Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:11]([F:13])([F:14])[F:12]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask, 2-fluoro-4-nitro-1-trifluoromethyl-benzene (1.00 g, 4.78 mmol) was dissolved in 10 mL of methanol. To this solution was added 10% palladium on carbon (100 mg) and the solution was stirred overnight at room temperature under hydrogen (1 atm). The solution was filtered and concentrated to afford 3-fluoro-4-trifluoromethyl-phenylamine. 1H NMR (300 MHz, DMSO-d6) δ 7.3 (m, 1H), 6.6 (d, 2H), 6.2 (s, 2H)
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([N+:9]([O-:11])=[O:10])([Br:8])[CH2:4][O:3]1.Cl>CO>[CH2:4]([OH:3])[C:5]([Br:8])([N+:9]([O-:11])=[O:10])[CH2:6][OH:7]
Reactant: CC1(C)OCC(Br)([N+](=O)[O-])CO1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])C(Br)(CO)CO
Temperature: 25 °C
Yield: 95 %

Procedure:
To a 50 ml round bottom flask equipped with a stir bar and reflux condensor topped with a nitrogen inlet was added 0.5 g (.004 mol) 2,2-dimethyl-5-nitro-5-bromo-1,3-dioxane, 10 ml methanol and 0.3ml concentrated HCl. The reaction was heated to 35°-40° C. for 1 hour. After cooling to room temperature, the volatiles were removed to give crystalline bronopol (95% yield) which on recrystallization from acetone had a melting point of 120° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[Cl-].[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10]([O-])=[O:11]>C(Cl)Cl>[O:11]=[C:10]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)[CH2:9][C:8]([O:14][CH3:15])=[O:13]
Reactant: C1CSCCN1
Reactant: COC(=O)CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC(=O)N1CCSCC1
Yield: 97.1 %

Procedure:
20.6 g of thiomorpholine were added dropwise to a solution of 13.6 g of methyl malonate monochloride in 100 ml of methylene chloride. After stirring the mixture was diluted with 200 ml of methylene chloride, washed with water in a separating funnel, then dried, filtered and evaporated. The residue was purified by chromatography on silica gel with methylene chloride and then methylene chloride/acetone (1:1). There were obtained 17.6 g of methyl tetrahydro-b-oxo-4H-1,4-thiazine-4-propionate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(OCCl)c1cc(F)cc(F)c1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.32 g of chloromethyl 3,5-difluorobenzoate was added, and the mixture was stirred at 70° C. for 5 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.23 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3,5-difluorobenzoate (present compound (40)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Temperature: 25 °C

Procedure:
To a stirred and ice-cooled solution of 1-(4-chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea (0.1 g, 0.2923 mmol), triphenyl phosphine (0.291 g, 1.1078 mmol) and 1-(2-hydroxy ethyl)-pyrrolidine (0.127 g, 1.099 mmol) in THF (25 mL) was added diisopropyl azodicarboxylate (0.224 g, 1.104 mmol) slowly over 10 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred further for 4 hrs at this temperature. THF was evaporated and the syrup was dissolved in DMSO and purified using a Varian preparative HPLC system (60 mL/min flow and λ=240 0.1% TFA/H2O:0.1% TFA/CH3CN). The fractions containing the product were evaporated. The pink colored residue was subjected to 2nd purification using SiO2 flash chromatography (eluant: 1% methanol in DCM to 15% methanol in DCM). The fractions containing the product were evaporated to give a colorless solid that was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1.[C:33]([C:35]1([CH2:39][C:40](O)=[O:41])[CH2:38][CH2:37][CH2:36]1)#[N:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[NH2:32][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:40](=[O:41])[CH2:39][C:35]4([C:33]#[N:34])[CH2:38][CH2:37][CH2:36]4)[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#CC1(CC(=O)O)CCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3(C#N)CCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (24 uL, 0.17 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (15 mg, 0.034 mmol), (1-cyanocyclobutyl)acetic acid (5.3 mg, 0.038 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (17 mg, 0.038 mmol) in N,N-dimethylformate (0.5 mL). The mixture was stirred at r.t. for 30 min., and purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=446.1.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:26]([O:25][C:23]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36])=[O:24])[CH3:27]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)C1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.4 %

Procedure:
A mixture of ethyl 6-(bromomethyl)-4-(2-nitrophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.4 g, 5.3 mmol), morpholine-3-carboxylic acid hydrochloride (0.9 g, 5.37 mmol) and potassium carbonate (1.48 g, 10.74 mmol) in ethanol (60 mL) was stirred at 25° C. for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a light yellow solid (1.1 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([CH:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:6][C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH:26]([CH3:28])[CH3:27])[CH:17]=2)=[CH:4]1)[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH:5]2[CH2:6][CH2:7][N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:4]2)=[CH:17][C:18]=1[O:25][CH:26]([CH3:27])[CH3:28]
Reactant: CCC1C=C(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CC(c2ccc(N)c(OC(C)C)c2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 84.8 %

Procedure:
In a microwave tube, 470 mg of 2-methylpropan-2-yl 6-ethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate are introduced into 20 ml of methanol. 456 mg of ammonium formate and 385 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure. The residue is taken up with 30 ml of ethyl acetate and 3 ml of water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to obtain 370 mg of 2-methylpropan-2-yl 4-[4-amino-3-(propan-2-yloxy)phenyl]-2-ethylpiperidine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:6]([O:27][CH3:28])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:26]=2)[CH:22]=[N:23]1
Reactant: C1COCCN1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCOCC1

Procedure:
The title compound was prepared by the procedure of Example 167 using 0.616 g of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.094 g of sodium iodide and 2.03 ml of morpholine to give after purification by chromatography (Silica Gel: ethyl acetate, ethyl acetate/methyl alcohol/triethyl amine 6:4:0.1) 0.196 g (28%) of the desired product. MP 133-135° C. :mass spectrum (electrospray m/e): M+H=445.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH3:9])(=O)=O.[F:10][C:11]([F:24])([F:23])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])=[O:13].[OH-].[K+]>CC(C)=O>[CH2:6]([N:14]([C:12](=[O:13])[C:11]([F:24])([F:23])[F:10])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])[CH2:7][CH2:8][CH3:9]
Reactant: O=C(Nc1ccc(F)cc1F)C(F)(F)F
Reactant: CCCCOS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCN(C(=O)C(F)(F)F)c1ccc(F)cc1F
Yield: 53.4 %

Procedure:
A mixture of 60.8 g of n-butyl methanesulphonate and 22.5 g of trifluoroacetyl-2,4-difluoroaniline is dissolved in 50 ml of acetone at 40° C., and 22.4 g of KOH powder are added. The reaction mixture is kept at reflux for 30 minutes, filtered and evaporated on a rotary evaporator. The oily residue is rectified. 15 g of N-butyltrifluoroacetyl-2,4-difluoroaniline are obtained as a yellowish oil which distills at 106 - 110°/11.7 mbar.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:42]=2[CH3:51])=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:40]2[CH:39]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:42]=3[CH3:51])[CH:37]=[CH:36][C:35]=2[Cl:34])[O:9][C:8]1=[O:24]
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(B3OC(C)(C)C(C)(C)O3)c2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (103 mg, 0.172 mmol, in 515 μL toluene), methyl 4′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (100 mg, 0.259 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (14 mg, 10%), aqueous potassium carbonate (344 μL, 2M, 0.688 mmol), and ethanol (2 mL) were sealed in a microwave vessel. The reaction mixture was irradiated by microwave at 140° C. for 45 minutes. LC/MS analysis indicated complete consumption of starting material. Crude material was purified by SiO2 (Prep-TLC 30% EtOAc/hex) to afford a yellow residue. The residue was further purified by a preparative reverse phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/ a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture affording methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=729.13; found=730.14 (M+1)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH2:36][CH2:37][N:38]=2)=[CH:30][CH:29]=1>O1CCCC1.CCCCCC.O>[O:35]1[CH2:36][CH2:37][N:38]=[C:34]1[C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:19][C:17]2[O:16][N:15]=[C:14]([CH3:13])[CH:18]=2)=[CH:29][CH:30]=1
Reactant: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Reactant: Cc1cc(C)on1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6.0 ml of diisopropylamine in 50 ml of tetrahydrofuran at 0° C. was added 22 ml of 2.1M n-butyllithium in hexane over a period of 20 minutes. The mixture was stirred 30 minutes at 5° C., then cooled to -55° C., and 4.5 g of 3,5-dimethylisoxazole was added dropwise during 15 minutes. The resulting slurry was stirred for 30 minutes at -60° C. and 12.4 g of 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole in 35 ml of tetrahydrofuran was then added dropwise. After the addition was complete, the mixture was stirred for one hour during which the temperature rose to -40° C. The reaction mixture was allowed to warm to room temperature, 75 ml of water was then added dropwise, and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were dried and concentrated in vacuo, and the residue triturated with ether. The ether insoluble fraction (10.5) consisted essentially of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, identical with the product of Example 1, part (c).
Reaction SMILES: COC1C=CC(C2CCC(=O)C2)=CC=1.COC1C=CC(C2CCC(=O)CC2)=CC=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.CC1(C)C[O:51][B:50]([C:53]2[CH:54]=[C:55]([C@@H:61]3[CH2:65][CH2:64][C@H:63]([C:66]([O:68][CH3:69])=[O:67])[CH2:62]3)[CH:56]=[CH:57][C:58]=2[O:59][CH3:60])[O:49]C1>>[CH3:60][O:59][C:58]1[CH:57]=[CH:56][C:55]([C@H:61]2[CH2:65][CH2:64][C@@H:63]([C:66]([O:68][CH3:69])=[O:67])[CH2:62]2)=[CH:54][C:53]=1[B:50]([OH:49])[OH:51]
Reactant: COC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(B3OCC(C)(C)CO3)c2)C1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: COc1ccc(C2CCC(=O)C2)cc1
Agent: COc1ccc(C2CCC(=O)CC2)cc1
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OC)c(B(O)O)c2)C1

Procedure:
The title compound was synthesized from 3-(4-methoxyphenyl)cyclopentanone (INTERMEDIATE 75, Step B) and commercially available starting materials using an analogous method to that described for INTERMEDIATE 7. Bis(neopentyl glycolato)diboron was used instead of BISPIN to afford a mixture of the titled compound and methyl (1S,3R)-3-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methoxyphenyl]cyclopentanecarboxylate. The mixture was used without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C.[CH3:52][C:53]1[N:58]=[CH:57][C:56]([CH2:59][NH2:60])=[CH:55][N:54]=1>ClCCl.CO.C(OCC)(=O)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:60][CH2:59][C:56]3[CH:55]=[N:54][C:53]([CH3:52])=[N:58][CH:57]=3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: Cc1ncc(CN)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(CNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
In a 25 mL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.1 g, 1.0 eq.) was charged along with dichloromethane (5.0 mL, 50 V) and ethyl acetate (5.0 mL, 50 V). The reaction mixture was cooled to 0° C. and then added T3P (50% in ethyl acetate) (0.214 g, 1.2 eq.) followed by DIPEA (0.073 g, 2.0 eq.) and (2-methylpyrimidin-5-yl)methanamine (0.038 g, 1.1 eq.). The clear reaction mixture was stirred at 0° C. for 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 10% Methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in 30 mL ice-water slurry. Organic layer was separated and aqueous layer was extracted with dichloromethane (2×20 mL) to ensure complete extraction. The organic layer was washed with brine solution and dried over anhydrous Na2SO4 and concentrated by rotary evaporation under reduced pressure (35° C., 20 mm Hg) to afford 0.129 g of crude compound. (cis: 81.98%; trans: not detected; unreacted SM: 13.95%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[CH:18]=1)=[O:5]>C1COCC1.CCCCCC>[OH:17][CH:12]1[C:11]2[CH:18]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:21])([CH3:1])[CH3:22])[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]=2[O:14][C:13]1([CH3:16])[CH3:15]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Yield: 92 %

Procedure:
Using 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide obtained in Reference Example 65, the title compound was synthesized in the same manner as in Example 234. Yield: 92%. Melting point: 184-185° C. (THF-hexane).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4].C(OC(=O)C)(=[O:23])C.C([O-])(=O)C.[K+]>C(O)(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:23])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(ncn2CCCCCCO)n(C)c1=O
Yield: 90 %

Procedure:
3.4 g of 1,3-dimethyl-7-(6-bromohexyl)-xanthine are boiled overnight under reflux in 50 ml of glacial acetic acid to which 1 ml of acetic anhydride and 5 g of potassium acetate have been added. After evaporated of the solvent by distillation in vacuo the residue is dissolved in 50 ml of 5% sulfuric acid on the addition of 20 ml methanol. The solution is boiled under reflux for 1 hour. The mixture is extracted with chloroform. The chloroform phase is washed until it is neutral and concentrated in vacuo. 1,3-dimethyl-7-(6-hydroxyhexyl)-xanthine having a melting point of 80° C. is obtained in a yield of more than 90%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C>S(=O)(=O)(O)O>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([CH2:35][O:36][CH2:37][CH2:38][CH3:39])[C:2]=1[F:1]
Reactant: CCCOCc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: O=S(=O)(O)O
Product: CCCOCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
The above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-7-propyloxymethyl-4H-1-benzopyran-4-one was dissolved in 30 mL of a 50% aqueous solution of sulfuric acid, and the solution was stirred at 100° C. for 15 minutes. Then, the mixture was poured into ice-water and neutralized. The precipitate was collected and purified by silica gel column chromatography (chloroform:methanol=100:1) followed by recrystallization from ethyl acetate/n-hexane, to give 286 mg of Compound 150 (yield: 76%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[O:16][CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)Br
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 72.5 °C
Yield: 101.3 %

Procedure:
This compound was prepared in the manner of Example 4, using 221.0 grams (0.92 mole--1.0 equiv.) of 92.0% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, 202.3 grams (2.17 moles--2.36 equiv.) of triethylamine, 276.0 grams (2.17 moles--1.68 equiv.) of potassium carbonate, and 250.0 grams (1.63 moles--1.77 equiv.) of methyl 2-bromopropanoate in about 2000 mL (%Wt/Vol. Phenol to Solvent--11.1 %) of acetonitrile. This preparation differs in that the mixture was heated to 70° C. rather than 78° C. before the methyl 2-bromopropanoate was added and that the methyl 2-bromopropanoate was added during a 15 minute period at a rate to maintain the reaction temperature between 70-75° C. rather than during a ten minute period. A yield of 311 grams of 85.3% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]-propanoate was obtained (93.9% yield).