Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)(O)[O-].[Na+]>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.COCCOC>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:3][C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:7][N:6]=2)[S:10][CH:11]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
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
Product: Cc1csc(Nc2ncc(-c3cccnc3)cc2Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-Bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.070 g, 0.1932 mmol), pyridin-3-ylboronic acid (0.02850 g, 0.2319 mmol), Pd(PPh3)4 (0.02233 g, 0.01932 mmol), DME (10 mL), and 2M sodium bicarbonate (2 mL) were combined, heated to 80° C. and stirred overnight. The reaction mixture was cooled and partitioned between CH2Cl2 and water. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (30-40% EtOAc in hexane) to give N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-amine. N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-amine was dissolved in CH2Cl2 and 2M HCl in ether was added to give N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-amine dihydrochloride (0.050 g, 59.71% yield). 1H NMR (d6-DMSO) δ 9.19 (d, 1H), 8.78 (dd, 1H), 8.70 (m, 2H), 7.93 (m, 2H), 7.42 (t, 2H), 7.18 (t, 1H), 7.12 (d, 2H), 6.74 (s, 1H), 2.28 (s, 3H); Mass spectrum (apci) m/z=361.2 (M+H-2HCl).
Reaction SMILES: Cl[CH:2](C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].[Hg:18]>CO>[C:5]1([CH:3]([CH3:2])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[Hg:18]
Reactant: CC(Cl)C(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Hg]
Agent: [K+]
Solvent: CO
Product: CC(C(=O)O)c1ccccc1

Procedure:
A solution comprising 5 parts of α-chloropropiophenone and 3 parts of anyhydrous potassium carbonate in 300 parts of anhydrous methyl alcohol was irradiated by means of a medium pressure 200W mercury vapour lamp for 6 hours at 30° C. The solvent was removed by distillation and the resulting methyl ester of α-phenyl propionic acid was treated with 10% w/v aqueous alcoholic sodium hydroxide at 100° C. for 3 hours to effect hydrolysis and thereby to yield 3.2 parts of α-phenyl propionic acid b.p. 125° C. at 20 mm mercury.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][S:6]([O-:9])(=O)=[O:7])=[O:4].[Na+].P(Cl)(Cl)([Cl:13])=O>>[CH3:1][O:2][C:3]([CH2:5][S:6]([Cl:13])(=[O:9])=[O:7])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CS(=O)(=O)[O-]
Agent: [Na+]
Product: COC(=O)CS(=O)(=O)Cl
Yield: 65.7 %

Procedure:
The sodium methoxycarbonylmethylsulfonate salt was added in small portions to a stirred solution of 840 ml (9.14 mols) phosphorus oxychloride. The resulting mixture was then heated at 80°-100° C. for about 5 hours and allowed to cool overnight. The reaction mixture was filtered, the filtered solid was washed with dichloromethane and the filtrate distilled under reduced pressure to remove the dichloromethane and excess phosphorus oxychloride. The resulting oil residue was distilled through a short Vigreaux column to give 226.8 g (65.7% yield) of methoxycarbonylmethylsulfonyl chloride, as a yellow oil, b.p. 79°-80° C. (0.5 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([N+:20]([O-])=O)=[C:4]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1>[Pt].C1(C)C=CC=CC=1.CO>[NH2:20][C:5]1[C:4]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCNC(=O)OC(C)(C)C)c1C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Catalyst (5 g of 5% platinum on carbon) was added to a warm solution of tert-butyl 2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethylcarbamate (50.4 g) in a mixture of toluene (500 mL) and methanol (40 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4×105 Pa). After 2 hours more catalyst (4 g) was added and the hydrogenation continued overnight. The reaction mixture was filtered through a layer of Celite® filter aid and the filter cake was washed with hot toluene (1 L). The filtrate was concentrated under reduced pressure to provide 45.1 g of tert-butyl 2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.FC(F)(F)S(O[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH:24]=[O:25])[CH:17]=1)(=O)=O>>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([CH:17]=[C:16]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:21]=1)[CH:24]=[O:25]
Reactant: COc1cc(C=O)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccncc1
Product: COc1cc(C=O)cc(-c2ccncc2)c1

Procedure:
Pyridine-4-boronic acid (50 mg, 0.35 mmol) is coupled to aryl triflate 241 (66 mg, 0.23 mmol) using Method A to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O-:12].[K+].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A suspension of potassium 2-methoxy-4-nitro-phenolate (2.0 g, 9.7 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.0 g, 12 mmol) and cesium carbonate (7.0, 22 mmol) in DMF (35 mL) was heated at 80° C. for 16 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and used in the next step without purification. MS (ES+): m/z 267 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][NH:23][CH2:24][C:25]([O:27]C(C)C)=[O:26])[CH2:17]1.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O-]S([O-])(=O)=O.[Mg+2].[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.O>[CH2:31]([N:23]([CH2:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([O:15][CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH2:17]1)[CH2:24][C:25]([OH:27])=[O:26])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CNCC(=O)OC(C)C)C3)c(C)o2)cc1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN(CC(=O)O)Cc4ccccc4)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
120 mg of isopropyl 2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethyl]amino}acetate are dissolved in 1.5 ml of dichloromethane, and 62 mg of benzaldehyde, a spatula tip of MgSO4 and 68 mg of sodium triacetoxyborohyride are added successively. The suspension is stirred at RT overnight, and water is then added. The oraganic phase is separated off, washed with Na2CO3 solution, dried over MgSO4 and concentrated. The residue is dissolved in 0.7 ml of methanol and 0.23 ml of water, 20 mg of LiOH are added and the mixture is stirred at RT overnight. The solution is concentrated and the residue is purified by preparative HPLC, yielding 15 mg of 2-{benzyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}acetic acid. C28H34N2O4 (462.59); MS (ESI): 463 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[CH2:32][NH2:33].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:33][CH2:32][C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2ccc3c(ccn3Cc3ccc(F)cc3F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50 mg, 0.17 mmol, 1 equiv) in DCM (2 mL) were added the (2,4-dimethoxyphenyl)methanamine (27 μL, 0.18 mmol, 1.05 equiv) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (35 mg, 0.18 mmol, 1.05 equiv). The reaction mixture was stirred 2 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt and washed with a 0.5 N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo to afford a beige powder (56 mg, 0.13 mmol, 76%). ESI-MS (m/z): 437 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[O:19][CH3:20])[N:6]=1.C([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34])(=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO.O.C(N(CC)CC)C>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:33]([C:25]3[NH:24][C:32]4[C:27]([CH:26]=3)=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:34])[S:3][CH:4]=2)=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: COc1cc(C(F)(F)F)cc(OC)c1-c1csc(N)n1
Reactant: CC(=O)n1c(C(=O)O)cc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3[nH]2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.3 %

Procedure:
A mixture of 0.609 g of 2-amino-4-(4-trifluoromethyl-2,6-dimethoxyphenyl)thiazole, 0.447 g of N-acetyl-2-indolecarboxylic acid, 1.062 g of BOP and 0.243 g of triethylamine in 30 ml of DCM is stirred at r.t. for 48 hours. 100 ml of water are added, and the organic phase is separated after settling has taken place, dried over sodium sulphate and evaporated under vacuum. The derivative acetylated on the indole nitrogen which is obtained is taken up in 50 ml of MeOH, 2 g of sodium carbonate are added and the mixture is stirred overnight at r.t. It is evaporated under vacuum, the residue is taken up with 100 ml of water, the mixture is extracted with DCM, and the organic phase is dried over sodium sulphate and evaporated under vacuum. 0.54 g of the expected product is obtained after crystallization in DCM, m.p.>260° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:3]=1[CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:3]=1[CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Temperature: 60 °C
Yield: 35.6 %

Procedure:
To a solution of methyl [2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.226 g; 0.499 mmol) in methanol (5 mL) was added a solution of sodium hydroxide 5 N (1 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.078 g (36%) of the title compound as a light yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1.I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][N:14]([CH:18]([CH3:20])[CH3:19])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CC(C)I
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Cl)ncnc21
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Cs2CO3 (382 g, 1.2 mol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (120 g, 0.78 mol) in DMF (1.0 L) at room temperature. The resulting mixture was stirred for 30 min. 2-Iodopropane (267 g, 1.6 mol) was added and the reaction and stirred for 5 h at room temperature. The reaction mixture was filtered and the solid was washed with EtOAc (3×500 mL). The combined filtrates were washed with water (3×500 mL) and brine (3×250 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound as a yellow solid (151 g, 94%). MS: 19.6 (MH+); HPLC Rf: 4.89 min. (HPLC method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([OH:33])[CH2:32][O:31][CH2:30]4)=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: OC1(c2ccc(Br)cc2)COC1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: O=C1N(c2ccc(C3(O)COC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 3-(4-bromo-phenyl)-oxetan-3-ol (prepared as described in WO 2008/156726). White solid. MS (ESI): 477.1 (MH+).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)[CH2:5][CH3:6])[CH3:3]>O1CCOCC1>[ClH:1].[ClH:1].[CH2:5]([N:4]([CH2:2][CH3:3])[CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH3:6]
Reactant: CCN(CC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cooled with ice bath, 4M hydrochloric acid in dioxane (25 mL) was added to tert-butyl 4-(N,N-diethylamino)piperidine-1-carboxylate (6.1 g, 0.024 mol) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed under reduced pressure, and the residue was suspended in diethyl ether, then the precipitate was collected by filtration, washed with diethyl ether and then dried to afford 4-(diethylamino)piperidine dihydrochloride as solid (3.9 g, y. 99%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14](O)=[O:15])=[O:10].[CH3:28][NH:29][CH3:30].O>ClCCl.CN(C)C=O>[CH3:28][N:29]([CH3:30])[C:14]([C:13]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([CH:12]=1)[C:9]([O:8][CH3:7])=[O:10])=[O:15]
Reactant: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(=O)N(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.46 ml, 5.24 mmol) was added dropwise to a stirred solution of 3-[(methyloxy)carbonyl]-4-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 49; 300 mg, 1.05 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of dimethylamine (716 mg, 5.24 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 h. Water (40 ml) was added and the mixture was extracted with dichloromethane (3×60 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product as colourless oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[NH:10][C:9]1=[S:22])(=[O:3])[CH3:2].O.[OH-].[NH4+].I[CH3:27]>C(O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:22][CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Reactant: CI
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)=O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a round-bottomed flask containing 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propyl acetate (28.9 g, 76.0 mmol) was added water (180 mL), ethanol (180 mL), and ammonium hydroxide (38 mL). The resulting suspension was stirred at ambient temperature. To this suspension was added iodomethane (9.5 mL, 152 mmol), and the reaction was stirred for 2 h. The suspension was filtered through a sintered glass funnel and the residue was washed with diethyl ether and dried under reduced pressure to afford 3-[7-bromo-2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl]propyl acetate (22.2 g) as tan solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].C1COCC1.[F:30][C:31]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]2[C:32]=1[C:33](=[O:53])[C:34]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)=[CH:35][NH:36]2.[C:54]([CH:57](O)[CH2:58][NH-:59])([OH:56])=[O:55]>O>[F:30][C:31]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]2[C:32]=1[C:33](=[O:53])[C:34]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)=[CH:35][NH:36]2.[C:54]([CH:57]([Cl:21])[CH2:58][NH-:59])([OH:56])=[O:55]
Reactant: [NH-]CC(O)C(=O)O
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: [NH-]CC(Cl)C(=O)O
Temperature: 25 °C

Procedure:
Triphenyl phosphine (2.47 g, 9.8 mmol) and carbon tetrachloride (1.4 g, 9.1 mmol) were added to a THF solution (30 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydro-quinoline-2-carboxy-(2-hydroxyethyl)amide (3.0 g, 7.24 mmol) and heated under reflux for 2 hours. The mixture was cooled to room temperature, and water was then added thereto, followed by extraction with dichloromethane. The thus-obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=100:0→20:1). The purified material was concentrated to dryness under reduced pressure, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide (1.8 g, yield: 58%).
Reaction SMILES: C12(C3C=CC(OCC(N[C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23](O)=[O:24])=O)=CC=3)CC3CC(CC(C3)C1)C2.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:20][CH:21]=2)=[CH:34][CH:33]=1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 132.1 %

Procedure:
To a solution of 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid (20 mg, 0.049 mmol), 4-chloro aniline (9.4 mg, 0.073 mmol) and DIPEA (9.56 mg, 0.073 mmol) in DMF (5 mL) was added EDC (14.18 mg, 0.073 mmol) and HOBt (9.99 mg, 0.073 mmol) at room temperature and continued stirring for 16 h at room temperature. Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by column chromatography on silica gel (EtoAC:Hexane=1:5) to give 3-[2-adamantan-1-yl-phenoxy)-acetylamino]-N-(4-chloro-phenyl)-benzamide as a colorless crystals (15 mg, yield: 59%).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][NH:4][C:5](=[O:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.Cl>C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5](=[O:21])/[C:6](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:1]/[OH:2]
Reactant: CNC(=O)C(=O)c1ccccc1Oc1ccccc1
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Toluene (20 ml) and a 50% aqueous solution (0.71 ml, 12 mmol) of hydroxylamine were added to N-methyl-2-(2-phenoxyphenyl)-2-oxoacetamide (2.55 g, 10 mmol). The mixture was heated under reflux for 4 hours (E/Z=40/60). After cooling, conc. hydrochloric acid (3.0 ml, 30 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the resulting crystals were separated by filtration, washed with water and toluene and dried to give (E)-N-methyl-2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (2.65 g, Yield: 98.0%, E/Z=98/2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[O:11][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccccc2F)n1
Yield: 13.1 %

Procedure:
This compound was prepared according to general method 2 with 2-(2-fluorophenyl)acetic acid (1.19 g; 7.57 mmol) and oxalyl chloride (0.704 mL; 8.33 mmol) in dichloromethane (5 mL) with a few drops of DMF; and ethyl 2-amino-2-(hydroxyimino)acetate (1.0 g; 7.57 mmol) and N,N diisopropylethylamine (2.11 mL; 12.11 mmol) in dichloromethane (10 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.249 g (14%) of ethyl 5-(2-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.