Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1C=C(C2(O)CCCCC2CCN2CCN(C)CC2)C=CC=1OCC1C=CC=C(C(F)(F)F)C=1.Cl.Cl.[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=1>>[ClH:3].[ClH:40].[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:62][CH2:63][N:64]([CH3:4])[CH2:65][CH2:66]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:58])[F:56])[CH:50]=1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3cccc(C(F)(F)F)c3)c(Cl)c2)CC1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3cccc(C(F)(F)F)c3)c(Cl)c2)CCCCC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3cccc(C(F)(F)F)c3)c(Cl)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-(3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-2-(4-methylpiperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride (See Example 423). MS (ESI) m/z 511; HRMS: calcd for C27H34ClF3N2O2+H+, 511.23336. found (ESI, [M+H]+), 511.231.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]([N+:22]([O-])=O)=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[NH2:22][C:5]1[C:4]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Yield: 90.6 %

Procedure:
A solution of tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate (7.32 g, 17.00 mmol) in a mixture of toluene (150 mL) and isopropanol (10 mL) was combined with a slurry of 10% palladium on carbon in toluene. The mixture was place under hydrogen pressure on a Parr apparatus for 24 hours. Additional catalyst was added at 1.5 hours (2.2 g) and 3 hours (3 g). The reaction mixture was filtered through a layer of Celite® filter agent to remove the catalyst. The layer of filter agent was washed with ethanol (1 L), ethanol/methanol (1 L), and methanol (1 L). The filtrate was concentrated under reduced pressure. The residue was combined with dichloromethane and heptane and then concentrated under reduced pressure to provide 6.17 g of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate as a sludgy brown yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1>[N+:17]([C:16]1[C:11]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: OC1CCOCC1
Reactant: O=[N+]([O-])c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a stirred solution of tetrahydro-2H-pyran-4-ol (2.5 g, 24.5 mmol) in anhydrous THF (20 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 0.938 g, 24.5 mmol) and the mixture stirred at 0° C. for 0.5 h. A solution of 2-fluoro-3-nitro-pyridine (3.3 g, 23.2 mmol) in anhydrous THF (5 mL) was added drop wise with stirring and the solution allowed to warm to ambient temperature over 5 hours. The reaction was cooled in an ice-bath and water (50 mL) added. The mixture was extracted with EtOAc (2×100 mL) and the combined organic layers washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified flash column chromatography (20% iso-hexane/DCM DCM) to yield the title compound as pale yellow oil (2.67 g, 48% yield).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[S:43]([CH3:42])(=[O:45])=[O:44])[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-ethoxymethyl-1-(piperidin-2-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (0.60 g, 1.1 mmol) and triethylamine (0.79 mL, 5.7 mmol) in chloroform (50 mL) was cooled to 4° C. Methanesulfonyl chloride (0.12 mL, 1.5 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Additional methanesulfonyl chloride (2.5 equivalents) was added at 4° C. over the course of several days. The work-up procedure described in Examples 178 to 181 was carried out. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from about 100:0 to 70:30) followed by recrystallization from acetonitrile to provide 0.19 g of 2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-2-yl]methyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 152-154° C.
Reaction SMILES: [CH3:1][NH2:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:33][C@@:31]2([CH3:32])[C@@H:27]([CH2:28][CH2:29][C@@H:30]2[OH:34])[C@@:26]2([CH:35]=[CH2:36])[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:37])=[CH:22][C:23]=1[CH2:24][CH2:25]2>>[CH3:1][NH:2][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:33][C@@:31]2([CH3:32])[C@@H:27]([CH2:28][CH2:29][C@@H:30]2[OH:34])[C@@:26]2([CH:35]=[CH2:36])[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:37])=[CH:22][C:23]=1[CH2:24][CH2:25]2
Reactant: CN
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with methylamine (40% in water, 3 ml/mmol) with the addition of sodium carbonate analogously to instructions 17.2, 155 mg of product mixture 30b yields 152 mg of amine 31b as a colorless solid (GC-MS: m/z theor.: 411, pract.: 411).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1CN=[N+]=[N-]
Reaction time: 8 h

Procedure:
Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. Aqueous was extracted with ethyl acetate (3×30 mL) and combined organics were washed with water (2×40 mL) and 50 mL of brine. Organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1.[OH-].[K+]>CO.O>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)c2cccc(C(=O)O)c2C1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A solution of 2.5 g (11 mmol) of methyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (J. Org. Chem. 17 (1976), 2918) and 1.8 g (33 mmol) of potassium hydroxide in 50 ml of methanol and 5 ml of water was allowed to stand at room temperature overnight. After distilling off the methanol in vacuo, the residue was taken up in 40 ml of water and the mixture was acidified with dilute hydrochloric acid. The precipitated product was filtered off with suction and dried in vacuo, and 2.3 g of 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid were obtained; m.p. 167-168° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>C(C(C)=O)C(C)C>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8](=[O:18])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:28]
Reactant: CCN(CC)CCCl
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCOc1c(-c2ccccc2)c(=O)oc2ccccc12

Procedure:
11.9 g. (0.05 mol) of 3-phenyl-4-hydroxy-coumarin, 8.3 g. (0.06 mol) of anhydrous potassium carbonate and 200 ml. of methyl isobutyl ketone are placed in a dry reactor. The mixture is brought while stirring for 1 hour to 70° C. 0.5 g. of potassium iodide is then added, followed by dropwise addition of a solution of 8.8 g. (0.065 mol) of 2-diethylamino-1-chlorethane in 20 ml. of methyl isobutyl ketone.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51][S:52][CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH2:51][S:52][CH3:53])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSCO[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of the compound of Example 1 (5.0 g, 6.9 mmol) and methyl sulfide (4.1 mL) in acetonitrile (35 mL) at 0° C. was added benzoyl peroxide (6.7 g) in four portions over 20 minutes, and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient of 33-100% ethyl acetate in chloroform to give the title compound (4.56 g, 84% yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15](=[O:16])[NH:13][C:10]2[CH:11]=[N:12][C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][CH:9]=2)=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(OC2CCCC2)nc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC2CCCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 6-cyclopentyloxy-pyridin-3-ylamine (0.248 g, 1.39 mmol) in THF (2 mL) was added 4-nitrophenyl chloroformate (0.280 g, 1.39 mmol) portionwise. After stirring at rt for 1 h, a heavy precipitate formed in the organic layer. Filtration of the organic layer provided the title compound as a light pink solid (0.368 g, 77%). 1H-NMR (400 MHz, CDCl3): δ 11.1 (s, 1H), 9.11 (s, 1H), 9.04 (d, 1H), 8.26 (d, 2H), 7.40 (d, 2H), 7.14 (d, 1H), 5.36 (m, 1H), 2.11 (m, 2H), 1.97 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17].C(OC(C)C)(C)C>CO>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)O
Temperature: 50 °C
Yield: 52.7 %

Procedure:
To a solution of KOH (0.26 g, 4.7 mmol) in methanol (13 ml), methyl (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoate (0.3 g, 1.17 mmol) was added and the solution was heated at 50° C. for 1 hour under nitrogen. The solvent was removed under vacuum and the residue was dissolved in water (20 ml) and washed with isopropyl ether. The aqueous phase was adjusted to pH 5 with 10% HCl and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and the solvent removed under reduced pressure obtaining, after trituration with isopropyl ether, 0.15 g (52.7%) of the title compound as a solid, m.p.=189-190° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3.2 g (12.2 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 6.7 ml (60.3 mmol) 1-methylpiperazine was stirred at 100° C. for 2.5 h. The reaction mixture was cooled to r.t., treated with 10 ml 0. 1N NaOH and extracted. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with brine. The combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2: MeOH=99:1) to yield 3.3 g (83.7%) product as beige foam.
Reaction SMILES: [CH3:1][C:2]([C:10]1[O:14][CH:13]=[N:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:6][CH:5]=1)([C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[CH3:1]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(c1ccccc1)c1cnco1
Product: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1cnco1
Temperature: 60 °C
Yield: 63 %

Procedure:
A solution of 5-(1-Methyl-1-phenylethyl)oxazole (3.87 mmol, 1.0 eq.) in CDCl3 (0.3 mL) was stirred at 0° C. and chlorosulfonic acid (11.7 mmol, 3.0 eq.)was slowly added in. The mixture was heated to 60° C. for 3 h and cooled to room temperature. The solution was further mixed with crushed ice (15 g) and extracted with EtOAc (3×15 mL). The extracts were combined, washed by saturated aqueous NaCl solution, dried by MgSO4, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (697 mg, 63%) which was used as it was. 1H NMR: δ (400 MHz, CDCl3) 7.97 (d, 2H), 7.83 (s, 1H), 7.47 (d, 2H), 6.96 (s, 1H), 1.74 (s, 6H). MS (M+H+): 286.0
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl.ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1O
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-hydroxybenzoate (152 g, 1.0 mol) in chloroform (500 mL) was added dropwise with stirring a solution of bromine (172 g, 1.08 mol) in chloroform (300 mL) at 10° C. After the addition, the solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (500 mL), washed with water (1 L×3), saturated sodium bicarbonate solution (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was re-crystallized from methanol to give methyl 5-bromo-2-hydroxybenzoate (192 g, yield 83%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.89 (d, J=8.8 Hz, 1H), 7.52-7.55 (dd, J=8.8 Hz, J=2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 10.7 (s, 1H); LC-MS (ESI) m/z 233 [M+1]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:34]5[CH:33]=[C:32]6[C:37](=[CH:36][CH:35]=5)[N:28]=[CH:29][CH:30]=[CH:31]6)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=486.5 [(M+H)+], mp 211.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH2:22][CH2:23][CH2:24][PH:25](=[O:27])[OH:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([NH:31][CH2:32][CH2:33]O)(=[O:30])[CH3:29]>O1CCCC1.CN(C)C1C=CN=CC=1>[C:16]1([CH2:22][CH2:23][CH2:24][PH:25](=[O:26])[O:27][CH2:33][CH2:32][NH:31][C:28](=[O:30])[CH3:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[PH](O)CCCc1ccccc1
Reactant: CC(=O)NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCO[PH](=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
To a solution of 0.31 g (1.5 mmol) of 1,3-dicyclohexylcarbodiimide in tetrahydrofuran (3 ml) is added 0.28 g (1.5 mmol) of 3-phenylpropylphosphinic acid in tetrahydrofuran (1 ml). The resulting suspension is stirred for 10 minutes at room temperature. N-acetyl ethanolamine (0.10 g, 1.0 mol) is then added, followed by 18 mg or 4-dimethylaminopyridine. The mixture is stirred for 2 hours. The solvent is evaporated under reduced pressure, and the residue is stirred with ethyl acetate (20 ml). The resulting suspension is filtered. The filtrate is washed with 5% potassium hydrogen sulfate (8 ml), saturated sodium bicarbonate (2×5 ml), and brine (5 ml), and evaporated to give 0.12 g of a colorless oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]1[N:18]=[C:17](S)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=1>CN(C)C=O>[Cl:3][C:17]1[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]([C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[F:6])[N:18]=1
Reactant: Cn1c(S)nc(-c2ccncc2F)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Temperature: 60 °C
Yield: 73.3 %

Procedure:
After one hour stirring of a solution of phosphorus oxychloride (45 g, 293 mmol) in dimethylformamide (450 ml) at room temperature, 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (46.3 g, 195 mmol) was added and heated at 60° C. for 2 hours. The resulting suspension was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed by hexane to furnish 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (34.2 g, 143 mmol, 73%) as white crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]([OH:23])=O)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:25]([NH:29][C:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)[CH:12]=2)[N:17]=1)=[O:23])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CN
Reactant: CC(C)N1CCC(Oc2ccc3nc(C(=O)O)ccc3c2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)CNC(=O)c1ccc2cc(OC3CCN(C(C)C)CC3)ccc2n1

Procedure:
According to the procedure described for the synthesis of example 1, (6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutyl-amide was synthesized from 6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride, isobutylamine (commercially available) and 1,1′-carbonyl-diimidazole. MS (m/e): 370.6 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:28](=[O:30])[CH3:29])[CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(-c3cccc(O)c3)nc(=O)n(C(C)C)c2c1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 5.0 g of refined 1-isopropyl-4-(3-hydroxyphenyl)-7-methyl-2(1H)-quinazolinone in a vessel, is added 100 ml of acetic anhydride and 0.5 ml. of concentrated sulfuric acid. The resulting mixture is allowed to stand for 16 hours. The reaction mixture is then poured over salted ice in a vessel. After the ice has melted, the resulting liquid is extracted twice with 300 ml portions of benzene: n-butanol (4:1) and the combined extracts washed with distilled water until free of acid, and then evaporated to obtain a residue. The residue is crystallized from methanol to obtain the title product, m.p. 148°-150°.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[N+:14]([C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])([O-:16])=[O:15]>CC(C)=O>[N+:14]([C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([O:21][CH3:1])=[O:20])([O-:16])=[O:15]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2M hexane solution (4.5 mL) of trimethylsilyldiazomethane was added to the mixture of 2-Nitro-3-methylbenzoic acid (1.6 g) and acetone (15 mL) and stirred for 3 hours. After removing the solvent, the residue was diluted with ethyl acetate and washed with 1M sodium hydrate aqueous solution, water and saturated aqueous solution of sodium chloride respectively. Then the obtained substance was concentrated and dried to obtain methyl 2-nitro-3-methylbenzoate.