Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>>[C:15]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)=[CH:21][CH:22]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OCc2ccc(-c3ccccc3)cc2)n1
Yield: 61.8 %

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol), p-phenylbenzyl alcohol (607 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). Recrystallization from hexane gave 0.55 g (88%) of the title compound: mp 86-87° C. MS m/z: 297 (M+H)+. Anal. (C17H13ClN2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6]O.[CH3:14][O:15][C:16](=[O:34])[CH:17](P(OCC)(OCC)=O)[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.[Mn]>[C:22]([O:21][C:19]([NH:18]/[C:17](=[CH:6]\[C:5]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:16]([O:15][CH3:14])=[O:34])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOP(=O)(OCC)C(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Mn]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccc([N+](=O)[O-])c(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Activated manganese IV oxide (26 g) was added to a mixture of 3-methoxy-4-nitrobenzylalcohol (5.26 g, 28.7 mmol), N-(t-Butyloxycarbonyl)-α-(diethylphosphono)glycine methylester (described in WO99/47547) (8.91 g, 27.4 mmol) and DBU (4.29 ml, 28.7 mmol) in DCM (150 ml) at 0°. The mixture was stirred at RT overnight then filtered. The filtrate was washed with dil. HCl, dried (Na2SO4) and evaporated in vacuo. Recrystallisation from MeOH gave the title compound as pale brown crystals (4.6 g). δH (DMSO d6) 8.94 (1H, br s), 7.91 (1H, d, J 8.4 Hz), 7.56 (1H, d, J 1.5 Hz), 7.36 (1H, dd, J 8.5, 1.3 Hz), 7.12 (1H, br s), 3.92 (3H, s), 3.75 (3H, s), 1.37 (9H, s). m/z (ES+, 70V) 375 (M++Na).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:30])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:17](=[O:19])[CH3:18].[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].P([O-])(O)(O)=O.[K+].N1C=CC=CC1=O>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:30][N:14]([CH3:13])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)[C:17](=[O:19])[CH2:18][C:34](=[O:35])[CH2:33][O:32][CH3:31]
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Reactant: COCC(=O)Cl
Agent: O=P([O-])(O)O
Agent: O=c1cccc[nH]1
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCC(=O)CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
A 3.9 g. portion of diisopropylamine was dissolved in 170 ml. of dry tetrahydrofuran, and the mixture was chilled under a nitrogen blanket to about -70°. Sixteen ml. of 2.4-molar n-butyllithium solution was added dropwise at constant temperature and the mixture was stirred for 55 minutes. To the mixture was then added 8.3 g. of 1-dimethylamino-2-(3-trifluoromethylphenyl)-1-butene-3-one dissolved in 25 ml. of tetrahydrofuran and 50 ml. of hexamethylphosphoramide over a period of 5 minutes. The mixture was stirred for 1 hour, and to it was added 4.2 g. of methoxyacetyl chloride dissolved in 40 ml. of tetrahydrofuran. The reaction mixture was then allowed to warm slowly to ambient temperature, and was stirred for 5 days. The mixture was then made acid to pH 5 with saturated potassium dihydrogen phosphate solution, and was partitioned between diethyl ether and water. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue was chromatographed on a 300 g. silica gel column with 15 percent ethyl acetate in dichloromethane as the eluting solvent. The product-containing fractions were combined and evaporated under vacuum to dryness to obtain 1 g. of the desired product, which was identified by conversion to the pyridinone in Preparation 2 below.
Reaction SMILES: [CH3:1][N:2]([C:12]1[S:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[N:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=[O:10])=[CH:5][CH:4]=1.[H][H]>[Pd].CN(C=O)C>[OH:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([C:12]2[S:13][C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH3:1])=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: CN(c1ccc([N+](=O)[O-])cc1)c1nc(=O)c2cccnc2s1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN(c1ccc(NO)cc1)c1nc(=O)c2cccnc2s1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A mixture of 1.181 g (3.76 mmol) of 2-[N-methyl-N-(4-nitrophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one obtained in Example 63, 100 ml of DMF and 250 mg of 10% Pd on carbon was stirred in an atmosphere of hydrogen for 6 days. The reaction mixture was then heated so that the compound thus precipitated was dissolved. The insoluble matters were hot-removed by filtration. The solution thus obtained was then allowed to cool to room temperature. The resulting crystal was collected by filtration, washed with THF and then with ethanol, and then dried under reduced pressure to obtain 77 mg of 2-[N-(4-hydroxyaminophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[F-].[K+].Br.Br.[CH2:22]1[C:24]2([CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23]1>CS(C)=O.CCOC(C)=O>[CH3:7][N:6]1[C:2]([N:26]2[CH2:27][CH2:28][NH:29][CH2:30][C:24]3([CH2:22][CH2:23]3)[CH2:25]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: C1CNCC2(CC2)CN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Br
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1ncc([N+](=O)[O-])c1N1CCNCC2(CC2)C1
Temperature: 65 °C
Yield: 30.4 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (323 mg, 2.0 mmol), triethylamine (0.7 mL, 5.0 mmol) and potassium fluoride (581 mg, 10.0 mmol) in dry DMSO (20 mL) was added 5,8-diazaspiro[2.6]nonane dihydrobromide (686 mg, 2.4 mmol) and the mixture was heated in the microwave at 65° C. for 4 hr. The mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (3×20 mL). The aqueous layer was further extracted with DCM (3×20 mL) and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. The residue was loaded onto an SCX-2 column which was washed with MeOH and eluted with 3% 7M ammonia in MeOH/DCM and concentrated under reduced pressure to give 5-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,8-diazaspiro[2.6]nonane as a yellow gum (153 mg). To a solution of this intermediate in DCM (10 mL) was added di-tert-butyl dicarbonate (157 mg, 0.72 mmol) and DMAP (4 mg, 0.03 mmol) and the mixture stirred at room temperature for 2 hr. The mixture was washed with water (3×10 mL) and the organic layer separated, passed through a phase separation cartridge and concentrated under reduced pressure to give tert-butyl 8-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,8-diazaspiro[2.6]nonane-5-carboxylate as a yellow gum (200 mg, 28% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.02 and 8.00 (2s, 1H), 3.85-3.77 (m, 3H), 3.75-3.67 (m, 2H), 3.47-3.27 (m, 4H), 3.29-2.97 (m, 2H), 1.49 (s, 9H), 0.73-0.55 (m, 2H), 0.47-0.38 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(-c2ncc(Br)cn2)cc1
Yield: 60.2 %

Procedure:
5-bromo-2-iodopyrimidine (250 mg), 4-trifluoromethylphenylboronic acid (167 mg), bis(triphenylphosphine)palladium(II) chloride (22 mg) and Na2CO3 (2.1 ml, 1M in H2O) in argon saturated acetonitrile (2.1 ml) was heated under microwave conditions (150° C., 10 minutes). The conversion was monitored and analyzed by HPLC. The crude reaction mixture was concentrated to dryness, then diluted with CH2Cl2, washed with water (3×10 ml), dried over Na2SO4, concentrated under vacuum and purified by chromatography column using CH2Cl2-hexane 1:10 as eluent to give 160 mg of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12]
Reactant: COc1cccc2c(O)c(C)c(C)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1cccc2c(Cl)c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline (3.0 g) in phosphoryl chloride was dropwise added N,N-dimethylaniline (3.58 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature, for 30 minutes at ambient temperature and then for 1 hour at 70° C. The solvent was removed, and saturated sodium bicarbonate solution and 10% solution of methanol in dichloromethan were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The residue wa purified by flash chromatography (Ethyl acetatein-hexane=1:2 v/v) to give 4-chloro-2,3-dimethyl-8-methoxyquinoline (3.02 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(Nc2ccccn2)nc2cc(F)cc(F)c2c1Cl
Temperature: 97 °C

Procedure:
A mixture of 2,4-dichloro-5,7-difluoro-3-methylquinoline (400 mg, 1.61 mmol), 2-aminopyridine (152 mg, 1.61 mmol), Pd2dba3 (148 mg, 0.161 mmol), XPhos (154 mg, 0.323 mmol), sodium tert-butoxide (465 mg, 4.84 mmol) in toluene (10.8 mL) was heated at 97° C. for 18 h. Upon completion, the reaction was concentrated, diluted with EtOAc, and washed with saturated aqueous NaHCO3, water, and brine. The organic layer was then dried over MgSO4 and evaporated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, 0-15% EtOAc in hexanes as eluent) to give 4-chloro-5,7-difluoro-3-methyl-N-(pyridin-2-yl)quinolin-2-amine as a pale yellow solid. Mass Spectrum (ESI) m/e=306.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=2)[CH:9]=1)(C)(C)C.Br>C(O)(=O)C>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc2cc(O)ccc2c1
Yield: 97.6 %

Procedure:
(6-Methoxy-naphthalen-2-yl)-carbamic acid tert-butyl ester (10.05 g, 36.8 mmol), prepared in the previous step, was suspended in 300 mL of glacial acetic acid plus 200 mL of 48% HBr and under nitrogen the mixture was refluxed for 6 h. The glacial acetic acid and the 48% HBr were removed under reduced pressure and the residue partitioned between methylene chloride and water. The aqueous layer was made basic by the addition of NaHCO3. A solid precipitated. The solid was collected by filtration and dried under reduced pressure to give 6-amino-naphthalen-2-ol (5.72 g, 98%) as a gray solid, MS m/z: 160 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])(C)(C)C.[Cl:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>CCOCC>[Cl:16][C:17]1[N:18]=[C:19]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=2[CH3:10])[CH:20]=[C:21]([CH3:23])[N:22]=1
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: Cc1ccnc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: Cc1cc(C)c(-c2cc(C)nc(Cl)n2)c(C)c1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
Part A: 2-Bromomesitylene (1.49 g), dry ether (45 mL), and t-butyllithium (1.5 M, 9 mL) were stirred at -78° C. for 10 minutes and 2-chloro-4-methylpyrimidine (643 mg) dissolved in dry ether (10 mL) was added. The reaction was stirred at -30° C. for 1.5 hours and quenched with a mixture of acetic acid (386 μL), water (23 μL), and tetrahydrofuran (5 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.25 g) dissolved in tetrahydrofuran (10 mL) was added to the reaction which was then stirred 15 minutes and washed with 1 N sodium hydroxide (three 50 mL portions), dried, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:9) as eluent affording 2-chloro-6-methyl-4-(2,4,6-trimethylphenyl)pyrimidine (0.99 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([Cl:19])(=[O:18])=[O:17])[CH2:4]1)[CH3:2].C(N1CC[C@H](CC2C=CC=C(F)C=2)C1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([Cl:19])(=[O:17])=[O:18])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Agent: CCN1CC[C@H](Cc2cccc(F)c2)C1
Product: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 96, starting from (S)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (Intermediate 115).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][C:42]([CH3:44])=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][C:11]=4[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:40]4[N:41]=[C:42]([CH3:44])[N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.5 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 28%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.O=S(Cl)[Cl:28]>C(Cl)(Cl)Cl>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[C:9]=2[Cl:28])[CH2:3]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(Cl)c(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O

Procedure:
Compound 4 (40 mg, 0.1 mmol) in CHCl3 (2 mL) was treated with SOCl2 (200 μL) at 100° C. for 30 min, concentrated, and then purified by LC-MS to give the title compound 7. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.73 (d, J=7.6 Hz, 1 H), 7.64 (t, J=7.6 Hz, 1 H), 7.45 (t, J=7.6 Hz, 1 H), 7.14 (d, J=8.1 Hz, 1 H), 5.32-5.42 (m, 2 H), 3.43 (s, 3 H), 3.33-3.40 (m, 2 H), 3.17 (m, 2 H), 2.87 (s, 1 H), 2.08 (m, 1 H), 1.70 (m, 1 H), 1.32-1.43 (m, 2 H). MS (ES) [m+H] calc'd for C18H21ClN5O2, 374.1; found, 374.1.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:34]=[CH:33][C:9]2[C:10](=[O:32])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[O:13][C:8]=2[C:7]=1[CH2:35][CH2:36][CH3:37].O.[OH-].[Li+]>O.O1CCCC1.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:12]2[CH2:11][C:10](=[O:32])[C:9]3[CH:33]=[CH:34][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[C:7]([CH2:35][CH2:36][CH3:37])[C:8]=3[O:13]2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCCCCC2CC(=O)c3ccc(OCC(=O)OC)c(CCC)c3O2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCCC2CC(=O)c3ccc(OCC(=O)O)c(CCC)c3O2)ccc(C(C)=O)c1O

Procedure:
A solution of 0.3 g of the ester product from Example 17 and 0.48 g of lithium hydroxide monohydrate in 10 ml of 1:1 water-tetrahydrofuran was stirred at room temperature for 24 hours then diluted with water and extracted with ether (the ether extract was discarded). The aqueous solution was acidified with 1N hydrochloric acid and extracted 3 times with ether. The ether extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo giving a solid residue which was chromatographed on 12 g of silica gel. Elution with tetrahydrofuran gave the acid which was recrystallized from methanol yielding rac.-[[2-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl]-3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid as an off-white solid, m.p. 163.5°-167.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C=O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([O:1][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: Cc1cc(C)nc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(OCCOc2ccc([N+](=O)[O-])cc2)c1
Temperature: 120 °C
Yield: 13.3 %

Procedure:
A mixture of 2-hydroxy-4,6-dimethylpyridine (1.7 g, 13.8 mmol), potassium carbonate (3.82 g, 27.6 mmol) and 1-(2-bromo-ethoxy)-4-nitro-benzene (4.0 g, 16.6 mmol) in DMF (30 mL) was heated to 120° C. and maintained for 15 h. The mixture was cooled to ambient temperature, filtered and concentrated to give a residue which was purified by column chromatography using 4% ethyl acetate/petroleum ether as eluent to afford 2,4-dimethyl-6-[2-(4-nitro-phenoxy)-ethoxy]-pyridine as yellow solid (530 mg, 11%)
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[NH2:23])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C1COCC1>[ClH:1].[NH:9]1[CH2:10][CH2:11][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH2:23])=[O:24])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(N)=O)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
Add hydrochloric acid (4M in dioxane, 3 mL) dropwise to a solution of 4-(4-carbamoyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (228 mg, 0.711 mmol) in THF (2 mL). Stir at room temperature for 7 hours (h). Filter the solids and dry under reduced pressure to give the title compound (180 mg, 99%) as hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([CH2:14]O)[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl.C(#N)C>[C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([CH2:14][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(CO)c(-c2ccccc2)c1-c1ccccc1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(CN2CCCCC2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Compound 24 described above (0.17 g, 0.620 mmol) was dissolved in chloroform (4 mL) (Wako Pure Chemical Industries, Ltd.), and thionyl chloride (0.5 mL) (Wako Pure Chemical Industries, Ltd.) was added dropwise while cooling with ice. The mixture was returned to room temperature and stirred for 2 hours, and then the solvent was distilled off under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (4 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.19 g, 2.23 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.18 g, 85% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N+:61]([C:64]1[O:68][C:67]([C:69](O)=[O:70])=[CH:66][CH:65]=1)([O-:63])=[O:62]>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:69]([C:67]1[O:68][C:64]([N+:61]([O-:63])=[O:62])=[CH:65][CH:66]=1)=[O:70]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 47.4 %

Procedure:
DIPEA (50 mg, 0.38 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone-TFA salt (66 mg, 0.15 mmol) in DMF (1 mL). HOBT (21 mg, 0.15 mmol) and EDCI.HCl (29 mg, 0.15 mmol) were added at room temperature. After 2 minutes, 5-nitro-furan-2-carboxylic acid (20 mg, 0.13 mmol) was added. The resulting mixture was stirred at room temperature for four hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (using silica gel of mesh size of 60-120 and 3% methanol in chloroform as the eluent) afforded 28 mg (49.12% yield) of 5-nitro-furan-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.329%, HPLC Purity %: 95.234, 1H NMR (CDCl3): δ 7.8-7.7 (d, 1H), 7.7-7.5 (m, 3H), 7.4-7.3 (m, 2H), 4.4-4.3 (t, 1H), 4.2 (bt, 1H), 4.1-3.8 (m, 2H), 3.8-3.5 (m, 4H), 3.4 (bt, 1H), 3.3-3.2 (m, 2H).