Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[O:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N:12]1([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([C:21]([C:6]3[O:5][C:4](=[O:7])[NH:3][C:2]=3[CH3:1])=[O:22])=[CH:24][CH:25]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1coc(=O)[nH]1
Reactant: O=C(Cl)c1ccc(-n2ccnc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c(=O)oc1C(=O)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h

Procedure:
In 50 ml methylene chloride were placed 1.30 g (0.0132 mol) 4-methyl-2(3H)-oxazolone and 5.22 g (0.039 mol) aluminum chloride. The mixture was stirred 30 minutes and 2.72 g (0.0132 mol) 4-(1H-imidazol-1-yl)benzoyl chloride were added. The mixture was heated on the steam bath allowing the methylene chloride to evaporate, after which the residue was heated an additional 30 minutes. The residue was quenched with water and the water solution neutralized with sodium bicarbonate. The solution was evaporated to dryness and the residue was leached with hot methanol. Evaporation of the methanol provided the crude product which was purified by chromatography; m.p. 320°.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([O:33][C:34]([F:36])([F:37])[F:35])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(OC(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 3.00 g, 8.08 mmol), 2-bromo-4-(trifluoromethoxy)aniline (2.44 mL, 16.16 mmol), p-toluenesulfonic acid monohydrate (1.64 g, 8.65 mmol) and xylene (7.0 mL) was stirred at 130° C. for 12 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale red oil (1.38 g, 2.34 mmol, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[C:21][Si](C)(C)C)[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:26])[CH3:6])[CH3:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[CH:21])[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:26])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCC2(CC#C[Si](C)(C)C)CC2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CCC1(COc2ccc(OC(C)(C)C(=O)OCC)c(C)c2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.201 (0.50 mmol) 2-methyl-2-{2-methyl-4-[1-(3-trimethylsilanyl-prop-2-ynyl)-cyclopropylmethoxy]-phenoxy}-propionic acid ethyl ester in 5 ml THF were treated at 0° C. with 0.55 ml (1 M solution in THF, 0.55 mmol) of n-Bu4NF and stirred for 1.5 h at this temperature. The reaction mixture was then diluted with water and extracted with ether (three times). The organic layers were washed with water, dried (Na2SO4) and evaporated to give 0.152 g of the title compound as light yellow oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[O:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[O:33]1[C:37]2([CH2:42][CH2:41][N:40]([C:15]([N:13]3[CH2:14][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)[CH2:10][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]3)=[O:16])[CH2:39][CH2:38]2)[O:36][CH2:35][CH2:34]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1

Procedure:
6.00 g (13.3 mmol) of the compound from Example 58A, 4.75 g (33.2 mmol) of 8-aza-1,4-dioxa-spiro[4.5]decane and 1.83 g (13.3 mmol) of potassium carbonate were reacted according to General Method 8A. Yield: 5.15 g (81% of theory)
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:38]1([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:43][CH2:42]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride (example 23) in an analogous manner as described in example 25. LR-MS: 700.4 [(M+H)+]
Reaction SMILES: Br[CH:2]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([O-:6])=[O:5].[OH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2([OH:15])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[S:22][C:21]([C:20]3[CH:24]=[CH:25][C:17]([OH:16])=[CH:18][CH:19]=3)=[N:23]2)=[CH:9][CH:10]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C([O-])CC(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(O)CC1SC(c2ccc(O)cc2)=NC1(O)c1ccc(Cl)cc1

Procedure:
3-Bromo-3-(4-chlorobenzoyl)propionate acid and an equimolar amount of 4-hydroxythio-benzamide are stirred in isopropyl alcohol solvent containing sodium carbonate to give 4-(4-chlorophenyl)-4-hydroxy-2-(4-hydroxyphenyl)-2-thiazolin-5-acetic acid. This compound is dehydrated by heating to give the title compound.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[O:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC>C(O)C.O>[O:3]1[CH2:8][CH2:7][C:6](=[CH:12][C:11]([CH3:21])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: O=C1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)C=C1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
A solution of potassium hydroxide (4.66 g, 83.1 mmol) in ethanol (181 mL) and water (45 mL) was cooled to approximately 0° C. Tetrahydro-4H-pyran-4-one (7.56 g, 75.5 mmol) and diethyl (2-oxopropyl)phosphonate (16.1 g, 83.1 mmol) were sequentially added. The reaction was allowed to warm to room temperature and stirred for five hours. The reaction mixture was washed with brine and the organic layer was separated. The aqueous layer was extracted three times with tert-butyl methyl ether. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of 20% ethyl acetate in hexane and chloroform, dried again over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by automated flash chromatography (eluting with 35% to 45% ethyl acetate in hexane). The resulting colorless oil was dried under a stream of nitrogen to provide 8.03 g of 1-tetrahydro-4H-pyran-4-ylideneacetone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1([CH2:14][CH2:15][CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[C:23]2[CH2:30][CH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][NH:36][CH2:35][C@@H:34]1[C:39]([OH:41])=[O:40].O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[C:23]2[CH2:30][CH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][N:36]([CH2:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:35][C@@H:34]1[C:39]([O:41][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:40]
Reactant: COc1ccc2nccc(CCC[C@@H]3CCNC[C@@H]3C(=O)O)c2c1
Reactant: CCCC1(Br)C=CC=CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3C(=O)OCCCc3ccccc3)c2c1
Reaction time: 17 h

Procedure:
1.75 g of potassium carbonate and then 1.15 cm3 of 1-bromophenylpropane were added with stirring, at a temperature in the region of 25° C., to a solution of 0.91 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid hydrochloride in 20 cm3 of anhydrous dimethylformamide. The suspension was brought to a temperature in the region of 60° C. for 17 hours. After cooling, the mixture was poured onto 200 cm3 of water and extracted with 3 times 30 cm3 of ether. The combined ethereal extracts were washed with 2 times 20 cm3 of water. The ethereal solution was extracted with 20 cm3 of normal aqueous hydrochloric acid and twice with 20 cm3 of water. The combined aqueous extracts were rendered alkaline by addition of solid sodium hydrogencarbonate. After extracting with 3 times 20 cm3 of ether and washing the ethereal extracts with 3 times 20 cm3 of water, drying was carried out over magnesium sulfate in the presence of 0.1 g of animal charcoal. After filtering through paper and then concentrating under reduced pressure (5 kPa) at a temperature in the region of 30° C, 0.84 g of 3-phenylpropyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate was obtained in the form of an oil with a light brown color.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:32][CH:33]1[CH:40]2[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:32][CH:33]2[CH:34]3[CH2:42][CH:38]4[CH2:37][CH:36]([CH2:41][CH:40]2[CH2:39]4)[CH2:35]3)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 4-fluorobenzoic acid (15.0 g, 0.11 mol) in DMF (400 mL) was added HOBt (24.59 g, 0.16 mol) and EDAC (20.53 g, 0.11 mol). The resulting mixture was stirred for 1 hr at room temperature at which time a solution of 2-amino-adamantane.HCl (20.1 g, 0.11 mol) and DIPEA (20.52 mL) in DMF (100 mL) was added dropwise. The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in AcOEt and washed with aq. NaHCO3, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo affording 28.66 g, (98%) of 4-fluoro-N-adamantan-2-yl-benzamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>ClCCl.CO>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cc(O)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To a solution 2.00 g (10.7 mmol) of benzaldehyde 12 in 20 mL of dichloromethane under argon at 0° C. was added 1.20 mL (11.8 mmol) of boron tribromide. The solution was stirred at 0° C. for 0.3 h and 25° C. for 4 h, diluted with 40 mL of methanol, and the solvents were removed on a rotary evaporator (the trimethylborate was removed). To it was added 40 mL of methanol and methanol and trimethyl borate were removed by evaporation on a rotary evaporator, and this process was repeated three times. The residue was diluted with dichloromethane and filtered and washed with a small amount of dichloromethane to give 1.722 g (94% yield) of pure 5-chloro-3,4-dihydroxybenzaldehyde. This material was used in next step without purification. 1H NMR (CDCl3) δ 10.43 (s, 2H, OH), 9.70 (s, 1H, CHO), 7.42 (d, J=2.0Hz, 1H, C6-H), 7.22 (d, J=2.0Hz, 1H, C2-H); 13C NMR (DMSO-d6) δ 190.6 (C═O), 148.3 (s), 146.9 (s), 128.4 (d), 124.2 (d), 120.3 (s), 112.5 (s).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:48])=[C:42]([CH:47]=1)[C:43]([O:45][CH3:46])=[O:44]>CN(C)C=O.O>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[C:38]([NH:37][C:4]([C:3]2[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)=[O:6])[CH:39]=[CH:40][C:41]=1[Cl:48]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2ccc(C(F)(F)F)nc2C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 2-methyl-6-trifluoromethylnicotinic acid (4.77 g; 23 mmol) in dimethyl formamide (100 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 g; 23 mmol) and 1-hydroxy-7-azabenzotriazole (3.17 g; 23 mmol) and the resulting solution was stirred at room temperature for 30 minutes. To this was added a solution of methyl 5-amino-2-chlorobenzoate (3.6 g; 19 mmol) in dimethyl formamide (25 ml) and the resulting solution stirred at room temperature for 18 hours. Water (200 ml) was added to the reaction mixture and this was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (2×300 ml). The organic layer was dried (magnesium sulphate), filtered and evaporated to give 2-chloro-5-[(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-amino]-benzoic acid methyl ester (6.6 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)[N:13]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2cccc(F)c2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 2,4-dichloro-6methyl-benzenesulfonyl chloride (0.074 g) as a yellow solid (0.12 g). MS (ESI−): 453.1 ([M−H]−).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[C:37](O)=[O:38]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:37]([C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:35]=[CH:36][C:27]=4[CH3:26])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1ccc2ccccc2c1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(C)ccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methylnaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [CH2:1]([N-]CC)C.[Li+].[C:7]([O:11][C:12]1[CH:17]=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:9])[CH3:8].CI>C1COCC1>[C:7]([O:11][C:12]1[C:17]([CH3:1])=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC[N-]CC
Reactant: CC(C)(C)Oc1cc(F)nc(F)c1F
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)nc(F)c(F)c1OC(C)(C)C
Reaction time: 0.83 h

Procedure:
A freshly prepared solution of lithium diethylamide (LDA) (58.21 mmol) in 30 mL of THF at -78° C. was added to 10.0 g (48.74 mmol) of 4-t-butoxy-2,3,6-trifluoropyridine in 50 mL of THF at -78° C, and the reaction was stirred for 50 min. To the reaction mixture was added 4.3 mL (69.07 mmol) of methyl iodide, and the mixture was stirred at -78° C. for 1 hour and stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl solution, extracted with hexane, and the extracts washed with water, dried over MgSO4 and concentrated to give 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine as a pale yellow oil, which was taken directly to the next step. MS (220) (M+H)+ ; 1H NMR (CDCl3)∂: 1.47 (m, 9H), 2.12 (m, 3H). 19F NMR (CDCl3, CFCl3 as reference)∂: 75.91 (dd apparent, J1 =15.0, J2 =22.1 Hz), 93.17 (dd apparent, J1 =15.0, J2 =22.1 Hz), 156.54 (m).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH2:25]([O:10][C:9](=[O:11])[CH2:8][C:3]([CH2:2][C:1]([OH:13])=[O:12])([C:5]([OH:7])=[O:6])[OH:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCOC(=O)CC(O)(CC(=O)O)C(=O)O

Procedure:
A blend of citric acid (63 grams, 0.3 mole), dodecyl alcohol (55.8 grams, 0.31 mole), p-toluene sulfonic acid (0.1 gram, 0.6 mole) and 300 ml. of dioxane was refluxed for 72 hours, passing the condensed vapor through 4A molecular sieve. The dioxane solvent was then evaporated under reduced pressure (30 mm.) to a 150 gram residue. This mixture was diluted with 200 ml. of toluene and the reaction mixture subsequently stripped to 60° C. at 5 mm. pressure. The residue was an amber oil which solidified to a cream colored soft solid, weight 106.6 grams (Theory 108 grams).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:37][C:27]1[CH:28]=[C:29]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:31]([F:32])[C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([OH:10])[C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: Cn1cc(C(O)Cc2cccc(Br)n2)cn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cn1cc(C(O)Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)cn1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using (2-(6-bromopyridin-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethanol (0.090 g, 0.32 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>O1CCCC1>[C:1]1([N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCNc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCCCN1c1ccccc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
2.5 g (16.5 mM) of N1 -phenylpropane-1,3-diamine are dissolved in 56.5 ml of anhydrous tetrahydrofuran. A mixture of 3.8 g (23.3 mM) of carbonyldiimidazole in 115 ml of anhydrous tetrahydrofuran is poured into the solution, and the mixture is left at room temperature overnight. The mixture is concentrated, taken up in ethyl acetate, washed with normal HCl and dried over MgSO4 to yield 2 g of a white solid that melts at 210°-211° C. and corresponds to the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]([CH3:13])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloro-6-trifluoromethylpyrimidine (XXVII) (1.00 g, 4.6 mmol) was dissolved in dry THF (5 mL). To this solution was added N-methyl-4-trifluoromethoxyaniline (0.88 g, 4.6 mmol) and diisopropylethylamine (0.8 mL, 4.6 mmol). The resulting solution was stirred at room temperature for 18 hrs, then the volatiles were removed in vacuo and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with 2N HCl, dried over MgSO4, filtered and then concentrated in vacuo to give a brown color oil. Purification of the brown oil by chromatography (silica, hexane/EtOAc) afforded the product (XXVIII) as a yellow solid (0.95 g, 56%): 1H NMR (CDCl3) δ 7.42-7.27 (m, 4H), 6.4 (s, 1H), 3.5 (s, 3H); GC/MS m/z (relative intensity) 374 (26), 373 (45), 372 (76), 370 (100).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(Cl)Cl>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:18](=[O:19])[C:17]1[CH:21]=[C:22]([CH3:26])[C:23]([O:24][CH3:25])=[C:15]([CH3:14])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Solvent: O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(C)c(OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran and 11.5 g. (0.058 mol.) of 3,5-dimethyl-4-methoxybenzoic acid chloride in 100 ml. of methylene chloride was added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture was allowed to warm to ambient temperature, then stirred for 2 hours. Water was slowly added to the mixture and it was stirred an additional 30 minutes. The layers were separated and the organic phase was washed with water until the washings were neutral, dried (MgSO4) and concentrated to give 2-n-butyl-3-(3',5'-dimethyl-4'-methoxybenzoyl)benzofuran.