Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:16]([O:25][CH3:26])([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.CC(O)=[O:38].[N+](=C)=[N-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:16]([O:25][CH3:26])([CH2:18][C@@H:19]([OH:38])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:28])[CH3:29])[CH:11]=[C:10]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: COC(=O)CCCP(=O)(C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
A mixture of (S)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-butanoic acid, methyl ester (750 mg, 1.00 mmol) tetra-n-butylammonium fluoride (1.0M in THF, 3.50 mmol), and HOAc (330 mg, 5.50 mmol) in THF (12 ml) was stirred at room temperature for 15 hours. The solution was partitioned between 5% KHSO4 and EtOAc. The layers were shaken and separated and the EtOAc layer was washed again with 5% KHSO4. The pooled aqueous washings were back-extracted twice with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration and removal the solvent afforded a yellow oil. The oil was dissolved in Et2O and treated with excess diazomethane for 20 minutes. The excess diazomethane was destroyed by the addition of HOAc and the solvent was removed in vacuo. The residue was chromatographed (flash, Merck SiO2, 40% acetone in hexane followed by 1:1 acetone:hexane) to afford (S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (446 mg, 88%) as a colorless oil.
Reaction SMILES: C(OC1C=C2C(C=C(Br)CC2)=CC=1)C1C=CC=CC=1.BrC1C=C(OC)C=CC=1[N+]([O-])=O.C([O:39][C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[C:45]([C:50]3[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=3[N+:58]([O-])=O)[CH2:46][CH2:47]2)=[CH:42][CH:41]=1)C1C=CC=CC=1>>[NH2:58][C:51]1[CH:52]=[CH:53][C:54]([O:56][CH3:57])=[CH:55][C:50]=1[CH:45]1[CH2:46][CH2:47][C:48]2[CH:49]=[C:40]([OH:39])[CH:41]=[CH:42][C:43]=2[CH2:44]1
Reactant: COc1ccc([N+](=O)[O-])c(C2=Cc3ccc(OCc4ccccc4)cc3CC2)c1
Agent: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: COc1ccc([N+](=O)[O-])c(Br)c1
Product: COc1ccc(N)c(C2CCc3cc(O)ccc3C2)c1
Yield: 67.7 %

Procedure:
To a solution of 3-bromo-4-nitrophenol (4.1 g) in N,N-dimethylformamide (40 ml) were sequentially added cesium carbonate (9.2 g) and methyl iodide (1.5 ml), and the solution was stirred overnight at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-bromo-4-methoxy-1-nitrobenzene (4.1 g). Synthesized from 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-4-methoxy-1-nitrobenzene according to an analogous synthetic method to Preparation Example 107, 7-benzyloxy-3-(5-methoxy-2-nitrophenyl)-1,2-dihydronaphthalene (3.4 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (1.6 g).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:22][CH2:23][CH2:24][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8]3.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br>O1CCCC1>[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47][CH:14]([CH2:13][N:10]1[CH2:11][CH2:12][C:7]2([C:5]3[S:6][C:2]([F:1])=[CH:3][C:4]=3[CH2:24][CH2:23][O:22]2)[CH2:8][CH2:9]1)[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)CCN1CCC2(CC1)OCCc1cc(F)sc12
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccccc1F)CN1CCC2(CC1)OCCc1cc(F)sc12
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a stirred solution of tert-butyl 3-(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)propanoate (4.9 g, 13.78 mmol) in tetrahydrofuran (41 mL) under N2 and cooled to −78° C., lithium bis(trimethylsilyl)amide 1M (41.35 mL, 41.45 mmol) is added dropwise. The resulting mixture is stirred at that temperature for 3 hours. Then, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.33 mL, 11.03 mmol) is added, and the resulting solution is stirred at the same temperature for 30 min. To the resulting mixture, 2-fluorobenzyl bromide (2.33 mL, 19.3 mmol) in dry tetrahydrofuran (1 mL) is added and stirring is continued. The temperature is allowed to go from −78° C. to room temperature overnight. The crude reaction mixture is quenched with aqueous saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer is decanted, dried over magnesium sulfate, the solvent is evaporated and the crude obtained is purified by normal phase Isco chromatography using ethyl acetate/hexane from 5/95 to 20/80 to yield 5.06 g of the title compound obtained as colorless oil. MS (m/z): 464 (M+1).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22](O)=[O:23].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:14]3[O:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzofuran-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.29-7.38 (m, 1H), 7.44-7.52 (m, 1H), 7.57 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H). MS (DCI/NH3) m/z 297. Anal. Calculated for C18H20N2O2HCl: C, 64.96; H, 6.36; N, 8.42. Found: C, 64.51; H, 6.23; N, 8.14.
Reaction SMILES: [N+]([C:4]1C=C(N)C=C[C:5]=1C(O)=O)([O-])=O.[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([OH:19])=[O:18].C(O)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([O:19][CH2:4][CH3:5])=[O:18]
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1c(F)c(F)c(N)c(F)c1F

Procedure:
Thus, in accordance with Reaction Scheme 6, 3-nitro-6-methyl-fluorobenzene (Aldrich) is subjected to oxidation, conversion of the resulting carboxylic acid to an acid chloride and thereafter to an ethyl ester, followed by reduction of the nitro group, to yield ethyl 2-fluoro-4-amino-benzoate (Compound C1)- 3-Nitro-6-methyl-bromobenzene (Aldrich) and 3-nitro-6-methyl-chlorobenzene (Aldrich) are subjected to essentially to the same series of reactions to yield ethyl 2-bromo-4-amino-benzoate (Compound D1) and ethyl 2-chloro-4-amino-benzoate (Compound E1), respectively. 2-Nitro-4-aminobenzoic acid (Research Plus) is converted to its methyl ester (Compound F1) through the corresponding acid chloride. 2,3,5,6-Tetrafluoro-4-amino-benzoic acid (Aldrich) is esterified by treatment with ethanol in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine in CH2Cl2 to give ethyl 2,3,5,6-tetrafluoro-4-amino-benzoate (Compound G1). 2,4,6-Trifluorobenzoic acid (Aldrich) is converted to the methyl ester through the acid chloride, and the 4-fluoro atom is displaced by reaction with sodium azide, followed by hydrogenation, to yield methyl 2,6-difluoro-4-amino benzoate (Compound H1). Compounds C1, D1, E1, F1, G1 and H1 serve as amine reagents in accordance with Formula 3. Further examples of reagents in accordance with Formula 3 are nitro, fluoro, chloro, bromo and trifluoromethyl derivatives of amino substituted heteroaryl carboxylic acids, or their lower alkyl esters, such as ethyl 2-amino-4-chloropyridine 2-carboxylate, ethyl 5-amino-3-chloropyridine 5-carboxylate, and 3,4-dibromo-5-aminothiophene-2-carboxylic acid. The latter examples can be prepared by respective chlorination or bromination of 2-aminopyridine-5-carboxylic acid or of its ester, 3-aminopyridine-6-carboxylic acid or of its ester (described in WO 93/06086) and of 2-aminothiophene-5-carboxylic acid (described in PCT/US92/06485).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:19])=[O:18]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccsc1

Procedure:
The 2-(3-thienyl)ethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](Br)[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C([O-])=O)C=CO1)#[N:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:9]1[C:10]([O:13][CH3:14])=[N:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1)#[N:17]
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Reactant: COc1ncc(-c2ccccn2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc(-c2ccccn2)cc1-c1ccccc1C#N
Temperature: 140 °C
Reaction time: 5 h

Procedure:
Tetrakistriphenylphosphine palladium (0.15 g) was added to a mixed solution of 0.50 g of 5-(2-pyridyl)-3-bromo-2-methoxypyridine, 0.42 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 0.82 g of cesium carbonate and 20 ml of dimethylformamide and the mixture was stirred at 140° C. in a nitrogen atmosphere for 5 hours. After cooling to room temperature, ethyl acetate was added thereto, the mixture was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3) to give 0.36 of the title compound as pale yellow powder.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=[C:25]=[O:26])CCCCC.N12CCN(CC1)CC2.ClC(OC(Cl)(Cl)Cl)=O>C1(C)C(C)=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:25]=[O:26])(=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1Oc1ccccc1
Reactant: CCCCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1Oc1ccccc1
Yield: 82.6 %

Procedure:
25.0 g of 2-phenoxyphenylsulfonamide, 14.0 g of n-hexyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 150 ml xylene were refluxed with stirring for an hour. Thereafter, the mixture was reacted with a solution of 11.9 g of trichloromethyl chloroformate in 30 ml of xylene in a manner similar to that of Example (1). At the end of the reaction, the xylene and n-hexyl isocyanate were distilled off, to obtain 22.8 g of 2-phenoxyphenylsulfonylisocyanate. B.p. 146°-150° C./0.7 mmHg.
Reaction SMILES: Cl.O=[C:3]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)[CH:4]([CH3:9])[CH2:5][C:6](O)=[O:7].O.[NH2:20][NH2:21]>C(O)C>[CH3:9][CH:4]1[C:3]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)=[N:21][NH:20][C:6](=[O:7])[CH2:5]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)CCN2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)CCN2

Procedure:
A solution of 27 g of 4-oxo-4-(indolin-5-yl)-3-methylbutanoic acid hydrochloride and 15 ml of hydrazine hydrate in 200 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off, washed with water and recrystallized from ethanol to give 20 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline as white crystals, melting at 187°-189° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].[H-].[Na+].C1[CH2:20][O:19][CH2:18]C1>O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:18][O:19][CH3:20])[CH:7]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cccc(OCOC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (3-Hydroxy-phenyl)-acetic acid ethyl ester (27.6 g) in THF was added NaH (7.35 g), MOM-CI (14.8 g) slowly at 0°. After stirred for 14 h at the same temperature, the reaction mixture was warmed to room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=15:1 to 10:1) to afford the product as colorless oil. (31.2 g, 90.9%)
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:8][OH:9])[CH2:6][O:7][CH2:13][O:5][CH2:4]1)[CH3:2]
Reactant: CCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(CO)COCOC1
Reaction time: 3 h

Procedure:
In a one-liter three neck flask were placed 405 grams of 2-ethyl-2-hydroxymethyl-1,3-propanediol, 90 grams of paraformaldehyde, 0.9 grams of p-toluene sulfonic acid monohydrate and 150 ml of toluene. The flask was equipped with a Dean-stark trap and a condenser. The reaction mixture was stirred at a bath temperature of 120° C. to 170° C. for three hours. The toluene-water was collected, and after removing the toluene, the crude product was distilled under vacuum at 10-11 mm Hg and 115° C. to 117° C. 410 grams of 5-ethyl-5-hydroxymethyl-1,3-dioxane (EHMDO) were collected. The product was then dried by molecular sieve and had a water content of about 350 ppm. NMR spectra confirmed that EHMDO was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[C:14]([OH:18])(=[O:17])[CH:15]=[O:16].C(=O)(O)[O-].[Na+].C(=O)(O)[O-].S(=O)(=O)(O)[O-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:15]([OH:16])[C:14]([OH:18])=[O:17])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=CC(=O)O
Reactant: NC(=O)Cc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1cc(F)cc(F)c1)NC(O)C(=O)O

Procedure:
A mixture of 7.2 g of (3,5-difluorophenyl)acetamide 1 and 4.6 g of glyoxylic acid hydrate in 75 mL of acetone was refluxed 24 hours. The solvent was evaporated and the residue was dissolved in 300 mL of ethyl acetate. This solution washed with 150 mL of distilled water. The aqueous phase was discarded. The organic phase was extracted with a solution prepared by diluting 50 mL of a saturated aqueous solution of sodium bicarbonate with 150 mL of distilled water. The organic phase was discarded and the aqueous bicarbonate solution was acidified with 80 mL of 1 N aqueous sodium bisulfate solution. The acidified solution was extracted with three successive 125 mL portions of ethyl acetate. The combined organic extracts were washed with brine and then dried over magnesium sulfate. The solution was filtered and the solvent was evaporated to yield 2-[(3,5-difluorophenyl)acetylamino]-2-hydroxyacetic acid as 5.2 g of a white solid. 1H-NMR (DMSO-d6): δ 8.95 (d, J=8 Hz, 1H), 7.15-6.90 (m, 3H), 5.37 (d, J=8 Hz, 1H), 3.50 (s, 2H). 13C-NMR (DMSO-d66) δ 171.5, 169.4, 162.4 (dd, JC-F=13, 244 Hz), 140.6 (t, JC-F=10 Hz), 112.6 (dd, JC-F=8, 17 Hz), 71.5, 41.7. MS (CI+): m/z 246. EA Calc'd for C10H9F2NO4: C, 48.98; H, 3.71; N, 5.71. Found: C, 49.02; H, 3.72; N, 5.51.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:24]#[C:25][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Add copper (I) iodide (45.0 mg, 0.24 mmol), bis(triphenylphosphine)palladium (II) dichloride (147.4 m g, 0.21 mmol) and triethylamine (2.37 mL, 16.8 mmol), to a solution of 1-bromo-3-trifluoromethoxybenzene (0.62 mL, 4.15 mmol) and trimethylsilylacetylene (0.78 mL, 5.4 mmol), in ethyl acetate (4 mL) and stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify by silica gel chromatography, eluting with hexanes to give the title compound (1.07 g, 100%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:6]=1[CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:15]=2[N:16]=1>C(O)(=O)C.CO>[Cl:4][C:5]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:6]=1[CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([O:2][CH3:1])[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:15]=2[N:16]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To solution of NaOMe (15 mg, 0.3 mmol) and MeOH (1.5 mL) was added [2-(2,6-dichloro-benzyl)-5-methanesulfonyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (25 mg, 0.05 mmol) and the resulting mixture was heated to 60° C. After 4 h, the resulting solution was acidified with 1 drop of acetic acid and purified directly by reverse phase HPLC to afford a colorless solid (10.3 mg, 45%). MS (ESI): mass calcd. for C20H13Cl2F3N4OS, 484.0; m/z found, 485.0 [M+H]+. 1H NMR (CDCl3): 8.01 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.30-7.25 (m, 1H), 4.74 (s, 2H), 4.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=O.Cl.[NH2:12][OH:13]>C(O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1cncc(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: ON=Cc1cncc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
A solution of 4,5-dichloropyridine-3-carbaldehyde (8.01 g, 45.51 mmol) in ethanol (50 ml) was added to a rapidly stirred solution of hydroxylamine hydrochloride (3.48 g, 50.06 mmol) in water (50 ml). The reaction was stirred at room temperature for 45 min then partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic layers were dried over magnesium sulfate before being concentrated in vacuo to afford the title compound as a white solid (8.3 g, 96%).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:33]3[CH2:35][CH2:34]3)=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:36])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH:33]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[N:19]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3cccc(C(F)(F)F)c3)nc2C2CC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCc2cnc(-c3cccc(C(F)(F)F)c3)nc2C2CC2)ccc1OC(C)(C)C(=O)O
Reaction time: 7 h

Procedure:
0.240 g (0.466 mmol) of the above prepared 2-{4-[4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 2.8 ml of THF/EtOH=1/1, treated with 1.40 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 7 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded finally 0.196 g of the title compound as white solid of mp. 175–176° C.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[CH:11]1([NH:17][C:18]([NH2:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[CH:11]1([NH:17][C:18]([NH:20][C:2]2[CH2:3][S:4][CH2:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=O)NC1CCCCC1
Reactant: COC(=O)C1CSCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)C1=C(NC(=O)NC2CCCCC2)CSC1

Procedure:
15.1 parts by weight of methyl 3-keto-1,5-dihydrothiophene-4-carboxylate, 14.2 parts by weight of cyclohexylurea and 0.5 part by weight of p-toluenesulfonic acid in 100 parts by weight of xylene were refluxed for 4 hours in an apparatus equipped with a water separator. The mixture was cooled, and the residue was then filtered off under suction and recrystallized from toluene. 20.3 parts by weight of N-cyclohexyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 154°-155° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:3]=2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(Cl)nc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OC1CCCC1
Temperature: 69 °C
Yield: 100.3 %

Procedure:
To a mixture of 6-chloro-2-cyclopentyloxy-nicotinonitrile (1.32 g, 5.92 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.43 g, 7.10 mmol) in DMF (10 mL) was added potassium carbonate (1.22 g, 8.88 mmol). The resulting mixture was heated at 69° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give white solid, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (2.30 g, quantitative) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1 H), 8.24 (d, J=8.2 Hz, 1 H), 7.88 (d, J=8.6 Hz, 1 H), 7.70 (s, 1 H), 7.60-7.46 (m, 1 H), 6.79 (d, J=8.2 Hz, 1 H), 4.95 (br. s., 1 H), 1.87-1.50 (m, 6 H), 1.52-1.30 (m, 2 H).