Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[S:8]1[C@@H:3]2[CH2:2][C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7]1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Yield: 248.6 %

Procedure:
A solution of 7-amino-3-cephem-4-carboxylic acid (1.0 g.) and trimethylsilylacetamide (3.8 g.) in ethyl acetate (10 ml.) and a solution of 2-[2-(2,2,2-trifluoroacetamidothiazol-4-yl)]-2-(2,4-dichlorobenzyloxyimino)acetic acid (syn isomer, 2.0 g.), phosphoryl chloride (0.9 g.) and N,N-dimethylformamide (0.43 g.) in ethyl acetate (16 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(2,4-dichlorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC.CS(C)=O>[C:12]1([S:18]([N:3]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1ccc2ncccc21
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
Sodium hydride (60% in mineral oil, 203 mg, 5.08 mmol) was washed twice with hexane, and the residue suspended in DMSO (5 ml). 1H-Pyrrolo[3,2-b]pyridine (500 mg, 4.24 mmol) was added and the reaction stirred for 15 minutes. Benzenesulphonyl chloride (749 mg, 4.42 mmol) was added rapidly and the reaction stirred for 0.5 h. After quenching with water the product was extracted into EtOAc, dried (Na2SO4) and concentrated in vacuo. Chromatography (EtOAc, silica) yielded the title compound as a white crystalline solid (903 mg, 83%). δH (d6-DMSO) 8.48 (1H, dd, J 0.8, 3.8 Hz), 8.31 (1H, m), 8.15 (1H, d, J 3.8 Hz), 8.04 (2H, m), 7.72 (1H, m,), 7.61 (2H, m,), 7.36 (1H, dd, J 4.7, 8.4 Hz), 6.98 (1H, dd, J 0.8, 3.8 Hz). LCMS (ES+) RT 3.056 minutes, 259 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCOC(C)=O>CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step C (14.0 g, 59.4 mmol) in 180 mL of dimethylformamide at 0° C. was added triethylamine (26.3 mL, 190 mmol), followed by methanesulfonyl chloride (10.5 mL, 137 mmol). The reaction was stirred overnight, allowing it to warm to room temperature. The solution was poured into EtOAc, washed with saturated NH4Cl solution, saturated aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 10 h

Procedure:
A mixture of methyl 4-bromobenzoate (21.5 g, 100 mmol), 4-fluorophenylboronic acid (14.7 g, 105 mmol), Pd(dppf)Cl2.CH2Cl2(1.48 g, 2.0 mmol), and 2M Na2CO3 (100 mL) in toluene (200 mL) and was heated to reflux, stirred for 10 hours, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethyl acetate/hexanes to provide the desired product. The mother liquor was concentrated and purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide additional product. MS (DCI) m/e 231 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[N:13][C:12]=2[N:19]2[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]2)[CH2:5][CH2:4]1.[C:29]([O:33][C:34](=[O:49])[NH:35][CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([Cl:44])=[C:39]([N:45]=[C:46]=S)[C:38]=1[Cl:48])([CH3:32])([CH3:31])[CH3:30].CC(C)N=C=NC(C)C>>[F:28][C:2]([F:1])([F:27])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[CH:16]=[C:15]3[N:17]=[C:46]([NH:45][C:39]4[C:40]([Cl:44])=[C:41]([F:43])[CH:42]=[C:37]([CH2:36][NH:35][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:49])[C:38]=4[Cl:48])[NH:18][C:14]3=[N:13][C:12]=2[N:19]2[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]2)=[O:26])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)nc1N
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl

Procedure:
The subtitle compound is prepared in analogy to 2d from N-(trans-4-trifluoromethyl-cyclohexyl)-5,6-diamino-2-(4-fluoro-piperidinyl)-nicotinic acid amide, (2,4-dichloro-5-fluoro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester and DIC. The product is purified via prep. HPLC (C-18 stable bond, eluent gradient: water(+0.15% HCOOH)/MeOH 9:1->MeOH).
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>CN(C=O)C.O.O.[Cu](Cl)Cl>[Cl:1][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(Cl)cc1OC(F)(F)F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A solution of copper(II)chloride dihydrate (37.2 mmol, 6.34 g) and lithium chloride (18.6 mmol, 788 mg) in DMF (60 mL) was heated to 80° C. before the addition of 2-(trifluoromethoxy)phenol (18.6 mmol, 4 g) dropwise. The reaction was stirred at 100° C. for 72 hours. After cooling, the reaction mixture was partitioned between EtOAc (60 mL) and water (120 mL), extracted with EtOAc (60 mL). The organic layer was washed with water (60 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting product with a gradient of 0-100% DCM in heptane to yield the title compound as a waxy solid (637 mg, 10%). This was used in the next step with no further purification.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C@@H:5]2[OH:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1([F:10])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C:5]2=[O:9]
Reactant: O[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Silica gel 60 (particle size, 0.040-0.063 mm, CAS # 63231-67-4, from EMD Chemical Inc. 4.0 g) was added to a solution of (1R,2S,4R)-5,5-difluorobicyclo[2.2.1]heptan-2-ol (0.800 g, 5.40 mmol) in anhydrous dichloromethane (20.0 ml). The mixture was cooled to 0° C., and pyridinium chlorochromate (1.86 g, 8.64 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred at this temperature overnight. After this time, the mixture was diluted with dichloromethane (30 mL) and then filtered through a pad of silica gel. Removal of the solvents gave the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C(N(CC)CC)C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:4][CH2:1][CH2:2][CH3:3])(=[O:20])=[O:19]
Reactant: CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 12 h
Yield: 94.7 %

Procedure:
A 100 L glass, jacketed reactor was charged with 1-propanol (2.098 kg; 34.9 mol), triethylamine (4.585 kg; 45.3 mol; 1.3 equivalents) and DCM (20.1 L). The mixture was cooled to a temperature of about 5° C. to 15° C. and cautiously charged with a solution of p-toluenesulfonyl chloride (6 kg; 31.47 mol; 0.9 equivalents) in DCM (10.5 L) over 30 minutes. Once the addition was complete, the mixture was warmed to a temperature of about 18° C. to 22° C. and stirred for 12 hours. The reaction mixture was assayed by 1H NMR (in CDCl3) and deemed complete. HCl (6 N; 2.98 L) was cautiously charged while maintaining the temperature below 25° C. The aqueous phase was removed, and the organic phase was washed 2× with water (21 L. each wash), dried with MgSO4, and filtered over Celite®. The filtered solids were then washed with DCM (4 L) and concentrated to a residue. The residue was dissolved in heptane and concentrated again to afford a final propyl tosylate product (6.385 kg, 95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1nc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(F)c1
Product: CC(C)(C)c1nc2ncc(C#Cc3cccc(F)c3)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=295.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and ethynyl-3-fluorobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:22]C(C)=O)[CH:5]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:7]=1[O:8][C:9]([F:17])([F:16])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12]>Cl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:18]([F:19])([F:20])[F:21])[C:7]=1[O:8][C:9]([F:16])([F:17])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12])[NH2:22]
Reactant: CC(=O)Nc1cc(Br)c(OC(F)(F)C(F)C(F)(F)F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Nc1cc(Br)c(OC(F)(F)C(F)C(F)(F)F)c(C(F)(F)F)c1

Procedure:
22.7 g of 3-bromo-4-(1,1,2,3,3,3-hexafluoropropoxy)-5-(trifluoromethyl)acetaminobenzene are heated at reflux for 4 hours in a mixture of 100 ml of concentrated hydrochloric acid and 300 ml of ethanol. The bulk of the solvent is then distilled off, the residue is made alkaline with 10% sodium hydroxide solution and extracted with ether. The ethereal extract is dried over sodium sulfate and the solvent is removed in vacuo. Fractional distillation of the residue affords the title compound as a yellowish oil with a boiling point of 115°-120° C./5·10-2 torr (a compound of formula II).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=O)[C:11]=3[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=2[O:2]1>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[CH:11]2[C:20]([OH:22])=[O:21])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Yield: 100 %

Procedure:
Ethyl 3-(3,4-Methylenedioxyphenyl)-1-oxoindene-2-carboxylate. A solution containing diethyl 2-[2-(3,4-methylenedioxybenzoyl)benzoylmalonate (crude material prepared above) in 5% aqueous Na2CO3 (100 ml) was heated at reflux for 10 min. The reaction mixture was then allowed to cool, and the aqueous material was removed by decantation. The residue was placed in H2O (50 ml), and the mixture was heated at reflux, cooled and concentrat-ed under reduced pressure. The residue was recrystallized from hexanes to afford the title compound as a yellow solid (5.0 g, 100% for two steps).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1.[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([OH:42])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([O:42][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=2)=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of 4-(4-chloromethyl-2-ethoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.33 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (3.02 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([F:49])[CH2:51]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: FC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCC(F)C3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3-fluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:55])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][CH2:13]2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:55])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([OH:48])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][CH2:13]2)([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)CCC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)O)CCC(C)(COc1ccc(CC3(CC(=O)O)SC(=O)N(CC(=O)O)C3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 0.41 g of di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate (prepared as described in Example 47) and 4 ml of a 4N dioxane solution of hydrogen chloride was allowed to stand at room temperature overnight. At the end of this time, the reaction mixture was treated in the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 105°-110° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1>FC(F)(F)C(O)=O.O.O=[Pt]=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNCCOCCn1c(CCOC)nc2c(N)nc3c(c21)CCCC3
Reaction time: 96 h
Yield: 74.6 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtO2 (0.5 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL of H2O and extracted with 50 mL of CHCl3. The organic portion was removed and discarded. The aqueous portion was then made basic (pH˜12) by addition of 10% NaOH solution. This was then extracted with CHCl3 (6×50 mL) and the combined organic layers were dried over Na2SO4 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal. The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with Et2O to give 3.19 g of 2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:11].[CH3:12][Zn]C>O1CCOCC1>[CH3:12][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:11]
Reactant: C[Zn]C
Reactant: Nc1ncnn2cc(Br)cc12
Solvent: C1COCCO1
Product: Cc1cc2c(N)ncnn2c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 79.8 %

Procedure:
To a degassed solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (Intermediate AAE) (316 mg, 1.48 mmol) and Bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.037 mmol) in 1,4-dioxane (10 mL), was added dimethyl zinc (2.97 mL, 5.93 mmol, 2.0 M in toluene). The mixture was allowed to stir at 90° C. for 17 hr and then cooled to 0° C. The reaction was quenched with MeOH (1.0 mL) and partitioned between ethyl acetate (200 mL) and potassium phosphate dibasic pH 10 buffer (100 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. Trituration with Et2O afforded 175 mg (79%) of the desired product. 1H-NMR (DMSO-d6) δ 7.69 (s, 1H), 7.39 (s, 1H), 6.61 (s, 1H), 2.18 (s, 3H); MS [M+H]+=148.9; LCMS RT=1.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Solvent: O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 102 mg, 61.8%). mp 154-156° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m, 2H), 7.93 (dd, 1H), 8.05 (m, 2H). MS (DCI/NH3) m/z 450 (M+H)+, 468 (M+NH4)+. Anal. calc. for C22H22FN2O3SCl.0.25 H2O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H, 5.12; N, 6.00.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH2:30])=[C:28]([CH3:35])[CH:27]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH:30][C:4]2[C:3]([C:23]#[N:24])=[CH:2][C:11]3[CH:6]=[CH:7][C:8]4[N:14]([CH2:15][CH2:16][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH:13]=[N:12][C:9]=4[C:10]=3[N:5]=2)=[C:28]([CH3:35])[CH:27]=1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3c(ccc4c3ncn4CCN3CCOCC3)cc2C#N)c(C)cc1Cl
Temperature: 132.5 °C
Yield: 69.9 %

Procedure:
A mixture of 86.5 mg (0.25 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 67.2 mg (0.39 mmol) of 4-chloro-5-methoxy-2-methyl aniline and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 3 mL of 2-ethoxyethanol is heated at 130-135° C. for 11 hours. After cooling, the mixture is diluted with water and neutralized with 2 equivalents of sodium carbonate, and then extracted with ethyl acetate. The separated organic layer is washed with brine and dried over sodium sulfate. Removal of the solvent yields a residue which is purified on preparative TLC (developing solvent: 1:9 methanol/methylene chloride), giving 83.3 mg (69.9%) of the product as a beige solid, mp 246-248° C.