Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([OH:15])[C@H:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C@@H:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[N:20]=[CH:19][N:18]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl.O>[C:39]([O:15][C@@H:13]1[CH2:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:11][C@H:12]1[NH:16][C:17]1[CH:22]=[C:21]([NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[N:20]=[CH:19][N:18]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)[C@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1Nc1cc(N[C@H]2CCc3ccccc32)ncn1
Reaction time: 8 h

Procedure:
To a solution of (1R,2R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)cyclopentanol (0.193 g, 0.424 mmol), N,N-dimethylaminopyridine (4.7 mg, 0.039 mmol) and pyridine (0.281 mL, 3.48 mmol) in DCM (2.1 mL) was added acetic anhydride (0.044 mL, 0.46 mmol) and the mixture stirred overnight. The reaction was diluted with CH2CL2 (10 mL) and H2O (20 mL) then stirred for 10 m. The organic layer was separated and the aqueous layer was extracted with CH2CL2 and combined organics were washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to obtain the title compound. LC/MS: Rt=1.74 min, ES+ 498 (FA Standard).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:19]=[C:18](C(O)=O)[S:17][C:16]=1[C:23]([OH:25])=O.[CH2:26]([NH2:36])[C:27]1[CH:35]=[CH:34][C:33]2[O:32][CH2:31][O:30][C:29]=2[CH:28]=1>>[O:32]1[C:33]2[CH:34]=[CH:35][C:27]([CH2:26][NH:36][C:23]([C:16]3[S:17][C:18]([C:1]([NH:8][CH2:12][C:11]4[CH:27]=[CH:28][C:29]5[O:30][CH2:31][O:32][C:33]=5[CH:34]=4)=[O:2])=[CH:19][C:15]=3[O:14][CH3:13])=[O:25])=[CH:28][C:29]=2[O:30][CH2:31]1
Reactant: COc1cc(C(=O)O)sc1C(=O)O
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1cc(C(=O)NCc2ccc3c(c2)OCO3)sc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 89.7 %

Procedure:
The title compound was prepared according to the procedure of Example 2 using carbonyldiimidazole (1.0 g, 6.2 mmol), 3-methoxy-2,5-thiophenedicarboxylic acid (0.5 g, 2.5 mmol), and piperonylamine (0.85 g, 5.6 mmol) to afford 1.05 g of 3-methoxy-thiophene-2,5-dicarboxylic acid bis-[(1,3-benzodioxol-5-ylmethyl)-amide]. Recrystallization of a sample from dimethylformamide gave product with a mp 191-195° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCCSc1ccc(Cl)c(C#N)n1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1

Procedure:
3-Chloro-6-propylthio-2-pyridinecarbonitrile (6.2 g) was mixed with 5.7 g of 3,4-dichlorophenol and 3.9 g of t-BuOK in 30 ml of DMSO and 30 ml THF. The desired, 3-(3,4-dichlorophenoxy)-6-propylthio-2-pyridinecarbonitrile was recovered, b.p. 203° C. (at 0.2 mm Hg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)CCO1.[H-].[Na+].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][N:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:22]2=[O:25])=[CH:17][C:16]=1F.[CH3:36][C:37](N(C)C)=[O:38]>>[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][N:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:22]2=[O:25])=[CH:17][C:16]=1[O:11][CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:36][CH2:37][O:38]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Reactant: CC(=O)N(C)C
Reactant: OC1CCC2(CCOO2)CC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Cn2ccc3cc(OC4CCC5(CC4)OCCO5)c(Cl)cc3c2=O)cc1

Procedure:
1.49 g (9.44 mmol) of dioxa-spiro[4.5]decan-8-ol were dissolved in 30 ml of dimethyl acetamide and 283 mg (11.8 mmol) of sodium hydride (60%) were added. After stirring for 30 min at room temperature a solution of 2.50 g (7.87 mmol) of 7-chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (10) in 20 ml of dimethyl acetamide was added and stirring was continued at room temperature. After the reaction went to completion the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and evaporated. Purification by silica gel chromatography yielded 1.84 g of the title compound. Rt=2.00 min (Method B). Detected mass: 456.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCCCCC.[N:28]1([C:38]([Cl:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>>[ClH:40].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][O:21][C:38]([N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][CH2:30][CH2:29]4)=[O:39])[CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(C2CCN(CCCO)CC2)c2ccc(F)cc21
Reactant: O=C(Cl)N1CCCc2ccccc21
Solvent: CCCCCC
Product: Cl
Product: Cn1nc(C2CCN(CCCOC(=O)N3CCCc4ccccc43)CC2)c2ccc(F)cc21
Yield: 8.6 %

Procedure:
Starting from 4-(6-fluoro-1-methyl-I H-indazol-3-yl)-1-(3-hydroxypropyl)piperidine (370 mg; 1.2 mmol), 3M N-butyl lithium in hexane (0.7 ml; 2.1 mmol) and 1,2,3,4-tetrahydroquinolin-1-carbonyl chloride (300 mg; 1.5 mmol) using the procedure described in example 7 was prepared 50 mg (9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(OC)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 83.1 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (860 mg, 5.76 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (81 mg, 0.12 mmol), copper(I) iodide (13 mg, 0.07 mmol), and TEA (1.26 g, 0.013 mol). After heating the reaction at 60° C. for 30 min, N-[5-ethynyl-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (560 mg, 2.30 mmol, obtained from composite batches) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight at 60° C. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M+H)+=356.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])[CH3:2].[CH3:19][O:20][C:21](=[O:31])[C@@H:22]([NH2:30])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:30][C@H:22]([C:21]([O:20][CH3:19])=[O:31])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])[CH3:2]
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1Oc2cccc(Cl)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.8 %

Procedure:
To a solution of 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 3.74 mmol) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (0.83 g, 3.74 mmol) and N,N′-diisopropylethylamine (1.30 mL, 7.49 mmol). The mixture was stirred at 25° C. for 10 h. At this time, sodium cyanoborohydride (0.47 g, 7.49 mmol) and acetic acid (0.47 mL, 7.49 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5-chloro-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (0.6 g, 35.7%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]#[N:20].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>>[NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]([NH2:20])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c(C#N)c1N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c(C(N)=O)c1N
Temperature: 65 °C
Yield: 85 %

Procedure:
Compound 26 (100 mg, 0.369 mmol) was added to concentrated sulfuric acid (1 mL) and heated to 65° C. for 3 hours. Afterwards, the reaction mixture was poured into ice water and the pH was brought to 14 with 10 M NaOH. The aqueous material was extracted several times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to a solid (91 mg, 85% yield): 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.21 (d, J=8.2, 1H), 7.98 (d, J=7.7, 1H), 7.69 (t, J=8.0, 1H), 6.20 (br, 2H), 4.51 (hept, 1H), 1.35 (d, J=6.5, 6H); 13C NMR (100 MHz, DMSO) δ 166.17, 149.37, 147.65, 145.50, 135.63, 134.92, 129.69, 122.79, 122.43, 95.43, 47.11, 21.50; [M+H]+ calculated for C13H15N5O3 290.1, found 290.0.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([OH:37])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C:26](=[O:37])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](OC(C)=O)[C@@H](O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](OC(C)=O)C(=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1

Procedure:
(3β,5α,11α,12β,25R)3,11-di(acetoxy)spirostan-12-ol was oxidized with chromium trioxide and pyridine in methylene chloride according to the procedure described in Org. Syn., 1976, 55, 84 to give the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1.C(O)(=O)C>CC(C)=O.O>[CH3:13][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[S:23])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=S)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 132 %

Procedure:
1N sodium hydroxide solution (6 mL, 6 mmol) was added to a solution containing the 4-toluenesulfonamide (1 g, 5.85 mmol) in acetone (25 mL). After stirring at room temperature for 30 min, the 4-chlorophenyl isothiocyanate (1.0 mmol) was added. After refluxing for 4 h, the mixture was cooled to room temperature and neutralized with 1N acetic acid solution to pH 5. The mixture was allowed to stir at room temperature for 30 min before adding water (45 mL) to produce a white precipitate which was collected by filtration. After the solid was dried in the oven, it was recrystallized to give 0.45 g (22.6%) of N-[(4-methylphenyl)sulfonyl]-N'-(4-chlorophenyl)thiourea. To an aqueous solution (50 mL) of sulfonylthiourea (1.2 g, 3.67 mmol), 1N sodium hydroxide solution (4 mL) was added and stirred for 2 minutes, followed by addition of methyl iodide (4.04 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and neutralized with 1N acetic acid (4 mL). The resulting mixture was extracted with chloroform to give 1.06 g (85%) of N-[(4-methylphenyl)sulfonyl]-N'-(4-chlorophenyl)-S-methylpseudothiourea. The S-methyl pseudourea (0.99 g, 2.8 mmol) was added to a stirred solution of hydroxylamine hydrochloride (8.4 mmol) and triethylamine (1.2 mL, 8.4 mmol) in chloroform (50 mL). The solution was refluxed for 48 h and the solvent was removed by evaporation to produce a solid residue. Ether (20 mL) was added to the residue and the white precipitate was collected by filtration. The solid was then heated with toluene and the undissolved solid was removed by filtration. The filtrate was again evaporated to obtain a solid which was subsequently recrystallized from methanol to yield the target compound (0.12 g, 12.7%); mp: 201-203° C.; MS m/z 294 (M+ -32); 1H NMR (300 MHz, DMSO-d6) d 2.36 (s, 3H, CH3), 7.31-7.36 (m, 4H, ArH), 7.45 (d, J=8.8 Hz, 2H, ArH), 7.71 (d, J=8.1 Hz, 2H, ArH), 9.40 (s, 1H, NH), 9.69 (br s, 2H, NH & OH); 13C NMR (100 MHz, DMSO-d6) d 20.9, 124.7, 125.9, 128.2, 128.3, 129.1, 136.2, 140.6, 141.6, 154.0. Analysis for C14H14ClN3O3S (339.8): theory: C, 49.49; H, 4.15; N, 12.37. Found: C, 49.67; H, 4.16; N, 12.47.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.[CH3:24]N(C(N(C)C)N(C)C)C.[NH2:34][OH:35]>CCO>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)=[N:34][O:35][CH:24]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: NO
Solvent: CCO
Product: CCn1c(Cc2conc2-c2cccc(F)c2)nc2cc(Br)ccc21
Temperature: 60 °C

Procedure:
A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. To the residue is added EtOH (5 mL) and hydroxylamine (1.1 mmol). The mixture is heated at 120° C. for 2 hours. The solvent is removed. To the residue is added NaHCO3 (aq.) (10 mL) and DCM (30 mL). The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-isoxazol-4-ylmethyl]-1H-benzoimidazole as a solid. 1H NMR (CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 7.31-7.52 (m, 4H), 7.18-7.22 (m, 2H), 4.14 (s, 2H), 4.04 (q, 2H), 1.18 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[NH:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([OH:32])=O)(=[O:26])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]([CH3:22])[C:30](=[O:32])[C:29]1[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:25])=[O:26])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnccc1-c1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(2-(benzyloxy)phenyl)-N-methylpyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow foam (83%). MS (ESI): m/z=541.140 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[F:17][C:13]1[CH:12]=[C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[O:8][N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(-c2cccc(F)c2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Yield: 97.7 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylate (6.0 g, 25.51 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.51 g, 24.92 mmol, 98%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35]([O:42][CH2:43][CH2:44][NH:45][CH:46]([CH3:48])[CH3:47])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:32]([N:45]([CH2:44][CH2:43][O:42][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[CH:46]([CH3:47])[CH3:48])=[O:34])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropyl-2-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)pyrimidine-4-carboxamide (476) was synthesized from 5-(benzyloxy)-6-hydroxy-2-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)pyrimidine-4-carboxylic acid (475) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22](O)=[O:23])[CH2:9][C:10]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[C:38]1[C:46]2[N:45]=N[NH:43][C:42]=2C=[CH:40][CH:39]=1.Cl.N1CCC[C@H]1C#N>CN(C)C=O.C(N(CC)CC)C>[C:42]([C@@H:46]1[CH2:38][CH2:39][CH2:40][N:45]1[C:22](=[O:23])[CH2:21][N:8]([CH2:9][C:10]([N:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)=[O:11])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])#[N:43]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)N1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)N1Cc2ccccc2C1)CC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.4 %

Procedure:
{t-Butoxycarbonyl-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino}acetic acid (260 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg) and hydroxybenzotriazole (120 mg) were dissolved in N,N-dimethylformamide (5.0 ml). Triethylamine (110 μl) and (S)-pyrrolidine-2-carbonitrile hydrochloride (100 mg) were added thereto, and the mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated under reduced pressure, then ethyl acetate and 10% citric acid solution were added to the residue, and the organic phase was separated. The organic phase was washed with 4% sodium bicarbonate solution and a saturated saline solution and dried over sodium sulfate anhydrous. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 20:1) to give t-butyl (S)-[2-(cyanopyrrolidin-1-yl)-2-oxoethyl]-[2-(1,3-dihydrois oindol-2-yl)-2-oxoethyl]carbamate (290 mg, Y.:90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11]=[CH: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][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH3:28]
Reactant: COc1ccc(OC)cc1
Reactant: C=CCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCC(C)c1cc(OC)ccc1OC
Yield: 52.8 %

Procedure:
33.5 g of p-dimethoxy benzene, 68.0 g of 1-octadecene and 7.7 g of dry silica alumina were heated at 225°-240° C. for 6 hours. After being allowed to cool, the reaction mixture was extracted with ethyl acetate and filtered. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give 50.0 g of 2-sec-octadecylhydroquinone dimethyl ether having b.p. 220°-223° C./2.5 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[NH:10]([CH2:13][CH3:14])[CH2:11][CH3:12].C(N(CC)C=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12]
Reactant: Clc1c(Br)cncc1Br
Reactant: CCNCC
Agent: CCN(C=O)CC
Solvent: CCOC(C)=O
Product: CCN(CC)c1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
A mixture of trihalopyridine VII (W=Br) (18.8 g, 70.0 mmol), Et2NH (21.7 mL, 0.210 mol), and N,N-diethylformamide (35 mL) was kept in a sealed high-pressure tube at 170° C. for 20 h. The reaction mixture was cooled to room temperature, dissolved in EtOAc (300 mL), and washed with 1M K2CO3 (200 mL) and water (8×200 mL). The organic layer was dried with MgSO4 and evaporated in vacuo to give a brown oil. Purification by flash chromatography (CH2Cl2) gave the title compound, 3,5-dibromo-4-(diethylamino)pyridine (VI, R1=R2=Et, W=Br), (20.3 g, 94%) as a yellow oil: Rf=0.45 (CH2Cl2); 1H NMR (250 MHz, CDCl3) δ1.01 (t, J=7.0 Hz, 6H), 3.26 (q, J=7.0 Hz, 4H), and 8.49 (s, 2H); 13C NMR (63 MHz, CDCl3) δ14.10, 46.05, 122.9, 151.9, and 154.1; IR (CHCl3) νmax 2976, 1553, 1457, 1167 cm−1; MS (EI+) m/z (rel intensity) 308 (15%, M+), 193 (100), and 264 (30); HRMS calcd for C9H12Br2N2 (M+) 305.9367. found 305.9366.