Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:19]([CH3:20])[C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=1[C:24]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:18]1[N:19]([CH3:20])[C:15]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:7]=2[F:6])=[C:16]([C:24]([N:26]2[CH2:29][CH:28]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27]2)=[O:25])[CH:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(C(=O)N2CC(O)C2)c(Nc2ccc(I)cc2F)n1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N2CC(OS(C)(=O)=O)C2)c(Nc2ccc(I)cc2F)n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
Methane sulfonyl chloride (0.026 ml, 0.33 mmol) was added dropwise at 0° C. to a stirred solution of Example 27 (102 mg, 0.22 mmol) and triethyl amine (0.047 ml, 0.33 mmol) in CH2Cl2 (1.2 mL). After stirring for 10 min at 0° C., the reaction mixture was allowed to warm up at room temperature. After stirring for 2 hours, the reaction mixture was washed with a saturated solution of NaHCO3, extracted with CH2Cl2. The organics were washed with and brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography gave 100 mg (84%) of the title compound as beige solid. MS (ES) [m+H] calc'd for C18H19FIN3O5S, 536; found 536.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CCOCC2)c2c(C)cccc12
Reaction time: 8 h

Procedure:
To a mixture of 4-methoxy-8-methyl-1-naphthoic acid (above Step-5 intermediate) (1 equiv) in dry DMF (8 mL) was added, EDC.HCl (1.4 equiv) and HOBt (1.4 equiv) and the mixture was stirred for 10 min. To this, morpholine (1.5 equiv) and DIPEA (3 equiv) were added and the reaction mixture was stirred overnight. It was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (4×20 mL). The combined organic layer was washed with water (20 mL), 5% NaHCO3 solution (20 mL), brine (25 mL), dried (Na2SO4) and filtered. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to furnish the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1.[N:9]1[C:8]2[C:13](=[CH:14][CH:5]=[CH:6][N:7]=2)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: OCCN1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(CCO)CC4)cc3nc21
Product: O=C(O)c1cnc2ncccc2c1

Procedure:
7-Fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1 but starting from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 6.8 g of 1-(2-hydroxyethyl)piperazine in 16 cm3 of pyridine. After concentrating the reaction mixture to dryness under reduced pressure, the residue is taken up in 50 cm3 of water. The mixture is brought to pH 6.9 by adding 0.4 cm3 of acetic acid. The precipitate obtained is drained, washed with twice 10 cm3 of water and recrystallized twice from 10 cm3 of dimethyl-formamide. 1.1 g of 7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-benzo[b]1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 275°-276° C.
Reaction SMILES: [C:1]([O-:8])(=O)/[CH:2]=[CH:3]\C([O-])=O.[N:9]1([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C1OC2C=CC(C(Cl)=O)=CC=2O1>CN(C)C=O>[C:1]([N:12]1[CH2:13][CH2:14][N:9]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:11]1)(=[O:8])[CH2:2][CH3:3]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N1CCN(c2ncccn2)CC1
Temperature: 130 °C

Procedure:
5.6 g of acid maleate of 2-(1-piperazinyl)pyrimidine are dissolved in 80 ml of dimethylformamide, then 5.6 ml of triethylamine and 3.8 g of 3,4-methylenedioxy benzoyl chloride are added. The mixture is heated for 12 hours at 130° C. then the solvent is evaporated to dryness in vacuo. The residue is taken up in a dilute solution of hydrochloric acid and washed with ether. The aqueous phase is rendered alkaline by a sodium carbonate solution and extracted with ethyl acetate. The solution is dried over sodium sulfate and the solvent is evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:4][CH:3]=1.[C:14]([O:17][CH2:18][C@@:19]([NH:29][C:30](=[O:32])[CH3:31])([CH3:28])[CH2:20][CH2:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)(=[O:16])[CH3:15].C([O:36][CH2:37][CH3:38])(=O)C.O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:14]([O:17][CH2:18][C@@:19]([NH:29][C:30](=[O:32])[CH3:31])([CH3:28])[CH2:20][CH2:21][C:22]1[N:23]([CH3:27])[C:24]([C:11]([O:12][C:37](=[O:36])[CH2:38][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:25][CH:26]=1)(=[O:16])[CH3:15]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(CCCC(=O)Cl)cc1
Reactant: CC(=O)N[C@](C)(CCc1cccn1C)COC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N[C@](C)(CCc1ccc(C(=CCCc2ccc(C)cc2)OC(=O)CCCc2ccc(C)cc2)n1C)COC(C)=O
Temperature: 110 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
Thionyl chloride (9.0 mL, 123 mmol) and N,N -dimethylformamide (50 μL) were added to a solution of 4-(4-methylphenyl)butyric acid (11.0 g, 62.0 mmol) in benzene (220 mL) and the mixture was stirred at 80° C. for 2 hours. After cooling the mixture to room temperature, the solvent was evaporated under reduced pressure to obtain 5-(4-methylphenyl)butyric chloride. A solution of 4-dimethylaminopyridine (15.2 g, 124 mmol) and 4-(4-methylphenyl)butyric chloride (12.2 g, 62.0 mmol) in toluene (50 mL) was added to a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-(1-methylpyrrol-2-yl)butane (5.00 g, 18.8 mmol) obtained in Reference example 1 in toluene (150 mL) and the mixture was stirred at 110° C. for 48 hours. The temperature of the mixture was returned to room temperature and ethyl acetate and water were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane, 3:2-2:1) to obtain the title compound (5.15 g, yield: 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](Cl)(Cl)=[O:9])=[CH:4][CH:3]=1.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+].[CH2:18]1COC[CH2:19]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:9])([CH:12]=[CH2:13])[CH:18]=[CH2:19])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C[Mg]Br
Reactant: O=P(Cl)(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CP(=O)(C=C)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
4-Fluorophenyl-phosphonic dichloride (6.86 g, 32.2 mmol) was dissolved in dry THF (50 mL), placed under a nitrogen atmosphere, and chilled to −70° C. To this stirred solution was added dropwise a solution of vinyl magnesium bromide in THF (80.5 mL, 1M). The resulting solution was stirred for 90 minutes at −70° C. An aqueous solution of ammonium chloride (500 mL, 2M) was chilled to 0° C. and stirred rapidly while the cold reaction mixture was added. The product was extracted into dichloromethane and washed with saturated aqueous sodium bicarbonate followed by water. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation to yield 5.214 g of 4-fluoro-phenyl-divinyl-phosphine oxide (26.6 mmol, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.80-7.71 (m, 2H); 7.25-7.18 (m 2H); 6.56-6.22 (m, 6H); ESMS (m/z): (M+1)+ found, 197.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[Cl:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([NH:33][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[CH:19][CH:18]=3)=[O:22])[CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: Nc1ccc2nc(Cl)sc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2nc(Cl)sc2c1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Add oxalyl chloride (10 mL, 114.6 mmol) and DMF (4 drops) to a stirring suspension of 4′-fluoro-biphenyl-4-carboxylic acid (4.9 g, 22.7 mmol) in CH2Cl2 (150 mL). Stir the reaction mixture at room temperature for 3 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution to a mixture of 2-chloro-benzothiazol-6-ylamine (3.31 g, 17.9 mmol) and pyridine (3.0 mL) in CH2Cl2 (150 mL). Stir the reaction mixture overnight at room temperature. Dilute the reaction mixture with CH2Cl2. Wash the reaction mixture twice with 1.0M HCl and once with 1.0M NaOH. Dry the mixture over Na2SO4, concentrate in vacuo, and triturate with MeOH to yield the desired product (6.34 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ10.59 (s, 1H), 8.69 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.0 Hz, 2H), 7.96 (d, J=8.8 Hz, 1H), 7.87-7.79 (m, 5H), 7.38-7.31 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17].CC(C)([O-])C.[K+].O>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: Nc1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,4,6-trifluoronitrobenzene (1.37 g, 7.74 mmol) and 3,5 difluoroaniline (1 g, 7.74 mmol) in THF (23 mL) was added potassium tert-butoxide (1.3 g, 11.6 mmol) and reaction mixture was stirred at rt for 4 h. After completion of the reaction, water (50 mL) was added and the organic phase extracted with EtOAc (200 mL), dried over sodium sulfate and purified by column chromatography using 100-200 mesh silica gel and 0-10% EtOAc in hexane to provide N-(3,5-difluorophenyl)-3,5-difluoro-2-nitroaniline: LC-MS (ESI) m/z 284.9 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][OH:4].[CH3:5][C:6]1[CH:7]=[C:8]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:30]=[N:31][N:32]([CH2:34][C:35]([O:37]C)=[O:36])[CH:33]=3)=[N:27][CH:28]=2)[CH:9]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:11]=1>C1COCC1>[CH3:5][C:6]1[CH:7]=[C:8]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:30]=[N:31][N:32]([CH2:34][C:35]([OH:37])=[O:36])[CH:33]=3)=[N:27][CH:28]=2)[CH:9]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][N:14]=2)[CH:11]=1.[C:3]([OH:4])([C:19]([F:22])([F:21])[F:20])=[O:1]
Reactant: [OH-]
Reactant: COC(=O)Cn1cc(-c2ccc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)cn2)nn1
Reactant: CO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(-c3cn(CC(=O)O)nn3)nc2)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (1 M, 0.55 mL, 0.550 mmol) and methanol (1.5 mL) was added to a solution of methyl {4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-1H-1,2,3-triazol-1-yl}acetate (55.0 mg, 0.094 mmol) in THF (1.5 mL). The mixture was stirred at room temperature for 3 hours and then directly purified by reverse phase HPLC to afford {4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-1H-1,2,3-triazol-1-yl}acetic acid as a TFA salt. MS APCI C21H17F3N7O2 [M+H]456. found 456. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.85 (d, J=17.2 Hz, 2H), 8.63 (s, 1H), 8.12 (s, 2H), 8.02 (s, 1H), 7.57 (s, 1H), 7.27 (d, J=13.2 Hz, 2H), 5.36 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:14]3[CH:13]=[CH:12][C:3]([O:4][CH2:5][CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[C:2]([F:1])[CH:15]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Fc1cc(I)ccc1OCCN1CCCC1
Product: Fc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(2-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine (300 mg, 0.90 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (201 mg, 0.94 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][S:14]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])=[O:15].[CH3:24][CH:25]([CH2:28]O)[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[S:14](=[O:15])(=[O:16])[N:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:26][CH:25]([CH3:28])[CH2:24]1
Reactant: CC(CO)CO
Reactant: CCOC(=O)CNS(=O)(=O)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Temperature: -20 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
Ethyl 2-((N-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoyl)amino)acetate (300 mg, 0.76 mmol), 2-methylpropane-1,3-diol (75 mg, 0.76 mmol) and triphenylphosphine (498 mg, 1.90 mmol) were dissolved in anhydrous THF (30 mL), and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (384 mg, 1.90 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (225 mg, 66%, light yellow solid). 1H NMR (300 MHz, CDCl3): δ 7.65 (s, 1H), 7.63 (s, 1H), 4.44-4.38 (m, 1H), 4.30-4.17 (m, 2H), 4.11-4.03 (m, 1H), 3.98-3.87 (m, 2H), 3.53-3.44 (m, 1H), 3.24-3.17 (m, 1H), 2.59 (m, 1H), 1.31 (t, 3H, J=7.1 Hz), 0.94 (d, 3H, J=6.7 Hz).
Reaction SMILES: C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[C:43]1[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=1)[C:37]([OH:39])=O)[CH3:32].Cl.[NH:50]1[C:54]([C:55]2[CH:56]=[C:57]3[C:67](=[CH:68][CH:69]=2)[O:66][C:60]2([CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:59][C:58]3=[O:70])=[N:53][N:52]=[N:51]1>O.CN(C)C=O>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([C:37]([N:63]2[CH2:64][CH2:65][C:60]3([CH2:59][C:58](=[O:70])[C:57]4[C:67](=[CH:68][CH:69]=[C:55]([C:54]5[NH:53][N:52]=[N:51][N:50]=5)[CH:56]=4)[O:66]3)[CH2:61][CH2:62]2)=[O:39])[CH:40]=[CH:41][C:42]=1[C:43]1[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=1)[CH3:32]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)ccc1-c1cnn(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)ccc1-c1cnn(C)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (136 μL, 0.97 mol), 1-hydroxybenzotriazole hydrate (99.0 mg, 0.73 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg, 0.73 mol) were added to an N,N-dimethylformamide solution (4.0 mL) of 3-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (120 mg, 0.49 mmol) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (204 mg, 0.63 mol), and then stirred at 90° C. for 30 minutes. The reaction liquid was cooled to room temperature, and water was added thereto. The formed solid was taken out through filtration, and dried overnight at 75° C. under reduced pressure to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=8.5, 2.2 Hz), 8.12 (1H, s), 7.93 (1H, br s), 7.63 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.8 Hz), 7.03 (1H, br s), 6.97 (1H, dd, J=7.9, 1.6 Hz), 4.14 (2H, q, J=6.9 Hz), 3.87 (3H, s), 3.31-3.28 (4H, m), 2.97 (2H, s), 1.92-1.79 (4H, m), 1.43 (3H, t, J=7.0 Hz). MS [M+H]+=514.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][CH:14]([NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:15]([CH3:17])[CH3:16]>C(Cl)Cl.CCOCC>[CH:13]([CH:14]([NH:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: Cc1ccc(C(=O)NC(CO)C(C)C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC(C=O)C(C)C)cc1
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
To a suspension of PCC in 20 mL of CH2Cl2 was added N-(1-hydroxymethyl-2-methyl-propyl)-4-methyl-benzamide (2.2 g, 10 mmol) in 15 mL of CH2Cl2. After the mixture was stirred for 1.5 h, it was diluted with Et2O and filtered through a celite bed. The filtrate was concentrated and the residue purified on a silica gel column with 20% EtOAc in hexane to give 0.75 g of N-(1-formyl-2-methyl-propyl)-4-methyl-benzamide as a white solid (M++1: 220).
Reaction SMILES: [O:1]1[CH2:5][CH:4]([NH2:6])[CH:3]([NH2:7])[CH2:2]1.Cl.N=[C:10](OC)[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>C(O)C>[CH3:21][C:14]1[CH:13]=[C:12]([CH3:22])[C:11]([C:10]2[NH:7][CH:3]3[CH2:2][O:1][CH2:5][CH:4]3[N:6]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=N)c1cc(C(=O)OC)c(C)cc1C
Reactant: NC1COCC1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc(C2=NC3COCC3N2)c(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Into around-bottom flask, was placed a solution of tetrahydrofuran-3,4-diamine (compound 466.3, 140 mg, 1.17 mmol, 1.00 equiv, 85%) in ethanol (6 mL). Methyl 5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride (compound 466.4, 300 mg, 0.930 mmol, 1.00 equiv) and triethylamine (140 mg, 1.38 mmol, 1.00 equiv) were added and the resulting solution was stirred overnight at 80° C., then concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) as the eluent to obtain the title compound as a brown oil (120 mg, 34%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2)([O-:9])=[O:8].ClCC(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][C:19]1[C:10]([N+:7]([O-:9])=[O:8])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[N:14][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cccc2cnccc12
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(=O)CCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2cnccc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of potassium tert-butoxide (4.25 g, 37.9 mmol) in 13 mL of THF at −10° C. under an atmosphere of nitrogen was added a solution of 5-nitroisoquinoline (3.00 g, 17.2 mmol) and ethyl chloroacetate (2.32 g, 18.9 mmol) in 18 mL of THF dropwise. After 3 h, water (30 mL) was added and the reaction was stirred at rt for 3 d. Potassium carbonate (5.95 g, 43.1 mmol) was added, and after 24 h, the mixture was heated to 40° C. After 24 h, additional potassium carbonate (1.19 g, 8.62 mmol) was added, and the reaction was heated to 50° C. for another 3 h, then cooled to rt. The mixture was concentrated in vacuo, azeotroped 3× with toluene, and redissolved in dichloromethane. The organic solution was washed 3× with water, then with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 6-methyl-5-nitroisoquinoline that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 189.2 for [M+H]+.
Reaction SMILES: C([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(OC(C)(C)C)=O.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N[C@H](C(O)=O)CO)(=O)CCCCCCC/C=C\CCCCCCCC.N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:8][C@H:9]([C:12]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13])[CH2:10][OH:11]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(=O)[C@@H](N)CO
Temperature: 25 °C

Procedure:
0.03 moles of N-Boc-serine was constantly stirred under nitrogen in 100 mL of chloroform. 0.03 mole of oleoyl chloride was dissolved with 100 mL of chloroform and added to this heterogeneous mixture of N-Oleoylserine and followed by adding 10 mL of anhydrous pyridine. The reaction for 30 minutes under constantly stirring at room temperature, the mixture turned to homogeneous and the reaction was completed when no detectable oleoyl chloride was in the mixture. The bulk solvent was removed under vacuum and the crude product was used to next step without further purification. The resulting product (% of yields 75-80) is showed in Chemical Structure 4.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:34]=1)[CH:32]=O.CC#N.O>CC#N>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:32]=[CH:6][CH2:5][CH2:4][O:3][CH3:2])[CH:34]=1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(Br)cc1C=O
Agent: [Br-]
Solvent: O
Solvent: CC#N
Product: COCCC=Cc1cc(Br)ccc1C

Procedure:
The title compound is prepared analogously as described for the title B compound in Example 45 using (3-methoxy-propyl)-triphenyl-phosphonium bromide and 5-bromo-2-methyl-benzaldehyde (prepared in Example 48; containing 20% of 3-bromo-2-methyl-benzaldehyde): Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(-c3cccnc3F)ccc21
Product: CC1c2ccc(-c3cccnc3F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.