hexane (10 ml) was added, the mixture was filtered through anhydrous magnesium sulfate, and the magnesium sulfate was washed well with hexane. The combined filtrate and washes were evaporated under vacuum and dried at 35° C. under vacuum to provide 1.35 g (100%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzyl chloride. The chloride was suspended in absolute ethanol (10 ml) and stirred at ambient temperature while sodium azide (720 mg, 11.1 mmol) was added. The mixture was refluxed 3 hours, kept 16 hours at - 20° C., and evaporated to dryness under vacuum at 30° C. The residue was treated with diethyl ether (50 ml), filtered, and washed with diethyl ether. The combined filtrate and washes were evaporated under vacuum and dried to provide 1.38 g (100%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzyl azide as a colorless viscous oil; 60 MHz 'H NMR (CDCl3) 4.35 s (2H), 7.03 dm (J=8.5 Hz, 2H), 7.23 dm (J=8.5 Hz, 2H), 7.38 s (2H); IR (neat): 2110 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[CH:5]=[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:7]2.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[CH:5]=[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:7]2
Reactant: O=c1cc(-c2ccccc2)oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1cc(-c2ccccc2)oc2cc(N3CCCCC3)cc(O)c12
Temperature: 25 °C
Yield: 16.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (130 mg, 0.337 mmol), piperidine (0.040 mL, 0.40 mmol), tris(dibenzylideneacetone) dipalladium(0) (15 mg, 0.017 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (20 mg, 0.067 mmol), and tripotassium phosphate (K3PO4) (143 mg, 0.674 mmol) in THF (2 mL) was heated to reflux for 24 h, then cooled to room temperature for 24 h. The reaction mixture was filtered through a ¾″ silica gel (60 Å) plug. The plug was washed with EtOAc (75 mL), and the filtrate concentrated. The concentrate was purified via Biotage chromatography eluting with 5% EtOAc/hexanes to yield 18 mg (17%) of 5-hydroxy-2-phenyl-7-piperidin-1-yl-chromen-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH2:26]([O:28][CH:29]([O:32][CH2:33][CH3:34])[CH2:30][NH2:31])[CH3:27].CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>C1COCC1.O>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:31][CH2:30][CH:29]([O:32][CH2:33][CH3:34])[O:28][CH2:26][CH3:27])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CNC(=O)c1ccc(C(C)(C)C)cc1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
2-nitro-4-tert-butylbenzoic acid (1.5 g, 7 mmol, prepared according to J. Am. Chem. Soc, 1955, 77, 5441) was stirred in THF at room temperature, 1.7 mL diisopropylethyl amine (13 mmol, 2 eq) was added, followed by 984 mg (7.7 mmol, 1.1 eq) 2-amino acetaldehyde diethylacetal. (3-Dimethylamino-propyl)-ethyl-carbodiimide (1.55 g, 8 mmol, 1.2 eq) was added, followed by a catalytic amount (ca. 50 mgs) hydroxybenzotriazole hydrate. The mixture was stirred at room temperature for 16 hours, diluted with water, extracted with diethyl ether 3×, the ether layers were washed with water, brine, and dried over MgSO4. Removal of solvent under vacuum, followed by chromatography on silica gel, eluting with 25% ethyl acetate in hexanes, gave the title compound 0.950 g, (M+H)+=224.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:10][CH2:9]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].Cl>ClCCl>[CH2:25]([S:27]([N:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of Benzyl piperidin-4-ylcarbamate (5.09 g) at 0° C. followed by the dropwise addition of ethane sulfonylchloride (which may be referred to as sso10; 3.2 mL; TCI) and the resulting mixture was stirred overnight slowly raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium hydroxide (20% by weight, Wet-type, 5 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (3.32 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].II.C(O)C>C1C=CC=CC=1.CCOCC.C(O)(=O)C>[OH:12][C:9]1([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH:8]1[CH3:13]
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Reactant: COC(=O)CBr
Agent: II
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)CC1(O)c2cc(OC)ccc2CC1C

Procedure:
A solution of 13.4 g of 6-methoxy-2-methylindanone and 19.3 g of methyl bromoacetate in 45 ml benzene is added over a period of 5 minutes to 21 g of zinc amalgam (prepared according to Org. Syn. Coil., Vol. 3) in 110 ml benzene and 40 ml dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65°) with external heating. At three-hour intervals two batches of 10 g zinc amalgam and 10 g bromoester are added, and the mixture is then refluxed for 8 h. After addition of 30 ml of ethanol and 150 ml of acetic acid, the mixture is poured into 700 ml of 1:1 aqueous acetic acid. The organic layer is separated, and the aqueous layer is extracted twice with ether. The combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo followed by pumping at 80° (bath temp.) (1-2 mm) gives crude methyl (1-hydroxy-2-methyl-6-methoxy-indanyl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([N:5]([CH2:4][C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[NH:1][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[CH2:11]
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 101.8 %

Procedure:
The procedure of Example 33 was followed using the product from Example 32 (500 mg, 1.268 mmol), triethylamine (0.884 ml, 6.34 mmol), and benzoyl chloride (0.324 ml, 2.79 mmol) in methylene chloride (60 ml) to give 620 mg (100%) of the product.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:22]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Product: Clc1ccc2c(Nc3ccc(CN4CCN(c5ccccc5)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-phenyl-4-[(4-aminophenyl)methyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[[4-phenyl-1-piperazinyl]methyl]phenyl]amino]-7-(chloro)quinoline.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[CH:16]=[C:15]4[O:20][CH2:21][O:22][C:14]4=[CH:13][C:12]=3[C:11]2=[O:23])[CH2:4][CH2:3]1.Br.Br[CH2:26][C:27]1[N:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]3[C:18](=[O:19])[C:17]4[CH:16]=[C:15]5[O:20][CH2:21][O:22][C:14]5=[CH:13][C:12]=4[C:11]3=[O:23])[CH2:4][CH2:3]2)[N:28]=1
Reactant: BrCc1cccnn1
Reactant: O=C1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Agent: Br
Agent: Cl
Product: O=C1c2cc3c(cc2C(=O)N1CCC1CCN(Cc2cccnn2)CC1)OCO3

Procedure:
Compound I-37 was prepared according to the method in example 3, using 6-[2-(4-piperidyl)ethyl]-[1,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride (compound II-1) and 3-bromomethylpyridazine hydrobromide as the raw materials: 1H NMR (CDCl3): δ 1.26-1.32 (m, 3H), 1.58 (q, 2H, J=5.0 Hz), 1.75 (d, 2H, J=8.9 Hz), 2.12 (t, 2H, J=10.6 Hz), 2.81 (d, 2H, J=11.1 Hz), 3.65 (t, 2H, J=7.2 Hz), 3.84 (s, 2H), 6.15 (s, 2H), 7.19 (s, 2H), 7.45 (dd, 1H, J=8.4, 4.9 Hz), 7.66 (dd, 1H, J=8.4, 1.2 Hz), 9.07 (dd, 1H, J=4.8, 1.6 Hz): m/z 395 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[S:32](=[O:35])(=[O:34])[NH2:33])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][CH:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:28])=[CH:25][C:24]=1[S:32](=[O:35])(=[O:34])[NH2:33])([CH3:22])[CH3:21]
Reactant: CC(C)c1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(C(C)C)c(S(N)(=O)=O)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-isopropyl-3-sulfamoyl-benzoic acid. MS: 485.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][OH:34])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1>CO.[C].[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][OH:34])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Agent: [Pd]
Solvent: CO
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
10% Palladium carbon (0.35 g.) was added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.7 g.) in methanol (70 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 1.5 hours. The resultant mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous solution of sodium bicarbonate and the insoluble substance was filtered out. The filtrate was washed with ethyl acetate and methylene chloride in turn, bubbled with nitrogen gas and then lyophilized. The residue was dissolved in water (30 ml.) and adjusted to pH 3.8 with 10% hydrochloric acid. The solution was subjected to column chromatography on macroporous, nonionic adsorption resin "Diaion HP-20" (Trade mark; manufactured by Mitsubishi Chemical Industries Ltd., 20 ml.), washed with water, and then eluted with 40% aqueous acetone. After acetone was removed from the eluate under reduced pressure, the residue was lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 0.25 g.)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CC(=O)OCC>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=[O:37])[C:17]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)[nH]c2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(N)CC3)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of {1-[4-(4-cyano-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (50 mg, 0.096 mmol) in EA (10 mL) was added a 5M HCl solution in EA and the mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give 18 mg (40%) of the title compound as the hydrochloride salt. 1H NMR (400 MHz, CD3OD): δ 1.81-1.87 (m, 2H), 2.22-2.25 (m, 2H), 3.34-3.38 (m, 2H), 3.56-3.60 (m, 1H), 3.78 (s, 3H), 4.61-4.64 (m, 2H), 6.86 (d, J=7.2 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.37-7.38 (m, 1H), 7.51-7.53 (m, 1H), 7.74 (s, 1H). [M+H] Calc'd for C23H22FN5O2, 420. Found, 420.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH2:58])=[CH:52][CH:51]=1>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[NH:58][CH2:57][CH2:56][C:53]3[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=3)[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: NCCc1ccc(F)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCCc3ccc(F)cc3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and 2-(4-fluoro-phenyl)-ethylamine.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 76.8 %

Procedure:
A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1′-bis (diphenylphosphino)-ferrocene} dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2×sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20–30% EtOAc in hexanes affording the title compound (251 mg, 77% yield): ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24]>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:13]([C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:3]([CH:5]=1)[NH2:4])([O-:15])=[O:14]
Reactant: Nc1cc([N+](=O)[O-])c(C(F)(F)F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c([N+](=O)[O-])cc1N
Temperature: 70 °C
Yield: 56.5 %

Procedure:
To a solution of 2-bromo-5-nitro-4-(trifluoromethyl)aniline (10.0 g, 35.1 mmol) in toluene/H2O (100 mL, 1:1, v/v) was added CuI (0.4 g, 2.10 mmol), Et3N (9.5 mL, 68.16 mmol), Pd(PPh3)2Cl2 (5.0 g, 7.12 mmol) and ethynyltrimethylsilane (5.2 g, 53 mmol) successively under an atmosphere of nitrogen at room temperature. The reaction mixture was transferred to a sealed pressure flask and heated at 70° C. for 10 h. The reaction mixture was cooled down to room temperature, filtered, evaporated in vacuo and purified by silica gel column chromatography (1 to 20% EtOAc in petroleum ether as eluant) to afford 5-nitro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (6.0 g, 57%) as yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H), 7.13 (s, 1H), 4.86 (br s, 2H), 0.29 (s, 9H).