Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)=[O:14])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N(CC)C(C)C)(C)C.[Cl:31][C:32]1[C:33](F)=[N:34][CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>CS(C)=O>[C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:33]3[C:32]([Cl:31])=[CH:37][C:36]([C:38]([F:41])([F:39])[F:40])=[CH:35][N:34]=3)=[O:14])[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Nc1nc(-c2ccccc2)ns1)[C@@H]1CCCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1nc(-c2ccccc2)ns1)[C@@H]1CCCCN1c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a stirred solution of (S)-Piperidine-2-carboxylic acid (3-phenyl-1,2,4-thiadiazol-5-yl)-amide; hydrochloride (70 mg; 0.215 mmol) and N,N-diisopropylethylamine (0.037 mL; 0.215 mmol) in DMSO (1 mL) is added 3-chloro-2-fluoro-5-trifluoromethylpyridine (42.9 mg; 0.215 mmol). The reaction mixture is heated at 100° C. for 4 hours. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 468 [M+H+].
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(Cc2ccccc2)(c2ccccc2)C2=C1CCNC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C1OC(Cc2ccccc2)(c2ccccc2)C2=C1CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Benzyl isocyanate (0.02 6 g, 0.2 mmol) was added to a solution of 3-phenyl-3-benzyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.05 g, 0.16 mmol prepared in a manner analogous to compound 2) in dichloromethane (5 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.036 g, 50%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.93-2.08 (m, 1H), 2.11-2.23 (m, 1H), 3.11-3.35 (m, 2H), 3.39-3.49 (m, 1H), 3.52-3.62 (m, 1H), 3.97-4.08 (m, 1H), 4.42 (dd, J=5.27, 2.64 Hz, 2H), 4.59 (dt, J=19.12, 2.12 Hz, 1H), 4.90 (t, J=5.46 Hz, 1H), 7.15-7.47 (m, 15H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1.O[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:28]([C:24]1[CH:23]=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[CH:17]=2)[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1cccc(-c2cccc(O)c2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of 1.210 g (5.99 mmol) of diisopropyl azodicarboxylate is added dropwise to a solution, cooled to 0° C., under an argon atmosphere, of 0.974 g (4.99 mmol) of 3′-hydroxybiphenyl-3-carbonitrile, 1.205 g (5.99 mmol) of tert-butyl 4-hydroxypiperidine-1-carboxylate and 1.570 g (5.99 mmol) of triphenylphosphine in 12 ml of tetrahydrofuran. The mixture is subsequently stirred at ambient temperature overnight. 15 g of silica are added and the mixture is evaporated to dryness. The product is purified by chromatography on silica gel, elution being carried out with a 10:90 and then 15:85 mixture of ethyl acetate and cyclohexane, in order to obtain 1.538 g (4.06 mmol) of product in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]#[C:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:2]>[Pd].O.C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([OH:20])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:11][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
Palladium on carbon (5%, 1 g) in water (10 ml) was added to a solution of 1,1-dimethylethyl 4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate (from step (i) above; 14.6 g, 0.046 mol) in ethanol (200 ml) and the mixture was shaken under hydrogen (45 psi) for 90 minutes. The mixture was filtered through a glass fibre pad and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4]1.[BH4-].[Na+]>CO>[OH:1][C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate, prepared in accordance with Example 5, in 250 mL of CH3OH was cooled in an ice-CH3OH bath and 1.8 g of NaBH4 was added in portions. After 1 hr, the mixture was concentrated to a solid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion was extracted with EtOAc. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 9.5 g (70%) of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH3:46])=[CH:39][CH:38]=1>>[CH3:34][O:33][C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=2[O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH3:46])=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:23])[CH2:26]1)=[O:32]
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: CCCOc1ccc(CCl)cc1
Product: CCCOc1ccc(COc2ccc(CCCOc3ccc(C(=O)OC)cc3C(=O)NC3CCCC(C(=O)OC)C3)cc2)cc1

Procedure:
Methyl 3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-propoxybenzyl)oxy]phenyl}propoxy)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-propoxybenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(N2CCc3ccccc32)n1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
A mixture of 4-chloro-2-methylthiopyrimidine (4.02 g, 25 mmol), 2,3-dihydro-1H-indole (4.0 mL, 36 mmol) and N,N-diisopropyl ethyl amine (4 mL, 22 mmol) in DMF (10 mL) was heated to 100° C. under N2 for 16 h. The solidified reaction mixture was cooled, diluted with EtOAc, and filtered. The collected solids were dissolved in DCM and MeOH and recrystallized from DCM/EtOAc to give 1-(2-methylsulfanyl-pyrimidin-4-yl)-2,3-dihydro-1H-indole (2.32 g, 38% yield) as a light-yellow solid. MS=244[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:29])[CH2:14][NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][N:19]=2)=[O:17])[CH2:9][CH2:8]1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13](=[O:29])[CH2:14][NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:20][N:19]=2)=[O:17])[CH2:11][CH2:12]1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1)c1cc(-c2ccccc2)[nH]n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-nitro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.07 g, 0.00016 mole) in a mixture of methanol (5 mL) and THF (5 mL) was added 10% Pd/C (0.01 g). The resulting mixture was stirred under an atmosphere of hydrogen for 30 minutes. The mixture was then filtered through celite, and the celite was washed with methanol. The combined organic layers were concentrated under reduced pressure. The resulting residue was re-crystallized from a hexane/chloroform mixture to afford 0.025 g (39%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-amino-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 420.2 (M+1)+, 96.9%, 1H NMR (DMSO-d6): δ 8.1 (bs, 1H), 7.8 (d, 2H), 7.5-7.3 (m, 3H), 7.1 (m, 1H), 6.85 (d, 1H), 6.7 (m, 2H), 6.5 (m, 1H), 4.7 (s, 2H), 4.6 (s, 1H), 4.2 (s, 2H), 3.9 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5]CC)=[O:4].[OH-].[K+].Cl>CO.O>[F:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(c1ccc(Cl)cc1)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(F)(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
A mixture of ethyl α-fluoro-α-isopropyl-4-chlorophenylacetate (1.42 g) and potassium hydroxide (0.35 g) in methanol (5 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was acidified with hydrochloric acid, diluted with water and the aqueous mixture extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and the solvent removed by distillation under reduced pressure to give α-fluoro-α-isopropyl-4-chlorophenylacetic acid (1.10 g; 87%) m.p. 120° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[CH:2].C([Li])CCC.[CH:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>C1COCC1>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][C:25]([CH:23]([OH:24])[C:2]#[C:1][C:3]2[CH:8]=[C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[C:6]([O:14][CH3:15])=[CH:5][C:4]=2[O:16][CH3:17])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C#Cc1cc(-c2cccs2)c(OC)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Ex-1C: A solution of 2-(5-ethynyl-2,4-dimethoxy-phenyl)-thiophene (1.5 g, 6.14 mmol) from Ex-1B in THF (20 mL) was cooled to −78° C. n-Butyllithium (6.72 mmol, 4.2 mL of a 1.6 M solution in hexanes) was added dropwise while maintaining an internal temperature below −65° C. After aging for 30 min at −78° C., the reaction was transferred via cannula over 10 min to a cold (−78° C.) solution of methyl 4-formylbenzoate (1.07 g, 6.52 mmol) in THF (10 mL). The resulting solution was slowly warmed to 0° C. and then quenched with a saturated NH4Cl solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 3:1, 1:1) gave 2.2 g (88%) of the desired 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-benzoic acid methyl ester as a greenish yellow solid, m.p. 128–130° C. 1H-NMR (300 MHz, CDCl3) d 8.08 (d, 2H, J=8.3 Hz), 7.75 (d, 2H, J=8.3 Hz), 7.68 (s, 1H), 7.37 (dd, 1H, J=3.6 and 1.7 Hz), 7.28 (dd, 1H, J=5.1 and 1.7 Hz), 7.06 (dd, 1H, J=5.1 and 3.6 Hz), 5.79 (d, 1H, J=6.6 Hz), 3.96 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 2.53 (d, 1H, J=6.6 Hz).
Reaction SMILES: [C:1]([CH:4]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6])(=[O:3])[NH2:2].O1CCOCC1>[Pd].C(OCC)C>[C:1]([CH:4]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:5]([OH:7])=[O:6])(=[O:3])[NH2:2]
Reactant: CC1(C)CCC(C)(C)c2cc(C(C(N)=O)C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C(C(N)=O)C(=O)O)ccc21
Reaction time: 4 h

Procedure:
3.9 g (10 mmol) of benzyl α-carbamoyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetate, 1.2 g of palladium on carbon (10%) and 100 ml of dioxane were introduced into a reactor. The mixture was hydrogenated at room temperature and at a pressure of 7 bar for 4 hours, filtered on celite and the filtrate evaporated to dryness. The residue obtained was taken up in the minimum amount of ethyl ether, filtered and dried. 2.2 g (76%) of the expected acid were recovered.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:39])[CH3:38].C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:39])[CH3:38]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A mixture of 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), acetylchloride (71 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and partioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=1/4→ethyl acetate→ethyl acetate/methanol=1/10 as the eluant to give the title compound (320 mg).
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[N+:11]([C:14]1[CH:15]=[C:16]([N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)[C:17]([OH:20])=[N:18][CH:19]=1)([O-:13])=[O:12].[N+](C1C=C(N2C=CN=N2)C(O)=NC=1)([O-])=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[F:1][CH:2]([F:10])[O:20][C:17]1[C:16]([N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][N:18]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=[N+]([O-])c1cnc(O)c(-n2nccn2)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])c1cnc(O)c(-n2ccnn2)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(OC(F)F)c(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2,2-difluoro-2-(fluorosulfonyl)acetic acid (189 μl) was added to an acetonitrile (2 ml) solution containing the mixture (105 mg) of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol obtained in the 1st step, followed by stirring at room temperature for 21 hours. Subsequently, sodium sulfate (100 mg) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (126 μl) were added to the solution, followed by stirring at 70° C. for 7 hours. The reaction solution was adjusted to room temperature and a saturated sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was, purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A light yellow solid of 2-(difluoromethoxy)-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (15 mg) was thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[Na+].C1(C)C=CC=CC=1>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O>[CH2:25]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 75 g of 4-nitrophenol, 149.5 g of 1-bromotetradecane, 26.96 g of sodium hydroxide, 2.18 g of trioctyl methylammonium chloride, 400 ml of toluene and 400 of water is heated at reflux for 65 hours. The organic layer is separated, washed with 1N sodium hydroxide and dilute hydrochloric acid, dried and concentrated in vacuo. The residue is recrystallized from petroleum ether to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH2:7]1[O:22][CH:10]([C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[NH2:21])[O:9][CH2:8]1.[OH-].[Na+]>O1CCCC1.O>[CH2:8]1[O:9][CH:10]([C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[NH:21][C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:22][CH2:7]1
Reactant: COc1ccc(N)c(C2OCCO2)c1OC
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1ccc(OC)c(OC)c1C1OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethylchloroformate (1.9 g, 17.5 mM) is added with stirring to 2-amino-5,6-dimethoxybenzaldehyde-ethyleneketal (1.6 g, 7.1 mM) dissolved in tetrahydrofuran (50 ml). A solution of sodium hydroxide in H2O (0.72 g in 3.5 ml H2O) is added and the resulting solution is stirred for 2 hours at room temperature. The tetrahydrofuran is removed in vacuo and the residue extracted with CHCl3 (2×100 ml). The extracts are dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product is recrystallized from n-hexane; yield 1.2 g (57.1%); m.p. 95°-96° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:56]1[CH:61]=[CH:60][C:59]([N:62]2[CH2:67][CH2:66][C:65]3([CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)[CH2:64][CH2:63]2)=[CH:58][CH:57]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:56]1[CH:57]=[CH:58][C:59]([N:62]2[CH2:67][CH2:66][C:65]3([CH2:72][CH2:71][N:70]([C:18]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]5)=[CH:14][CH:13]=4)=[O:19])[CH2:69][CH2:68]3)[CH2:64][CH2:63]2)=[CH:60][CH:61]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (2 g, 0.0072 mol), 0-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (2.3 g, 0.0072 mol) and 1-hydroxybenzotriazole hydrate (0.99 g, 0.0072 mol) were dissolved in tetrahydrofuran, under nitrogen, and the mixture was stirred for 30 min at RT. A solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (F-09) (2.18 g, 0.0072 mol) and diisopropylethylamine (DIPEA) (4.28 g, 0.025 mol) in tetrahydrofuran was added, and the reaction mixture was stirred for 15 h at RT. Tetrahydrofuran was then removed in vacuo, the residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were in turn washed with sat. sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/methanol 20:1+1% 25% ammonia solution (aq.)). Yield: 1.91 g (54%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CCN
Product: CC(=O)c1ccc(NCCC(C)C)c([N+](=O)[O-])c1

Procedure:
4-chloro-3-nitroacetophenone was treated with 3-methylbutyl amine to give 1-[4-(3-methyl-butylamino)-3-nitro-phenyl]-ethanone, compound 282.