Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:11])[CH3:10].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1.ClCCl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:10])[N:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccccc1C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccccc1C(C)Oc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (0.67 g, 5.97 mmol) was added to a stirred solution of 1-(2-methoxyphenyl)ethanol (0.96 g, 6.28 mmol) in dioxane (15 mL) at 0° C. (ice-bath). After 5 min of stirring at room temperature, the reaction mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (0.78 g, 5.23 mmol) was added whereupon the reaction mixture turned yellow. After being stirred for 35 min, dichloromethane and K2CO3 were added and the mixture was filtered. Concentration in vacuo furnished a yellow oil that was purified by silica gel chromatography (15×4 cm) using n-hexane ethyl acetate (8:2) as eluent. This gave 1.21 g (92%) of the title compound as a colorless oil. HRMS m/z calcd for C13H13ClN2O2 (M)+ 264.0666, found 264.0677. Anal. (C13H13ClN2O2) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=1>>[N+:13]([C:10]1[CH:11]=[CH:12][C:2]([O:24][C:19]2[CH:18]=[C:17]([F:16])[CH:22]=[C:21]([F:23])[CH:20]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1cc(F)cc(F)c1
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1cc(F)cc(F)c1
Yield: 94.7 %

Procedure:
Using the method described in Example 21.2, ethyl 2-chloro-5-nitrobenzoate (0.6 g) and 3,5-difluorophenol (0.34 g) were combined to provide 0.8 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 60 °C
Yield: 60.4 %

Procedure:
A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and 2,4-difluorophenol (1 mL, 11 mmol) in NMP (20 ml) was treated with cesium carbonate (3.9 g, 12 mmol). The resulting mixture was heated to 60° C. for 12 h. The mixture was treated with water (100 ml) and extracted with EtOAc (3×50 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography (gradient of 5 to 30% EtOAc in hexanes) to afford the free base of the title compound (2 g, 59%) as a yellow solid. LCMS (M+H)+=332.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[C:3]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[NH:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[N:17]=4)=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:26][CH2:27]1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: c1ccc2[nH]c(Nc3ccc(Oc4nccnc4N4CCOCC4)cc3)nc2c1
Reaction time: 3 h

Procedure:
N-(4-(3-chloropyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (191 mg, 565 μmol) and morpholine (74 μL, 848 μmol) in DMSO was heated to 80° C. After 3 h, starting material remained so additional morpholine (74 uL, 848 umol) was added and the mixture was heated overnight. The hot solution was then poured onto ice water which caused a brown solid to precipitate. The solid was collected by filtration, washed and dried to give the desired product. MS (ESI, pos. ion) m/z: 389.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][C:3]=1[F:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:4][C:3]=1[F:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Fc1cc(C2CCCN2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)c(F)c1
Yield: 78.7 %

Procedure:
2-(4-Bromo-3-fluorophenyl)pyrrolidine (12.5 g, 51.4 mmol) was dissolved in a mixture of dioxane (180 mL) and water (120 mL) and treated with potassium carbonate (28.4 g, 0.21 mol) and benzyl chloroformate (9.65 g, 56.5 mmol) at ambient temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of 5-20% ethyl acetate in petroleum ether to give benzyl 2-(4-bromo-3-fluorophenyl)pyrrolidine-1-carboxylate as a yellow solid (15.3 g, yield 82%). LC-MS (ESI) m/z: 378 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:5]=2[N:6]=1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][C:2]1[O:3][C:4]2[CH2:9][NH:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(o1)CN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(o1)CNC2

Procedure:
tert-Butyl 2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d][1,3]oxazole-5-carboxylate (110 mg) obtained in Step C was dissolved in a mixture of trifluoroacetic acid and dichloromethane (2 mL, 1:1) and evaporated under reduced pressure after one h. The residue was then purified on a Biotage Horizon® system (silica, 4% methanol, 0.4% saturated ammonium hydroxide, 95.6% dichloromethane) to yield the title compound. LC-MS 125.2 (M+1).
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31](B2OC(C)(C)C(C)(C)O2)=[C:32]([NH2:34])[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.C(=O)([O-])O.[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:34][C:32]1[CH:33]=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:29]=[CH:30][C:31]=1[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2N)OC1(C)C
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3N)c(C3CCCCC3)c2s1
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a suspension of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (4.73 g, 13.8 mmol) and 5-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (5.84 g, 17.9 mmol) produced by the method described in WO2005/080399 in 1,2-dimethoxyethane (50 ml) and water (50 ml) were added sodium hydrogen carbonate (1.72 g, 20.7 mol) and tetrakis(triphenylphosphine)palladium (799 mg, 0.691 mol), and the mixture was stirred overnight with heating at 110° C. The reaction mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure and the residue was purified y silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 5-(2-amino-4-benzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (5.93 g, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([CH3:18])[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)=[CH:3][C:4]([CH3:18])=[C:5]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH:6]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(C(=O)N2CCOCC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C)c(C(=O)N3CCOCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 58.3 %

Procedure:
A mixture of (4-amino-5-methoxy-2-methylphenyl)(morpholino) methanone (2.12 g, 8.47 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (1.79 g, 8.47 mmol) and para-toluene sulfonic acid (1.62 g, 8.47 mmol) in dioxane (80 mL) was heated to 100° C. for 18 h. Saturated aqueous sodium bicarbonate solution (100 mL) and DCM (100 mL) were added, the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave (5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (2.1 g, 58%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=426 at 2.59 min. 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 6.71 (s, 1H), 5.25 (br s, 1H), 3.88 (s, 3H), 3.80 (br d, 4H), 3.59 (br s, 2H), 3.31 (br s, 2H), 3.12 (d, 3H), 2.28 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]=[CH:5]1.[Br:16]Br>CN(C=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>[Br:16][C:12]1[S:13][C:7]2[N:6]=[CH:5][N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: BrBr
Reactant: O=c1c2ccsc2ncn1CC(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)sc2ncn1CC(F)(F)F
Yield: 93.5 %

Procedure:
A solution of 3-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one (2 g, 8.54 mmol) and bromine (0.484 ml, 9.39 mmol) in DMF (20 ml) at 0° C. was stirred for 60 min. The reaction mixture was diluted with 1:1 sodium thiosulfate (25% aqueous solution)/saturated sodium bicarbonate (aq) solution (100 ml) and extracted with ethyl acetate (100 ml). The concentrated crude product was purified by flash chromatography (0-60% ethyl acetate/cyclohexane) to give the title compound (2.5 g, 94%). LCMS RT=1.16 min, M+H+=312.9/314.9.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][OH:18])[CH2:2][CH2:3][CH3:4].CS(C)=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:17]=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(CO)ccc2ccc(OC)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCc1c(C=O)ccc2ccc(OC)cc12

Procedure:
As in Example 136, 1-butyl-7-methoxy-2-naphthalenemethanol (2.25 g) was oxidized by using the reagent prepared from dimethylsulfoxide (0.54 mL) and oxalyl chloride (0.9 mL) in dry dichloromethane (25 mL). The usual work up gave 2 g of 1-butyl-7-methoxy-2-naphthalenecarboxaldehyde and distillation of a sample on a Kugelrohr apparatus (138°-140° C.; 0.1 mm) furnished the analytical specimen. Anal. Calcd for C16H18O2 : C, 79.31; H, 7.49 Found: C, 79.11; H, 7.49
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[NH:12][CH2:11][CH2:10][N:9]=2)=[CH:5][CH:6]=1.F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[F:20][C:18]1[CH:19]=[C:14]2[C:15]([N+:21]([O-:22])=[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:8]3[N:9]2[CH2:10][CH2:11][N:12]=3)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: c1ccc(CC2=NCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(F)ccc21
Temperature: 50 °C
Yield: 54.7 %

Procedure:
A mixture of tolazoline (40 g, 0.25 mol), 2,4-difluoronitrobenzene (39.75 g, 0.25 mol) and potassium carbonate (17.26 g, 0.125 mol) in isopropanol (500 ml) was heated to 50° C. for a period of two days. The solvent was removed in vacuo from the mixture and the residue was dissolved in dichloromethane. The resulting solution was filtered and the solvent removed in vacuo to yield a yellow solid which was chromatographed on silica gel using 2% methanol/chloroform as the eluent to yield 1,2-dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (38.5 g) as an orange solid, having a m.p. 188°-193° C., (Found: C, 68.07; H 4.23; N 14.82%; C16H12FN3O requires C 68.33; H 4.27; N 14.95%) and represented by the structural formula ##STR14##
Reaction SMILES: I[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(I)nc21
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3cncc(Cl)c3)nc21

Procedure:
Following the procedure of Example 15d, 4-(2-(2-iodo-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol (b) was reacted with 5-chloropyridin-3-ylboronic acid. The crude product was purified by reverse-phase HPLC(C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][N:30]3COCC[Si](C)(C)C)=[CH:26][CH:25]=2)=[CH:20]1.C(OCC)(=O)C>O1CCCC1>[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:20]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccsc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccsc3)ccc12
Temperature: 66 °C

Procedure:
8.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 570 mg of N-[6-(3-thiophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 18 hours. The heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with cyclohexane/ethyl acetate (60/40 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 2×5 cm3 of diisopropyl ether. This mixture is filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 40° C.) to give, after drying (90 Pa; 50° C.), 260 mg of N-[6-(3-thiophenyl)-1H-indazol-3-yl] butanamide in the form of a white solid melting at about 198° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3][CH2:2]2)=[O:23])=[CH:16][CH:17]=1
Reactant: O=C(O)C1CCNc2ccccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CCC(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
1,2,3,4-Tetrahydro-quinoline-4-carboxylic acid (305 mg, 1.89 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Anisoyl chloride (644 mg, 3.78 mmol) was added followed by diisopropylethylamine (733 mg, 1.01 mL, 15.67 mmol). The reaction was stirred at room temperature for 7 days. The mixture was concentrated and partitioned between chloroform and sodium hydroxide (1 M, aqueous). The chloroform extract was set aside. The aqueous phase was acidified with concentrated hydrochloric acid (pH=3-4). The aqueous phase was then extracted with ethyl acetate (three times). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was used without further purification. MS m/z: 312 (M+1).
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](=O)([OH:28])([OH:27])[OH:26]>P([O-])([O-])([O-])=O>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([OH:28])([OH:27])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: O=P(O)(O)O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(P(=O)(O)O)CC3)c(F)cc2c1=O

Procedure:
To a stirred solution of 2.34 g of the product of Example 40 in 25 ml of methylene chloride under argon was added 2.57 g of N,O-bis(trimethylsilyl)triflouroacetamide and then (after 10 minutes) 2.68 g of bromotrimethylsilane. After 17 hours, the solution was evaporated to dryness at 40° C./0.02mm. The evaporation was then repeated twice after redissolving the residue in 25 ml portions of methylene chloride. A solution of the residual solid in 25 ml of methylene chloride was added to a stirred solution of 1 ml of water in 100 ml of acetone and then stirred for 15 minutes, to hydrolyze silyl ester groups. The resulting solid was collected and washed with acetone to give 2.24 g of cream-colored solid, m.p. 246°-252° (dec.); 31P-NMR (in DMSO with 5% triethylamine) δ 9.34 compared to δ 0.54 (at 50° C.) for a salt of ciprofloxacin with an equimolar amount of phosphoric acid, and δ 0.35 for phosphoric acid. The product was soluble in 0.1M phosphate buffer, pH 7.5, unlike ciprofloxacin.
Reaction SMILES: [O:1]=[C:2]([NH:21][C:22]1[CH:23]=[C:24]2[C:34](=[O:35])[NH:33][N:32]=[CH:31][C:26]3=[CH:27][NH:28][C:29]([CH:30]=1)=[C:25]23)[C@H:3]([NH:13]C(=O)OC(C)(C)C)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:13][C@H:3]([CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]([NH:21][C:22]1[CH:23]=[C:24]2[C:34](=[O:35])[NH:33][N:32]=[CH:31][C:26]3=[CH:27][NH:28][C:29]([CH:30]=1)=[C:25]23)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](COCc1ccccc1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Yield: 100 %

Procedure:
Preparation of example 177 from the title compound of Example 159 (35 mg, 0.072 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner afforded the title compound (30 mg, 0.072 mmol) as an orange/yellow powder in 100% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21](Cl)=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]3=[O:33])[CH2:10][CH2:9]2)=[C:4]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:3]=1.[CH3:40][NH:41][CH3:42]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]([N:41]([CH3:42])[CH3:40])=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]3=[O:33])[CH2:10][CH2:9]2)=[C:4]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:3]=1
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O
Solvent: CCO
Product: CN(C)c1cn(COCC[Si](C)(C)C)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O
Temperature: 130 °C

Procedure:
A mixture of 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-chloro-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (0.5 g, 0.84 mmol), prepared as in Example 25, aqueous dimethylamine (40%, 3 mL) and ethanol (3 mL) was heated in a sealed tube 3 hours at 130° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5+3% ammonium hydroxide) to give 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-dimethylamino-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (0.26 g, 0.44 mmol).
Reaction SMILES: O[C:2]1([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH2:24][CH2:25][O:26]CC2C=CC=CC=2)=[C:3]1[C:34]([O:36][CH3:37])=[O:35].C(O)C>C(OC(=O)C)C>[OH:26][CH2:25][CH2:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[CH:6]=2)[CH:2]([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[CH:3]1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)C2(O)c1ccc2c(c1)OCO2
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A mixture of methyl (1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxy phenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladium on carbon (21 g), 0.65 L of absolute ethanol and 0.65 L of ethylacetate was hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filtered off, and the filtrate concentrated in vacuo to give an amorphous glass. Crystallization from 350 mL of absolute ethanol gave 59.5 g (81%) of white solid; m.p. 165°-168° C.