Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Product: CCOc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 73.3 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (Example 91, step A) (0.30 g, 0.90 mmol) and methyl vinyl sulfone (0.29 g, 2.7 mmol) in dioxane (9.0 mL) was stirred under N2. The reaction was heated to 95° C. and stirred for approximately 3 h, then cooled to rt. The reaction mixture was concentrated under vacuum. The residue was taken up in DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was chromatographed on silica gel to give the title compound of step A (294 mg, 0.66 mmol, 74%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, 1H, J=9.35 Hz), 6.56 (dd, 1H, J=9.44 and 2.29 Hz), 6.49 (d, 1H, J=2.38 Hz), 4.17 (q, 2H, J=6.96 Hz), 3.36-3.41 (m, 4H), 3.25 (t, 2H, J=6.78 Hz), 3.01 (s, 3H), 2.92 (M, 2H), 2.66 (t, 2H, J=6.78 Hz), 2.57 (m, 4H), 2.15-2.25 (m, 1H), 1.89-1.97 (m, 2H), 1.75 (m, 2H), 1.32-1.40 (m, 5H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14](=[O:18])[NH:15][N:16]=3)[CH2:11][CH2:10][C:9]=2[CH:19]=1)(=O)C>C(O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14](=[O:18])[NH:15][N:16]=3)[CH2:11][CH2:10][C:9]=2[CH:19]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCc1cc(=O)[nH]nc1-2
Solvent: CCO
Product: Nc1ccc2c(c1)CCc1cc(=O)[nH]nc1-2

Procedure:
In a manner similar to that described in Example 13, 8 -acetamido-5,6-dihydrobenzo[h]cinnolin-3[2H]-one was hydrolysed to give 8-amino-5,6-dihydrobenzo[h]cinnolin-3[2H]-one, (m.p. 290°-292°; from aqueous ethanol); ν(Nujol mull) 3300-2200, 1680,1605, 1585, 1560 and 1545 cm-1 ; δ(DMSO-d6) 2.80(4H,s,5,6-H2), 6.71(1H,s,4-H), 6.8-7.0(2H,m,7,9-H), 7.80(1H,d,10-H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C>>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:32][C@@H:28]3[CH2:29][CH2:30][CH2:31][NH:27]3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Product: c1ccc(Cc2ccc(-c3ccc(OC[C@@H]4CCCN4)cc3)s2)cc1
Yield: 85 %

Procedure:
The title compound was prepared from the product of example 170, step 4 (0.3 g, 1.1 mmol) and (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.4 mmol) using the procedure of Example 159, step 5 with 85% yield (360 mg). 1HNMR (CD3OD) 7.50 (d, J=8.8 Hz, 2H), 7.39-7.18 (d, J=3.6 Hz, 5H), 7.08 (d, J=3.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 4.58 (m, 1H), 4.32 (m, 1H), 4.12 (s, 2H), 4.03 (m, 2H), 3.34 (m, 2H), 2.26 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), LC/MS (ESI+) m/z: 99%; 351 (M+1, 100). Elemental analysis
Reaction SMILES: C[O-].[Na+].[Cl-:4].[NH2:5][C:6]([NH2:8])=[NH2+:7].[CH3:9][S:10]([C:13]1[C:22]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([CH3:27])[CH:14]=1)(=[O:12])=[O:11].Cl>CO.C1COCC1>[Cl-:4].[CH3:9][S:10]([C:13]1[C:22]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:16]([C:17]([NH:7][C:6]([NH2:8])=[NH2+:5])=[O:18])=[C:15]([CH3:27])[CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C
Reactant: NC(N)=[NH2+]
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)NC(N)=[NH2+]
Temperature: 20 °C
Reaction time: 2 h

Procedure:
87.4 ml of THF, were added with stirring to 50.4 g of a 30% sodium methoxide solution in methanol. 28.95 g of guanidinium chloride were subsequently introduced. The suspension was stirred at 16-24° C. for 2 h and cooled to 10° C., before 30.8 g of methyl 4,5-bismethanesulfonyl-2-methylbenzoate were introduced into the mixture. After the mixture had been stirred at 10° C. for 1 h, a corresponding amount of a hydrochloric acid solution was added to the mixture. Conventional work-up gave N-(4,5-bis-methanesulfonyl-2-methylbenzoyl)guanidinium chloride.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][C@H:19]([OH:25])[C@H:18]2[NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].P(=O)(O)(O)O.[ClH:47]>CS(C)=O.CO.O1CCOCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(OCC)(=O)C>[ClH:47].[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C@H:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:6]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[CH:16]=3)[O:21][CH2:20][C@@H:19]2[OH:25])=[O:35])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(N[C@H]1c2cc(Br)ccc2OC[C@@H]1O)c1ccc(F)cc1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(C)(C)[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@H]1c2cc(N3CCNCC3)ccc2OC[C@@H]1O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
Degas (bubble nitrogen through the mixture) a suspension of tri-t-butylphosphonium tetrafluoroborate (16.0 g, 54.6 mmol) and allylpalladium(II) chloride dimer (5.07 g, 27.3 mmol) in DMSO (1.40 L) with stirring at room temperature. Add N-tert-butoxycarbonylpiperazine (315 g, 1.64 mol, 97% pure) and N-[(3R,4S)-6-bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamide (200.0 g, 546 mmol). Stir the mixture for 15 min under nitrogen and then heat at 80° C. Add sodium tert-butoxide (179 g, 1.80 mol) and heat at 93-98° C. for 45 min. Pour the mixture over a solution of 1 M phosphoric acid (2.73 L, 2.73 mol, adjusted to pH=2.3 with 50% sodium hydroxide) and ethyl acetate (800 mL) and stir for 10 min. Separate the layers and extract the aqueous layer with ethyl acetate (3×300 mL). Wash the combined organic layer with semi-saturated brine (2×500 mL). Treat the organic layer with activated carbon (20 g) and silica gel (200 g) and stir for 30 min. Filter through a pad of diatomaceous earth and concentrate under reduced pressure to obtain a dark oil. Dissolve the oil in methanol (800 mL), add 4 M hydrogen chloride in dioxane (410 mL), and stir the solution at 40° C. for 1 hr. Evaporate the solvent in vacuo, suspend the residue in acetonitrile (1.6 L) and stir at room temperature for 1 hr. Collect the solid by filtration under nitrogen to avoid hydration of the salt. Wash the filtrate with acetonitrile (500 mL) and methyl tert-butyl ether (1 L), and dry under vacuum to obtain the title compound (262 g, 73%). LC-ES/MS m/z 372 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.CN.Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O.CN(C)C=O>[CH3:37][NH:39][C:30]([C:29]1[C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A 50 mL round-bottom flask was charged with 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 20 h, and poured into water (200 mL). The solid was collected by filtration, washed with water, dried and purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′ (2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-white solid: 1H NMR (300 MHz, CDCl3) 8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70 (ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5, 131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7, 64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]2=3)[CH2:30][CH2:29][O:28]4)[C:14]1=[O:33])C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]2=3)[CH2:30][CH2:29][O:28]4)[C:14]1=[O:33]
Reactant: O=C1N(Cc2cccc(OCc3ccccc3)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [Pd]
Solvent: CO
Product: O=C1N(Cc2cccc(O)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A mixture of 1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (1.30 g, 2.7 mmol) and 10% wt. palladium on carbon (0.25 g) in dry methanol (14 mL) was hydrogenated at ambient temperature under a balloon pressure for 16 h. The mixture was filtered through a pad of celite and concentrated in vacuo to dryness. The residue was subjected to column chromatography (hexanes/ethyl acetate from 2:1 to 1:1) to afford 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.97 g, 93%) as a colorless solid: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ9.48 (s, 1H), 7.30-7.22 (m, 1H), 7.20-7.11 (m, 2H), 7.06-6.94 (m, 2H), 6.81-6.76 (m, 1H), 6.72-6.69 (m, 1H), 6.68-6.63 (m, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 4.85 (ABq, 2H), 4.79 (ABq, 2H), 4.55-4.46 (m, 2H), 3.02-2.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.0, 161.1, 160.6, 157.6, 142.2, 137.6, 132.0, 129.7, 128.6, 123.6, 123.0, 120.4, 119.9, 118.9, 117.7, 114.4, 113.6, 109.4, 92.5, 79.8, 72.1, 56.9, 42.9, 28.3; MS (ES+) m/z 386.0 (M+1).
Reaction SMILES: B(Cl)(Cl)Cl.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][N:16]2[C:25](=[O:26])[C:24]3[C:19](=[C:20]([O:27]C)[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17]2)=[O:14])=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][N:16]2[C:25](=[O:26])[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17]2)=[O:14])=[CH:8][CH:7]=1
Reactant: COc1cccc2c(=O)n(NC(=O)Nc3ccc(Br)cc3)cnc12
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)Nn1cnc2c(O)cccc2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1.0 molar solution of boron trichloride in dichloromethane (24 mL, 24.0 mmol BCl3) is added to a mixture of 1-(p-bromophenyl)-3-(3,4-dihydro-8-methoxy-4-oxo-3-quinazolinyl)urea (3.08 g, 7.91 mmol) in dichloromethane. The reaction mixture is stirred for 20 hours at room temperature, adjusted to about pH 8 with sodium hydrogen carbonate and concentrated in vacuo to obtain a slurry. The slurry is filtered and the filter cake is washed with water and dried to give the title product as a white solid, 2.55 g, mp 276°-278° C., which is identified by 1HNMR spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH:9]1[CH2:40][C:41]([O:43]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH2:46].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:31][C:32]2[C:33]([CH3:39])=[CH:34][CH:35]=[CH:36][C:37]=2[CH3:38])=[O:15])[CH2:10][CH:9]1[CH2:40][C:41](=[O:43])[NH:46][CH3:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN
Reactant: COC(=O)CC1CN(C(=O)c2c(Oc3c(C)cccc3C)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CNC(=O)CC1CN(C(=O)c2c(Oc3c(C)cccc3C)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 168 h
Yield: 32.2 %

Procedure:
A solution of the crude compound of example 58, step 2, (140 mg, 234 μmol) in MOH (1 ml) was mixed with a 2 M methanolic solution of methylamine (2.60 ml, 5.19 mmol). The reaction mixture was stirred at 40° C. for 7 days. After cooling to room temperature, the mixture was neutralized with an aqueous solution of citric acid and extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated. 45 mg of crude title compound were obtained.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][O:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][O:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCO3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])OCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
H2O2 (70%, 0.16 mL, ca. 3.2 mmol) was added dropwise to a stirred solution of TFAA (0.45 mL, 3.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 236 (50 mg, 0.17 mmol) and TFA (0.12 mL, 1.6 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 237 (28 mg, 54%) as a red gum: 1H NMR δ 8.11 (d, J=9.5 Hz, 1H, H-5), 7.36 (d, J=9.5 Hz, 1H, H-6), 7.23 (br s, 1H, NH), 4.21-4.25 (m, 2H, H-8), 3.61 (br t, J=5.8 Hz, 2H, CH2N), 3.56 (br t, J=6.5 Hz, 2H, H-10), 2.62 (br t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.00-2.07 (m, 2H, H-9); 13C NMR δ 154.0, 148.4, 135.8, 130.6, 128.9, 116.0, 114.9, 66.2, 57.5, 45.1 (2), 38.7, 24.5, 21.9; MS (FAB+) m/z 306 (MH+, 60%), 290 (20), 176 (100); HRMS (FAB+) calcd for C14H20N5O3 (MH+) m/z 306.1566, found 306.1568. Anal. calcd for C14H19N5O3.½H2O.½MeOH: C, 52.7; H, 6.7; N, 21.2. Found: C, 52.8; H, 6.7; N, 21.2%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:10][CH2:11][CH2:12][C:13]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]4[NH:28][N:29]=[N:30][N:31]=4)[CH3:25])[CH2:22][S:23][C@H:18]23)=[O:15])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCS(=O)c1ccc(O)cc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CCCS(=O)c3ccc(O)cc3)[C@H]2SC1

Procedure:
456 mg. of 4-(p-hydroxyphenylsulfinyl)butyric acid and 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 245 mg. of 7-[4-(p-hydroxyphenylsulfinyl)butyramido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.O.Cl>CC(C)=O.[OH-].[Na+]>[Cl:15][C:16]1[N:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of 7.4 g (39.5 mMol) 6-hydroxy-1-naphthoic acid and 5.9 g (39.5 mMol) 2,4-dichloropyrimidin in 104 ml of acetone, 79 ml NaOH (1 M in H2O) are added dropwise. The mixture is stirred for 19 h at rt and finally 2 h at 50° C. Then it is poured into 1.3 l water and acidified by addition of 40 ml of a 2 M HCl solution. Filtration of the suspension, washing with water and drying gives the title compound: MS: [M+1]+=301.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29](O)=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].CCCCCCC=CCCC>O1CCCC1.O>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CCCC=CCCCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(CCCCOCC(=O)NS(C)(=O)=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Under an argon atmosphere, to a solution of 300 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid obtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 128 mg of 1,1′-carbonyl diimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes. After air-cooling to room temperature, 69 mg of methanesulfonamide was added. After stirring for 10 minutes, 0.11 ml of 1,8-diazabicyclo[5.4.0.]-7-undecene was added dropwise. After stirring at room temperature overnight, the reaction solution was diluted with water and then extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain 272 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].S(Cl)(Cl)=O.[CH:27](O)([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1.CN(C)C=O>[Br:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([O:19][CH:27]([CH3:29])[CH3:28])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: CC(C)O
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2Br)c(F)cc1Cl
Temperature: 45 °C

Procedure:
A solution of 100 g (0.25 mol) 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoic acid (Compound No. 3) in 580 mL of toluene was prepared and treated with 1 g of dimethylformamide (DMF). The stirred mixture was heated to 45° C., treated with 30 g (0.252 mol) of thionyl chloride and subsequently heated to 60° C.-65° C. for one hour. After cooling to 40° C., a solution of 30 g (0.50 mol) of isopropanol and 27.6 g (0.35 mol) pyridine was added at once. The mixture was stirred and heated to about 55° C. for 30 minutes to complete conversion of the intermediate acid chloride to the desired product. Treatment with 650 mL water and 45 g of acetone gave two clear layers. The aqueous layer was removed and the organic portion washed with water, saturated brine, dried with MgSO4 and concentrated to give a viscous oil. A solid was obtained by solution of the oil into 250 g of warm isopropanol, cooling of the mixture to room temperature and slow treatment with 600 mL of cold water. The resultant precipitate was collected by filtration, washed with water and air dried to give 105 g (94.7%) of a white solid: mp 79.5° C.-80.5° C.; 1H NMR (CDCl3) δ 1.49 (d, 6H), 4.21 (s, 3H), 5.38 (m, 1H), 7.43 (d, 1H), 8.14 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cc(F)ccc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cc(F)ccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(2,5-difluorophenoxy)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.6 Hz), 7.95 (2H, d, J=8.2 Hz), 7.60 (1H, d, J=7.4 Hz), 7.45–7.32 (3H, m), 7.25–7.13 (1H, m), 6.97–6.82 (2H, m), 6.80–6.67 (1H, m), 5.33 (1H, dq, J=7.4, 6.9 Hz), 3.90 (3H, s), 1.53 (3H, d, J=6.9 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: C([Cl:4])(=O)C.[O:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:7][CH2:6]1>C(O)C>[ClH:4].[ClH:4].[ClH:4].[O:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[N:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)Cl
Agent: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Solvent: CCO
Product: Cl

Procedure:
The resulting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate (7) and benzyl amine were coupled in anisole at high temperature to afford 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (Compound 134). An HCl solution formed by adding acetyl chloride to absolute ethanol was added to Compound 134 to form the bis-HCl salt, 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride, (KX2-di-HCl).