Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[N-:15]=[N+:16]=[N-:17].[Na+]>CCO.O>[N:15]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(CCOCCBr)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCOCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 2-(2-bromoethoxy)ethylphosphonate (1 eq) in EtOH (0.3 M) was added sodium azide (5 eq) in water (2 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with ethyl acetate. The organic layer was washed with 5% citric acid, saturated NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][N:4]([C:1](=[O:3])[CH3:2])[C:5]1[S:6][CH:7]=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1scc(C)c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of 2-acetylamino-3-benzoyl-4-methylthiophene in 20 ml of dimethylformamide is added 0.207 g of 63% sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 1.64 g of methyl iodide in 4.9 ml of dimethylformaide is added thereto. The mixture is stirred at room temperature for 3 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to give crystals, which are recrystallized from ether to give N-methyl-2-acetylamino-3-benzoyl-4-methylthiophene as crystals having a melting point of 121.5° - 122.5°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd].C([O-])([O-])=O.[Ca+2]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccc(C=CCCC(=O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: N#Cc1ccc(CCCCC(=O)O)cc1

Procedure:
A solution of 1.47 g (7.32 mmol) of (3) in 90 mL of methanol was hydrogenated over 200 mg of 5% Pd/CaCO3 at 5 psi hydrogen over a 1.2 hour period. After removing the catalyst by filtration and evaporation of the solvent in vacuo, the residue was triturated with ether followed by hexane which afforded a white solid: m.p. 101°-102° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([C:20]3[CH2:24][CH2:23][CH2:22][CH:21]=3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1=CCCC1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
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: O
Solvent: COCCOC
Product: C1=C(c2cnc3c(n2)OCCN(Cc2ccccc2)C3)CCC1
Temperature: 100 °C
Yield: 68 %

Procedure:
A solution of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (559 mg), cyclopent-1-en-1-ylboronic acid (273 mg), tetrakis(triphenylphosphine)palladium(0) (118 mg) and aqueous sodium carbonate solution (2M, 2 mL) in DME (10 mL) was stirred under an argon atmosphere with heating at 100° C. for 2 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (424 mg, 68%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:11]([F:14])([F:13])[F:12])[C:4]([F:10])([F:9])[C:5](I)([F:7])[F:6].[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=[C:20](I)[CH:19]=1.CS(C)=O>[Cu].O>[F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:11]([F:14])([F:13])[F:12])[C:4]([F:10])([F:9])[C:5]([F:7])([F:6])[C:20]1[CH:19]=[CH:18][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)I
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 130 °C
Reaction time: 14.5 h
Yield: 29.7 %

Procedure:
A mixture of 3-trifluoromethylperfluorobutyl iodide (19.5 g, 50 mmol), p-iodobenzoic acid (12.4 g, 50 mmol), activated copper (15.9 g, 250 mmol) and dried dimethyl sulfoxide (100 ml) is stirred at 130° C. in an autoclave for 14.5 hours. After cooling, the reaction mixture is poured into water (400 ml), and the precipitated solid material is collected by filtration and dried. Then, the solid material is extracted with ethanol (200 ml), and the ethanol extract is concentrated to yield crude p-(3-trifluoromethylperfluorobutyl)benzoic acid (5.8 g). The crude product is recrystallized from ethanol-water. The melting point of the purified product is 189°-190° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][N:23]([C@H:32]([CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[C:33]([O:35]CC3C=CC(OC)=CC=3)=[O:34])[CH2:22]2)[CH2:16][CH2:15]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][N:23]([C@H:32]([CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]3)[C:33]([OH:35])=[O:34])[CH2:22]2)[CH2:16][CH2:15]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4cnc5ccccc5n4)CC3)[C@@H](c3ccccc3)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cnc4ccccc4n3)CC2)[C@@H](c2ccccc2)C1
Yield: 90.1 %

Procedure:
The title compound was prepared from 77 mg (0.11 mmol) of 2-(R)-(3-(S)-((4-(3-(quinoxalin-2-yl)propyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 73, Step B) using a procedure analogous to that described in EXAMPLE 10, Step F. Flash chromatography using 95:5:0.5 v/v/v CH2Cl2/MeOH/NH4OH as the eluant afforded 55 mg (87%) of the title compound: 1H NMR (500 MHz) δ 0.874.00 (35H), 7.22-7.30 (5H), 7.69-7.76 (2H), 8.00-8.08 (2H), 8.70 (s, 1H); ESI-MS 555 (M+H); HPLC A: 2.27 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1
Reactant: COc1ccc(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To fuming nitric acid (20 mL, Spectrochem, India) was added (5-methoxy-2-methylpyridine 1-oxide (14 g, 0.100 mol) in one lot and the reaction was stirred at rt for 2 h. Reaction progress was monitored by TLC (50% EtOAc in pet ether.). After completion of the reaction, the reaction mixture was poured in to ice water (100 mL) and neutralized with 40% NaOH solution (PH˜7-7.5) to get a yellow precipitate. The precipitate was stirred for 5-10 min, then filtered and dried to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.21 (s, 1H), 3.95 (s, 3H), 2.31 (s, 3H). MS (ESI, positive ion) m/z: 184.8 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[CH:24][S:25][C:19]=4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:18]1[C:19]2[S:25][CH:24]=[CH:23][C:20]=2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:31])[CH3:30]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3sccc3c2=O)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
A mixture of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[2,3-d]pyrimidine-2,4-dione of Example 2 (1.7 g, 4.2 mmol), acetyl chloride (0.33 ml, 4.6 mmol) and triethylamine (1.8 ml, 12.6 mmol) in methylene chloride (40 ml) was stirred at room temperature for two days. The resultant solution was washed with H2O (2×50 ml), and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the resultant residue was purified by flash chromatography on silica gel 60 (80 g) using 2% methanol in methylene chloride as the eluant to give the named compound (1.3 g, 69% yield) as a colorless solid, mp 137°-141° C. IR(KBr): 1630, 1700 and 1775 cm-1 ; MS (DCI), m/z 444 (MH+); 1H NMR (CDCl3): δ 1.76-1.85 (m, 4H), 2.19-2.25 (m, 2H), 2.70 (t, J=7 Hz, 2H), 2.86 (s, 3H), 3.12-3.25 (m, 3H), 4.22 (t, J=7 Hz, 2H), 7.07 (d, J=6 Hz, 1H), 7.13 (t, J=8 Hz, 2H), 7.40 (d, J=6 Hz, 1H), 7.94-7.97 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=[O:20])[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14]([OH:18])[CH:13]=[CH:12][C:11]=3[F:19])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:18][C:14]1[CH:13]=[CH:12][C:11]([F:19])=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][CH:21]=1)[C:8](=[O:20])[NH:9]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(F)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-(4-bromobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][N:5]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][NH:5]1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-1-(Boc)-4-hydroxy-L-proline methyl ester (0.5 g) (2 mmol), 4-bromophenol (0.52 g) (1.5 eq.) and Ph3P (0.78 g) (1.5 eq.) in 10 mL of dry THF at 0° C. was added DEAD (0.47 mL) in a minimal volume of THF. The reaction mixture was warmed to RT overnight. The solvent was removed in vacuo and the resulting residue suspended in ether. The solids were removed by filtration and the solvent evaporated under reduced pressure to afford after SiO2 chromatography (eluent: cyclohexane/EtOAc-9/1), cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester as a colorless oil (0.54 g). NMR (CDCl3, 200 MHz): 7.37 (2H, d), 6.70 (2H, d), 4.85 (1H, m), 4.37-4.6 (1H, m), 3.6-3.85 (5H, m), 2.35-2.50 (2H, m), 1.4-1.5(9H). To a solution cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester (0.54 g) in 8 mL of DCM at 0° C. was added 2.5 mL of TFA. The reaction mixture was stirred at 0° C. for 1 h and warmed to RT for an additional hour. The solvents were evaporated in vacuo. The resulting residue was dissolved in water and the aqueous layer basified with aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and the solvent was evaporated under reduced pressure to afford the titled compound as a colorless oil which solidified upon standing (0.39 g). NMR (CDCl3, 200 MHz): 7.35 (2H, d), 6.70 (2H, d), 4.8 (1H, m), 3.92 (1H, dd), 3.72 (3H, s), 3.35 (1H, d), 3.1 (1H, dd) 2.25-2.55 (2H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[N:9]1)(=O)=O.[F-:33].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:12][N:8]([CH2:7][CH2:6][F:33])[N:9]=2)=[CH:20][CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)OCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: FCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Intermediate 3A, 2-(3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (11 g) was added to a 1M solution of tetrabutylammonium fluoride in THF (150 mL) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to obtain the desired Intermediate 3B, 4-(3-(4-(benzyloxy)phenyl)-1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridine (2.1 g, 23%) and the side product 4-(3-(4-(benzyloxy)phenyl)-1-vinyl-1H-pyrazol-4-yl)pyridine (2.0 g, 30%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>O1CCCC1>[CH:8](/[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[O:16])=[CH:11][CH:10]=1)=[CH:7]/[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCc1ccc(C=Cc2ccccc2)cc1)c1ccc2ncccc2c1
Solvent: c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(/C=C\c2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of quinoline-6-carboxylic acid 4-phenylethenyl-benzylamide described in Preparation Example E+-5 (48 mg, 0.13 mmol), quinoline (26 mg, 0.20 mmol) and tetrahydrofuran (2 mL) was added Linear catalyst (5.0 mg), and the solution was stirred under hydrogen atmosphere at room temperature for 1 hour. The interior of the reaction system was changed to nitrogen atmosphere, then, filtration was carried out through Celite pad. The filtrate was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), and the title compound (45 mg, 0.12 mmol, 92%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19](Cl)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:17]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
4-Amino-3,5-dichloropyridine (4.0 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture is melted, using a hot air gun external to the flask, stirring with a magnetic stirrer. After 10 minutes, heating is ceased and the melt is allowed to cool. The resulting material is triturated with dichloromethane and the residual solid is filtered off. The filtrate is concentrated to give a fawn solid, which is subjected to flash chromatography on silica gel, eluting with diethyl ether, to give N-(3,5-dichloro-pyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87 g), m.p. 155-157° C. [Elemental analysis: C,56.3; H,4.7; N,7.2; Cl,18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum: 1661 cm-1, 3244 cm-1 ].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH:14]=[O:15])=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C=O
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
Phosphorus oxychloride (2.0 mL) was added to N-methylformanilide (2.9 g), and after the mixture was stirred for 15 minutes, 1,2-dichloroethane (50 mL) and 5-chloroindole-2-carboxylic acid ethyl ester (4.0 g) were added thereto, followed by heating under reflux for 1 hour. The reaction mixture was poured into an aqueous solution (28 mL) of sodium acetate (14 g) under ice cooling, and the thus-obtained mixture was stirred for 18 hours. Insoluble matter was collected by filtration, and was sequentially washed with water and diethyl ether, to thereby give the title compound (3.56 g).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:28]=[CH:27][C:19]([O:20]C2CCCCO2)=[CH:18][CH:17]=1.CN(C)[CH:33]=[O:34].Cl>>[OH:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:29])[F:30])=[CH:28][C:27]=1[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(OC2CCCCO2)cc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Product: O=Cc1cc(C(F)(F)F)ccc1O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
At −15° C., an 1.6 N solution of n-butyllithium in hexanes (7.20 ml, 11.5 mmol) was added to N,N,N′,N′-tetramethylethylenediamine (1.72 ml, 11.4 mmol). The reaction mixture was stirred for 10 min at −10° C. 2-(4-(trifluoromethyl)phenoxy)tetrahydropyran (2.0 g, 8.12 mmol) was added. The reaction mixture was stirred for 2 h at −10° C. N,N-Dimethylformamide (0.88 ml, 11.4 mmol) was added. The reaction mixture was stirred for 15 min at −10° C. It was given onto a 6 M hydrochloric acid. This mixture was stirred at room temperature for 16 h. The organic layer was isolated and dried. The solvent was removed in vacuo. 659 mg of 2-hydroxy-5-(trifluoromethyl)benzaldehyde were isolated from the crude mixture by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:10 as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.Cl>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(NN)cc1
Reactant: COc1ccc(C(=O)CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(-c3ccc(OC)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), 4-methoxyphenyl hydrazine (1.5 equiv.), conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCI, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 1-[1,5-bis(4-methoxyphenyl)pyrazol-3-yl]-4methoxybenzene.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8]>C(Cl)Cl>[CH3:6][S:7]([O:5][CH2:1][CH2:2][C:3]#[CH:4])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCO
Solvent: ClCCl
Product: C#CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of but-3-yn-1-ol (45.0 g, 0.64 mol) and methanesulfonyl chloride (81.0 g, 0.71 mol) in 600 mL of DCM was added TEA (78.0 g, 0.77 mol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours then concentrated to dryness. The residue was dissolved in 1 L of EtOAc then washed with 1N HCl (2×200 mL), brine (200 mL), dried over anhydrous Na2SO4 and concentrated to afford but-3-yn-1-yl methanesulfonate.
Reaction SMILES: [ClH:1].C(C1C=CC([N:10]([CH2:18][C:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]=2[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)C(=O)OC(C)(C)C)=C(C)C=1)#N.O1[CH2:43][CH2:42]OCC1>>[ClH:1].[NH2:10][CH:18]([C:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=1)[C:22]1[CH:21]=[CH:20][C:19]([C:18]#[N:10])=[CH:24][C:42]=1[CH3:43]
Reactant: C1COCCO1
Reactant: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 5.50 mL, 22.0 mmol) is added to a solution of tert-butyl (4-cyano-2-methylphenyl)(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methylcarbamate (intermediate 51, 1.57 g, 3.14 mmol) in 1,4-dioxane (10 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is treated with tert-butyl methyl ether. The precipitate is filtered and dried. Yield: 1.18 g; ESI mass spectrum [M+H]+=400; Retention time HPLC: 0.56 min (X012_S01).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][Cl:7])=[O:2].C([O:15][C:16](=[O:18])[CH3:17])(=O)C>>[C:1]([O:2][CH:1]([O:15][C:16](=[O:18])[CH3:17])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:10](=[O:11])[CH3:9])[CH2:6][Cl:7])(=[O:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(CCl)ccc1O
Product: CC(=O)Oc1ccc(CCl)cc1C(OC(C)=O)OC(C)=O
Yield: 79 %

Procedure:
3-Formyl-4-hydroxy benzyl chloride (675 g., 3.96 moles) in 3.5 liters of acetic anhydride is refluxed for 24 hours. The reaction mixture is evaporated to dryness, triturated with a minimum amount of ether and filtered to yield 987 g (79%) of 3-(diacetoxymethyl)-4-acetoxybenzyl chloride, m.p. 93°-95°.