Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:7])=O)=[N+:2]=[N-:3].C(N(CC)CC)C.[C:15]1([CH:21]=[CH:22][CH:23]=[N:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[N:1]([C@H:4]1[C@@H:23]([CH:22]=[CH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:5]1=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: COc1ccc(N=CC=Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
2-Azidoacetic acid (24.26 g) is dissolved in 100 ml of methylene chloride and cooled in an ice bath. To this solution is added 48.57 g of triethylamine and 14.24 g of N-(3-phenyl-2-propenylidene)-4-methoxyaniline dissolved in 250 ml of methylene chloride. To the resulting solution is added 50.41 g of trifluoroacetic anhydride dropwise over a one hour period. After stirring for one hour in an ice bath, the mixture is warmed to room temperature and stirred for about 16 hours. The mixture is then diluted with 250 ml of methylene chloride and washed with water (750 ml), 5% sodium bicarbonate solution (two 750 ml portions), and 1N HCl solution (750 ml). The organic layer is dried over anhydrous sodium sulfate and stripped of solvent to give a solid. The crude product is recrystallized from ethyl acetate to give 11.39 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.Cl.Cl.[NH2:38][CH:39]1[CH2:47][CH2:46][C:42]2[NH:43][CH:44]=[N:45][C:41]=2[CH2:40]1.C(N(CC)CC)C>CC(N(C)C)=O.Cl>[NH:43]1[C:42]2[CH2:46][CH2:47][CH:39]([NH:38][C:12](=[O:14])[CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:15])=[CH:9][CH:8]=3)[CH2:40][C:41]=2[N:45]=[CH:44]1
Reactant: NC1CCc2[nH]cnc2C1
Reactant: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc(OC(F)(F)F)cc1)NC1CCc2[nH]cnc2C1
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-trifluoromethoxyphenyl)acrylic acid (186 mg, 1.0 mmol) in DMA (5 ml), HOAt (136 mg, 1.0 mmol) and DIC (126 mg, 1.0 mmol) were added and the mixture was stirred for 10 min. A mixture prepared from 5-amino-4,5,6,7-tetrahydro-1H-benzimidazole, dihydrochloride (210 mg, 1.0 mmol), DMA (5 ml) and triethylamine (202 mg, 2 mmol) was added to the activated ester and the mixture was stirred for 16 hours at ambient temperature. The volatiles were evaporated and the residue was stirred with a mixture of H2O (40 ml), 1 N hydrochloric acid (20 ml) and diethyl ether (25 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×25 ml) and then made alkaline to pH 10-11 with 4 N sodium hydroxide. The alkaline mixture was extracted with ethyl acetate (3×50 ml) and the combined organic extracts were dried (magnesium sulphate). The solvent was evaporated in vacuo to give a residue that was dissolved in 1 N hydrochloric acid (50 ml) and the acidic mixture was evaporated to dryness. The residue was re-evaporated with acetone (2×15 ml), stirred with acetone for 1 hour and the solid was isolated by filtration and dried. This afforded 141 mg (36%) of the title compound.
Reaction SMILES: [N:1]1[C:6]([C:7](OCC=C)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].C(O)C=C.[BH4-].[Na+].C(OCC)C.CCCCCC>C1COCC1>[OH:8][CH2:7][C:6]1[N:1]=[C:2]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH:3]=[CH:4][CH:5]=1
Reactant: C=CCOC(=O)c1cccc(C(=O)OCC=C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C=CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)c1cccc(CO)n1
Temperature: 25 °C

Procedure:
A mixture of diallyl 2,6-pyridinedicarboxylate (17.1 g, 0.069 mol) in 150 mL of THF, and 150 mL of allyl alcohol is stirred at room temperature. Sodium borohydride (1.32 g, 0.035 mol) is added in several portions over 10 minutes, and the reaction is allowed to stir at room temperature for 15 h. The reaction is quenched by slow addition of 30 mL of water, followed by 30 mL of 1.0 N HCl. The mixture is poured into a separatory funnel containing 100 mL of 5% ammonium hydroxide and extracted with 1:1 ethyl acetate-diethyl ether (3×100 mL). The combined organic fractions are washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to give a yellow oil which solidified on standing. Trituration with 1:1 diethyl ether/hexane affords allyl 6-(hydroxymethyl)pyridine-2-carboxylate as a white crystalline solid.
Reaction SMILES: CS(O[CH2:6][C:7]([CH3:17])([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)[CH3:8])(=O)=O.[I-:18].[Na+].O>CN(C)C=O>[I:18][CH2:6][C:7]([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)([CH3:17])[CH3:8]
Reactant: CC(C)(COS(C)(=O)=O)n1cc([N+](=O)[O-])cn1
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CI)n1cc([N+](=O)[O-])cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of the crude 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propyl methanesulfonate (18 g) obtained in Step A of Example 115 in N,N-dimethylformamide (150 mL) was added sodium iodide (20 g), and the mixture was stirred overnight at 130° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (14 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([NH:31][N:32]=[C:33]([C:36]5NN=N[N:37]=5)[C:34]#[N:35])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:41])=[O:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[K]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[S:24][C:23]([C:25]4[CH:26]=[CH:27][C:28]([NH:31][N:32]=[C:33]([C:34]#[N:35])[C:36]#[N:37])=[CH:29][CH:30]=4)=[N:22][C:21]=3[CH3:41])=[O:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C2=NN(C(=O)c3sc(-c4ccc(NN=C(C#N)c5nnn[nH]5)cc4)nc3C)CCC2)ccc1OC
Agent: [K]
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4ccc(NN=C(C#N)C#N)cc4)nc3C)CCC2)ccc1OC

Procedure:
2-[(4-{5-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine-1-carbonyl]4-methylthiazol-2-yl}phenyl)hydrazono]-2-(1H-tetrazol-5-yl)-acetonitrile, potassium salt
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]([CH3:27])[CH2:25][OH:26])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]([CH3:27])[CH:25]=[O:26])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(C)CO)C3
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(C)C=O)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
DMP (291 mg; 0.69 mmol; 1.25 eq.) was added at 0° C. to a solution of Example 143 (220 mg; 0.55 mmol; 1 eq.) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with sat. aq. NaHCO3 then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (25% to 65% EA in cyclohexane) afforded the title compound (170 mg, 78%) as a white solid. UPLC/MS: (MS+) 399.1 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]([C:15]2[C:16]3[CH2:17][C@H:18]4[CH2:31][C@H:19]4[C:20]=3[N:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:22]=2)=[O:14])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([NH:12][C:13]([C:15]2[C:16]3[CH2:17][C@H:18]4[CH2:31][C@H:19]4[C:20]=3[N:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:22]=2)=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CNC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-azetidine-1-carboxylic acid tert-butyl ester was dissolved in 20% TFA/DCM. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was purified by cation exchange resin to give (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (azetidin-3-yl)-amide. This material was mixed with 3-bromo-1,1,1-trifluoropropane and Et3N in IPA. The reaction was heated under microwave irradiation for 1 h at 150° C. The mixture was purified by preparative HPLC to provide the title compound. LCMS m/z=427.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:41]=[CH:40][CH:39]=[CH:38][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([O:29]C)=[O:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:41]=[CH:40][CH:39]=[CH:38][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH:26]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]([OH:29])=[O:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OC(Cc4ccccc4)C(=O)OC)ccc3c2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OC(Cc4ccccc4)C(=O)O)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of methyl 2-({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)-3-phenylpropanoate (346 mg, 0.633 mmol), prepared in the previous step, and 1 N NaOH (1.26 mL, 1.26 mmol) in 50 mL of THF was stirred at room temperature for 18 h (overnight). The reaction was acidified by the addition of 1.4 mL of 1N HCl and then concentrated under reduced pressure to remove the THF. The yellow solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (266 mg, 77%) as a yellow solid, mp 174-177° C. Elemental Analysis for C34H29NO5+0.039 H2O Calc'd: C, 76.72; H, 5.51; N, 2.63. Found: C, 75.36; H, 5.48; N, 2.44.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)=[N:17][CH:18]=2)=[C:8]([F:27])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:28]([N-:31]C(C)C)(C)C.[Li+].C1(C)C=CC(S(C#N)(=O)=O)=CC=1.C(O)C>CCCCCC.C1COCC1>[CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:28]#[N:31])=[C:21]([F:26])[CH:20]=3)=[N:15][CH:14]=2)=[C:8]([F:27])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(F)c(-c2cnc(-c3cc(F)cc(F)c3)nc2)c(F)c1
Reactant: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1cc(F)c(-c2cnc(-c3cc(F)c(C#N)c(F)c3)nc2)c(F)c1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
A mixture of 44 mmol of 1B and 80 ml of THF is added dropwise at -78° C. to a solution of 48 mmol of lithium diisopropylamide in hexane. The mixture is stirred at -50° C. for 2 hours and then re-cooled to -78° C., and a mixture of 48 mmol of p-toluenesulphonyl cyanide in 20 ml of THF is slowly added dropwise. After warming to room temperature and conventional work-up, the pure product is obtained by recrystallization from ethanol. C 85 N (75) I, Δε=71.3, Δn=0.232 (extrapolated from ZLI-4792)
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[C:13]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].C[N+](C)(C)C.C(O)(=O)C>C(O)(C)C>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH2:23])=[CH:24][CH:25]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=Cc1ccc(OC(C)(C)C)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: C=Cc1ccc(O)cc1

Procedure:
A mixture of 46.3 g of poly(p-acetyloxystyrene/p-tert-butoxystyrene) obtained according to (1) above and 100 ml of a 16% aqueous solution of tetramethylammonium hydroxide was refluxed with stirring in 300 ml of isopropanol for 4 hours. The reaction solution was neutralized with acetic acid and concentrated under reduced pressure, and the residue was dissolved in 150 ml of acetone and poured into 5,000 ml of water to cause crystallization. Precipitated crystals were filtered out, washed with water and dried in vacuo to give 33.8 g of poly(p-hydroxystyrene/p-tert-butoxystyrene). P-hydroxystyrene unit/p-tert-butoxystyrene unit molar ratio in the polymer≈3:1 (1HNMR). Mw≈8,540; Mw/Mn=1.30 (GPC with polystyrene calibration).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>O>[NH2:19]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: N
Solvent: O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 10.0 gm (0.0393 mol) of 2-benzoylbenzo[b]-thiophen-3-ol, 60 cc of concentrated aqueous ammonia and 250 cc of ethanol was heated for 20 hours at a temperature of 120° C. after introducing 5 bar of ammonia gas into the vessel. After cooling, the mixture was stirred into 1.5 liters of water, the precipitated pale yellow reaction product was filtered off with suction, washed thoroughly several times with 50 cc each of water and dried in the air. 4.23 gm (42% of theory) of yellow crystals, m.p. 121°-122° C., were obtained (after twice recrystallizing from petroleum ether/ethyl acetate 1:1 using activated carbon) and were found to be completely identical with the product obtained in Example 1 based on elemental analysis, IR and UV spectra.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]([CH2:9][C:10](OCC)=[O:11])=O>COCCOCCOC>[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]1[NH:3][N:2]([CH3:1])[C:10](=[O:11])[CH:9]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1Cl
Solvent: COCCOCCOC
Product: Cc1cc(-c2cc(=O)n(C)[nH]2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
13.5 g (292 mmol) of methylhydrazine were slowly added to 80.4 g (292 mmol) of ethyl 2,4-dichloro-5-methylbenzoylacetate in 300 ml of diethylene glycol dimethyl ether. After 4 hours at 100° C., the solution was stirred into 1 l of ice-water. The precipitate formed was filtered off, washed with a small amount of methylene chloride and dried. Yield: 38.8 g.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[NH2:6].[OH-].[Na+].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([NH:6][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reactant: CN(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)aniline (9.1 g) was dissolved in 200 ml of toluene, and 30 ml of 40% aqueous sodium hydroxide solution and 6.5 g of N,N-dimethylcarbamyl chloride were added thereto. The reaction mixture was heated under reflux for 10 hours and then cooled to room temperature. The toluene layer was washed with water, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from ethanol to obtain 5.1 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N,N-dimethylurea as white needles. M.P. 210°-211° C.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.[C:17]([C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:20]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[NH:39][S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:30][CH:29]=1)#[N:18].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([C:19]1[CH:24]=[C:23]([C:25]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:26])[CH:22]=[CH:21][C:20]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[NH:39][S:40]([CH:43]([CH3:45])[CH3:44])(=[O:41])=[O:42])=[CH:32][CH:33]=1)#[N:18]
Reactant: CS(N)(=O)=O
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)NS(C)(=O)=O)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add methanesulfonamide (0.28 mmol), EDCI (0.28 mmol) and DMAP (0.28 mmol) to a solution of 2-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.235 mmol) in DCM. Stir 8 h at RT. Add 1N HCl and extract with DCM. Concentrate all organic layers to dryness. Purify by HPLC to provide the title compound. MS (ES−): 502 (M−1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, (R)-3-(4-bromophenyl)-1-(6-methoxypyridin-3-yl)-3-o-tolyl-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+): m/z=396.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[C:18]([C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([N:28]4[C@H:27]([CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[CH3:25])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C#N)cc2C)CC1
Product: Cc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)N1CCN(c2ncc(C#N)cc2C)CC1
Yield: 65.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(4-bromo-2-methylbenzoyl)piperazin-1-yl]-5-methylnicotinonitrile (210 mg) described in Preparation Example 133 and (R)-4-methyloxazolidin-2-one (80 mg) described in Preparation Example 25, the title compound (145 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:38]([O:40]C)=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:37])[NH:19][S:20]([C:23]1[CH:33]([CH3:34])[CH:27]2[CH2:28][C:29]([CH3:32])([CH3:31])[O:30][C:26]2=[C:25]([CH3:35])[C:24]=1[CH3:36])(=[O:22])=[O:21])=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:38]([OH:40])=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:37])[NH:19][S:20]([C:23]1[CH:33]([CH3:34])[CH:27]2[CH2:28][C:29]([CH3:32])([CH3:31])[O:30][C:26]2=[C:25]([CH3:35])[C:24]=1[CH3:36])(=[O:22])=[O:21])=[O:11]
Reactant: COC(=O)[C@H](CCCNC(=N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2C1C)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C2OC(C)(C)CC2C(C)C(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)=C1C
Yield: 89.6 %

Procedure:
The same procedures as in Example 111 were carried out from the compound obtained in Example 59 (3.2 g), 1 mol/L of an aqueous sodium hydroxide solution (8.0 mL), and methanol (80 mL), to give the captioned compound (2.8 g, 91%) as an oily product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[O:13][CH:12]=1)=[O:10].[CH2:21]([O:28][CH2:29][C:30]1[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1.O.CCOC(C)=O>[CH3:7][O:8][C:9]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:34]3[CH:35]=[C:30]([CH2:29][O:28][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:31]=[CH:32][N:33]=3)=[CH:19][C:14]=2[O:13][CH:12]=1)=[O:10]
Reactant: COC(=O)c1coc2cc(O)ccc12
Reactant: Clc1cc(COCc2ccccc2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1coc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
415 mg (3.0 mMol) K2CO3 and 249 mg (1.5 mMol) KI are added to a solution of 192 mg (1.00 mMol) 6-hydroxy-benzofuran-3-carboxylic acid methyl ester (Step 9.4) and 258 mg (1.1 mMol) 4-benzyloxymethyl-6-chloro-pyrimidine (commercially available; [CAS: 914802-11-2]) in 1.6 ml NMP. This mixture is stirred for 4 h at 100° C., cooled to rt and diluted with water and EtOAc. The aq. phase is separated off and extracted twice with EtOAc. The organic layers are washed with a diluted solution of Na2S2O3 and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 19:1→1:1) and crystallization from hexane gives the title compound: m.p.: 85-86° C.; MS: [M+1]+=391; TLC(hexane/EtOAc 2:1): Rf=0.38.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[F:11].B(Br)(Br)Br>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[F:11]
Reactant: COc1ccc(F)c(N(C)C)c1
Agent: BrB(Br)Br
Product: CN(C)c1cc(O)ccc1F

Procedure:
The methyl ether of Example 21 is treated with boron tribromide using general method E to give Compound 22.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:10])[O:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:8][CH2:7][CH2:6][C:5]([OH:9])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCO1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CCCc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
Powdered aluminum chloride (200 g) was added to benzene (400 g) and stirred for 10 min at 50° C. Butyrolactone (86 g) was added in small portions. The temperature was maintained between 50 and 60° C. for 90 min and then the reaction mixture was added, with stirring, to a mixture of ice and 5% sodium hydroxide. The temperature was maintained below 35° C. and the pH was maintained between 9 and 9.5 for 2 hr. The mixture was filtered under vacuum. Phenylbutyric acid was precipitated from the aqueous fraction by the addition of ice and hydrochloric acid. Crude (93.7%-94.3%) 4-phenylbutyric acid was isolated by vacuum filtration.