Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][C@@H:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:21][C@H:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Reactant: CCCCCC[C@@H](C)O
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]

Procedure:
Methyl 4'-hydroxy-3'-nitro-4-biphenylcarboxylate was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-methyl 4'-(1-methylheptyloxy)-3'-nitro-4-biphenylcarboxylate (Compound 30, Scheme V, R1 =(S)--OCH(CH3)C6H13) as a slightly yellow solid after flash chromatography with hexanes/ethyl acetate [93/7]. Recrystallization from hexanes gave material with mp 69° C.; Rf [hexanes/ethyl acetate 90/10]: 0.23; 1H-NMR (300 MHz, CDCl3): δ 0.85(t, 3 H, J=6.8 Mz), 1.20-1.52(m, 8 H), 1.36(d, 3 H, J=6.1 Hz), 1.62(m, 1 H), 1.80(m, 1 H), 3.92(s, 3 H), 4.53(m, 1 H) , 7.12(d, 1 H, J=8.7 Hz), 7.59(d, 2 H, J=8.4 Hz), 7.72(dd, 1 H, J=2.4 Hz, J=8.7 Hz), 8.02(d, 1 H, J=2.4 Hz), 8.08(d, 2 H, J=8.4 Hz); 13C NMR (300 Mz, CDCl3):δ 13.99, 19.46, 22.50, 25.19, 29.09, 31.65, 36.13, 52.17, 76.58, 116.07, 124.04, 126.53, 129.31, 130.35, 131.90, 132.06, 141.11, 142.81, 151.49, 166.75; IR (CHCl3): 3020, 2920, 2850, 1725, 1625, 1620, 1540, 1490, 1360, 1280, 1180, 1120, 1020, 820 cm-1 ; Mass spectrum m/z(rel.intensity): 385(M+ 47), 354(27), 273(100), 242(34), 139(17), 71(10) 57(20), 43(45), (41(38).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH:8]=[N:9]O)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C.C(OCC)C>[C:15]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=1[OH:14])[C:8]#[N:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C=NO)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 54 %

Procedure:
A solution of 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde oxime (3.0 grams, 8.4 mmole) in acetic anhydride (6 ml) was was refluxed for 2 hours. The mixture was cooled to 0° C. and saturated sodium hydrogencarbonate was added. The mixture was extracted with methylene chloride. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to give a solid. This was dissolved in diethyl ether and extracted with 1 N sodium hydroxide which was then acidified to pH 1 and extracted with ethyl acetate. The extract was dried and concentrated to a yellow solid which was recrystalized from ethyl acetate/hexane to give white crystals (1.05 g). MW 231; MS (m/e) 249 (M++NH4+).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3](=[O:6])[CH2:4]Br.C(N(CC)CC)C.[NH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1(C)C(C)=CC=CC=1>[ClH:21].[CH2:33]([O:32][C:30]([NH:29][CH2:4][C:3]([N:2]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[CH3:1])=[O:6])=[O:31])[CH3:34]
Reactant: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(N)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(=O)N(C)c1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cl
Yield: 158.8 %

Procedure:
7.3 g of 2-(N-methyl-bromoacetamido)-5-chlorobenzophenone are heated in 200 ml of anhydrous xylene with 2.2 g of triethylamine and 2 g of urethane (NH2COOC2H5) for 12 hours under reflux whilst stirring. The triethylamine hydrobromide which has precipitated is filtered off with suction after cooling, the filtrate is extracted by shaking with three times 250 ml of water and the organic phase is dried over potassium carbonate, filtered and evaporated in vacuo. The oily residue is dissolved in 400 ml of anhydrous diethyl ether and filtered and 6.5 g of 2-(3-ethoxycarbonyl-N-methyl-3-aza-propanamido)-5-chlorobenzophenone hydrochloride (79% of theory), with a melting point of 156°-158°, are obtained by passing dry hydrogen chloride gas into the ethereal solution.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Reaction time: 17 h
Yield: 92.1 %

Procedure:
To a solution of 12.5 (53 mg, 0.116 mmol) in CH2Cl2 (2 ml) was added trifluoroacetic acid (3 ml) and the mixture was stirred for 17 h and concentrated. The crude product was purified by semi-preparative HPLC (gradient elution: 50 to 100% CH3CN/H2O+0.1% TFA) to afford 43 mg (72%) of 12.6. HRMS (ESI) calc'd for C25H27N2O3 403.2022, found 403.2026 (M+H+); 1H NMR (300 MHz, CDCl3) δ 7.59–7.56 (m, 3H), 7.46–7.34 (m, 6H), 7.13 (d, J=8.4, 2H), 6.74 (d, J=15.7, 1H), 5.12 (s, 2H), 4.20–4.11 (m, 1H), 2.07–2.03 (m, 2H), 1.95–1.89 (m, 2H), 1.75–1.71 (m, 3H), 1.28–1.25 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.C(Cl)Cl.C(O)(=O)C.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(Oc2ccc(N)c3ccccc23)ccn1

Procedure:
A solution of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (2.00 g, 7.11 mmol) in a mixture of methanol (70 mL), DCM (70 mL) and acetic acid (5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was taken up into DCM (100 mL), and was washed with sat. NaHCO3 (100 mL) and brine (100 mL) and then dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 20 to 80%, gradient elution) to afford the title compound, Intermediate E as a brown solid (1.70 g, 85%); Rt 1.04 min (Method 2); m/z 252 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.O.CCOC(C)=O>[CH2:26]([O:25][C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[F:15])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product from Step D (10 g, 45.8 mmol) in THF (90 mL) and water (20 mL) was added K2CO3 (8.23 g, 59.6 mmol). Once the solid was dissolved benzyl chloroformate (7.19 mL, 50.4 mmol) was added. The reaction was stirred vigorously at ambient temperature for 5.0 hours. Once the reaction was complete by TLC the reaction was diluted with EtOAc (100 mL) and water (20 mL). The layers were separated and the organic layer was washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by column chromatography (EtOAc/hexane) to afford 12.9 g (80%) of a sticky, white foam.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[O-:35][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: O=C(CCCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(CCCCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 6-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (2.0 g, 5.8 mmol) by reaction with m-CPBA (1.44 g, 6.41 mmol) to provide 6-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one followed by reaction with p-toluenesulfonyl chloride (1.22 g, 6.41 mmol) and ammonium hydroxide solution (10 mL) to provide 6-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (0.29 g) as an off-white solid after chromatography on silica gel (elution with 5% methanol in dichloromethane) and recrystallization from dichloroethane, mp 163-165° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[Br:17][C:13]1[CH:12]=[C:11]([C:8]2([NH2:7])[CH2:9][CH2:10]2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccnc(Br)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccnc(Br)c2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of [1-(2-bromo-pyridin-4-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.160 g, 0.511 mmol) in dichloromethane (3 mL) is added trifluoroacetic acid (1.0 mL, 13 mmol) at room temperature. After 18 hours, the reaction mixture is concentrated in vacuo to yield crude title compound (ES+ m/z 213.49, 215.40) as an oil, which is used without purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[OH:12][S:13]([OH:16])(=[O:15])=[O:14].[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[S:13]([OH:16])([OH:15])(=[O:14])=[O:12].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=2)[CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (60 mL) was charged into a flask, cooled in an ice/water bath, and 2-aminoindane hydrochloride (10.08 g) was added cautiously, followed by H2SO4 (6.0 mL) and HNO3 (3.0 mL). The ice bath was removed, and the mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was then placed in an ice water bath for the slow addition of diethyl ether (300 mL) over 35 minutes. The mixture was stirred at room temperature overnight, then the solids were filtered and dried in vacuo to give 15.43 g of 2-amino-5-nitro-indane sulfate.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C(O)C.[OH-].[K+]>O>[CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:30])([CH3:32])[CH3:31])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(/C=C(/c2cc3c(cc2C)C(C)(C)CCC3(C)C)[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1/C(=C/c1ccc(C(=O)O)cc1)[Si](C)(C)C)C(C)(C)CCC2(C)C
Temperature: 50 °C

Procedure:
To a solution of ethyl (Z)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trimethylsilyl)vinyl]benzoate (Compound 4, 0.034 g, 0.076 mmol) and 2 mL of ethyl alcohol was added aqueous 1 N KOH (0.5 mL). The resulting solution was heated in an 50° C. bath until the hydrolysis reaction was completed, as judged by thin layer chromatography. The solution was cooled to room temperature, diluted with water and washed once with 1:1 ether:hexane solution, and the layers were separated. The aqueous layer was acidified with 1 N aqueous HCl and the product extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered, and the solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]#[C:4][CH2:5][C:6]1([CH2:9]OS(C)(=O)=O)[CH2:8][CH2:7]1.[Na+].[I-:18]>>[I:18][CH2:9][C:6]1([CH2:5][C:4]#[C:3][Si:2]([CH3:16])([CH3:15])[CH3:1])[CH2:8][CH2:7]1
Reactant: [I-]
Reactant: C[Si](C)(C)C#CCC1(COS(C)(=O)=O)CC1
Agent: [Na+]
Product: C[Si](C)(C)C#CCC1(CI)CC1

Procedure:
In analogy to the procedure described in example 34G], methanesulfonic acid 1-(3-trimethylsilanyl-prop-2-ynyl)-cyclopropylmethyl ester and NaI gave after 30 min at reflux temperature the title compound as orange oil.
Reaction SMILES: N1N(C2C(C(OCC)=O)=NC3C(C=2)=CC=CC=3)N=CC=1.[CH3:21][C:22]1[C:23]([C:28]2[C:29]([C:35]([O:37]C)=[O:36])=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:21][C:22]1[C:23]([C:28]2[C:29]([C:35]([OH:37])=[O:36])=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(C)ccc1-c1ncccc1C
Agent: CCOC(=O)c1nc2ccccc2cc1-n1nccn1
Product: Cc1ccc(-c2ncccc2C)c(C(=O)O)n1

Procedure:
Prepared analogous to intermediate A-33 step B substituting ethyl 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylate with the title compound of step D. MS (ESI) mass calcd. for C13H12N2O2, 228.2; m/z found 229 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:29][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccc4ccccc4c3)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccc4ccccc4c3)c2c1

Procedure:
A mixed solution of 2.2 g of the above-mentioned 2-tert-butyl-9-(naphthalene-2-yl)anthracene, 3.7 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under nitrogen gas stream at room temperature for 1 hour. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-(naphthalene-2-yl)anthracene.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8](S(F)(=O)=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(NCC)C>ClCCCl>[C:4]([OH:6])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1cc(S(=O)(=O)F)ccc1Cl
Solvent: ClCCCl
Solvent: CCNCC
Product: O=C(O)c1ccccc1

Procedure:
A mixture of 2-chloro-5-(fluorosulfonyl)benzoic acid (11.93 g, 0.05 mol), diethylamine (10.97 g, 0.15 mol) and 1,2-dichloroethane (100 ml) is refluxed for 8 hours. The reaction mixture is evaporated, and the residue is dissolved in ethyl acetate. A solid is collected by filtration, and the filtrate is evaporated to dryness to afford 15.5 g of 2-chloro-5-diethylaminosulfonyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[C:22]([C:24]([CH3:36])([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[CH3:25])#[N:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([O:26][C:24]([C:22]#[N:23])([CH3:25])[CH3:36])[CH:28]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(OC(C)(C)C#N)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x) and 3-(1-cyano-1-methylethoxy)benzoic acid (219 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100), and crystallized from ethyl acetate to give the title compound (141 mg, 54%) as colorless crystals.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1N.[N+]([NH:12][C:13]1C=CC=[CH:15][CH:14]=1)([O-])=O.S(=O)(=O)(O)O.[As](=O)(O)(O)O.[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O>OCC(CO)O>[NH2:12][C:13]1[CH:14]=[CH:15][C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: O=[N+]([O-])Nc1ccccc1
Reactant: Nc1ccccc1N
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Solvent: OCC(O)CO
Product: Nc1ccc2ccccc2n1

Procedure:
In a Skraup synthesis, a phenylene diamine (148) or a nitroaniline is reacted with glycerine (149) and sulfuric acid or arsenic acid and an oxidizing agent, such as m-nitrobenzene sulfonic acid (Scheme 66). ##STR86## An intermediate amino- or nitro-guinoline or isoguinoline is produced. In the case of the amino-quinoline, it is not isolated, as it reacts immediately with excess reagents to yield the phenanthroline. If a nitro-aniline has been used to produce a nitroguinoline, it is isolated and purified if necessary. This often removes large amounts of tars produced by the Skraup synthesis. The nitro group is then reduced by standard conditions to yield an aminoquinoline. The aminoquinoline is then subjected to another Skraup reaction (sulfuric or arsenic acid, or both, glycerins and m-nitrobenzenesulfonic acid) to yield the phenanthroline.
Reaction SMILES: C1(C2C=CC=CC=2)C=C[C:4]([S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:9])=[O:8])=[CH:3]C=1.[S:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2C=C1S(N)(=O)=O>>[S:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH:3]=[C:4]1[S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]3[N:24]=[C:23]2[CH2:33][CH3:34])=[CH:18][CH:17]=1)=[O:12])(=[O:9])=[O:8]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cc3ccccc3s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J.; Leu, Y.; et al. J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard, K. L.; et al. J. Med. Chem., 1989, 32, 2548).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:38])=[C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:29])[CH2:23][CH2:22]3)[CH:19]=2)[C:14](=[O:39])[C:13]([C:40]([OH:42])=[O:41])=[CH:12]1>C(O)C.[H][H].[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:38])=[C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]([C:30]5[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=5)=[O:29])[CH2:25][CH2:26]4)[CH:19]=3)[C:14](=[O:39])[C:13]([C:40]([OH:42])=[O:41])=[CH:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(N)cc3F)CC2)cc1
Yield: 51 %

Procedure:
To a suspension of the 1-(2-fluoro-4-nitrophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [example 8] (0.58 g, 1 mmol) in ethanol (20 ml) was hydrogenated overnight in hydrogen in the presence of 10% Pd/C (25 mg) at room temperature. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give a solid, the resulting solid was recrystallized from ethanol to afford 1-(4-amino-2-fluorophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.28 g, 51%). Mp: 143° C. (dec). 1H NMR (DMSO-d6) δ 2.66 and 3.09 (two m, 8H), 3.85-3.84 (m, 5H), 6.05 (s, 2H), 6.47 (d, 1H, J=7.2), 6.58 (m, 2H), 7.02 (m, 2H), 7.36 (m, 1H), 7.97 (m, 3H), 8.62 (s, 1H), 15.06 (br s, 1H). Anal. Calcd. for C29H26F2N4O5•1.0 H2O: C, 61.48; H, 4.98; N, 9.89. Found: C, 61.81; H, 4.85; N, 9.81.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C[N:33](C)C=O>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:31])[C:23]2[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:33])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: NC(=O)c1ccccc1C(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 0 °C

Procedure:
15 g of 3-(1-piperidinylmethyl)phenol was dissolved in 80 ml of dry dimethylformamide. The solution was gradually added dropwise to a suspension of 3.14 g of 60% sodium hydride in 30 ml of dry dimethylformamide with stirring under ice cooling. After the addition, the mixture was stirred at room temperature for 20 minutes, and 21 g of N-bromopropylphthalimide was added. The mixture was reacted at room temperature for 1 hour, and ice water was added. The mixture was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. Distilling off the solvent afforded 28.5 g of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]phthalamide as an oil.