Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:27][CH:28]([F:38])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl>C(Cl)Cl.CN(C=O)C>[F:27][CH:28]([F:38])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([NH:34][C:4](=[O:6])[C:3]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(OCC(F)F)c1
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccc(OCC(F)F)c1)c1c(F)cccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
Under nitrogen, to 2-fluoro-6-nitrobenzoic acid (1.27 g, 6.28 mmol, 1.00 equiv) in CH2Cl2 (20 mL) at 23° C. was added oxalyl chloride (0.585 mL, 6.91 mmol, 1.10 equiv) and DMF (16 μL, 0.19 mmol, 3.0 mol %). After stirring for 1 hr at 23° C., the reaction mixture was cooled to 0° C. and triethylamine (2.63 mL, 18.8 mmol, 3.00 equiv) and 3-(2,2-difluoroethoxy)aniline (1.09 g, 6.28 mmol, 1.00 equiv) were added. After stirring for 15 min at 0° C., 3N HCl aq (50 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×3.0 mL). The combined organic phases were washed with brine (3.0 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 1.07 g of the title compound (50% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:20](CCC)([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:20]
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2ccc(Br)cc12
Yield: 64.9 %

Procedure:
Commercially available 5-bromoindole-3-carboxaldehyde (11.3 g, 50.4 mmol), ammonium hydrogen phosphate (47.0 g, 353 mmol), 1-nitropropane (4.49 g, 50.4 mmol), and glacial acetic acid (100 ml) were heated at a gentle reflux for 18 h. The resulting mixture was concentrated in vacuo and the residue mixed with 5 N sodium hydroxide (500 ml) and ice chips. The precipitate was collected by filtration and rinsed several times with water. The filtrate was concentrated in vacuo to afford 5-bromo-3-cyanoindole (7.23 g, 65%) as a dark solid. 1H-NMR (400 MHz, CDCl3) δ 10.0 (1H, s), 8.68 (1H, br s), 8.51 (1H, s), 7.85 (1H, s), 7.43 (1H, dd, J=8.6, 1.9 Hz), 7.32 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(Cl)Cl.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(OC(=O)C)C.C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:23])=[CH:6][N:5]2[C:24]=1[CH3:25]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)N2CCOCC2)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.44 mmol) were added to methylene chloride (10 ml). Morpholine (0.12 g, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was added to a column with silica gel and purification by chromatography using ethylacetate:methylene chloride (1:1) as eluent gave 0.12 g (66%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH:22]1[CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH:22]2[O:23][CH2:24]2)=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1cc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(OCC2CO2)ccc1OCc1ccccc1

Procedure:
Then, using 6.07 g of the compound of Example 18 above, 4.0 ml of chloromethyloxirane, 3.26 g of anhydrous potassium carbonate and 100 ml of methyl methyl ketone, reaction and workup carried out as in 1-A gave about 8.00 g of 1-(4-benzyloxy-3-tert-butylphenoxy)-2,3-epoxypropane as brown oil. Using the epoxy compound thus obtained, 4.82 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by recrystallization from isopropyl ether gave 6.48 g of white crystals, m.p. 133-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si](C)(C)C)=[CH:17][C:16]=1[F:25])[C:10](=[O:26])[NH:9][CH2:8]2)=[O:4].[I:27]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:27])=[CH:17][C:16]=1[F:25])[C:10](=[O:26])[NH:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1cc2c(cc1Nc1ccc([Si](C)(C)C)cc1F)C(=O)NC2
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1Nc1ccc(I)cc1F)C(=O)NC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
To a solution of 6-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (284 mg, 0.76 mmol) in DCM (5 ml) at 0° C. was added a solution of iodine monochloride (246 mg, 1.52 mmol) in DCM (1.5 mL). The reaction mixture was stirred at 0° C. for 4 hours. The reaction was quenched by the addition of water (10 mL) then diluted with saturated aqueous sodium thiosulfate solution (10 mL). The resultant mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-7% methanol in DCM) to yield the title compound as a brown solid (220 mg, 68%). LCMS (Method B): RT=3.65 min, 2M+H+=853.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C:14](=[O:15])[C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([Mg]Br)#[CH:36]>C1COCC1>[C:1]([O:9][C@@H:10]1[C@:14]([C:35]#[CH:36])([OH:15])[C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)C(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
Alternatively, the same procedure as that described in step 2 can be used, except that the reaction temperature is −30° C. and the reaction time is 3 hours, using (2R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-dihydrofuran-3-one (1.0 g, 2.17 mmol, 1.0 equiv.), 1M ethynylmagnesium bromide (13 ml, 6.51 mmol, 3 equiv.) CeCl3 (1.77 g, 7.16 mmol, 3.3 equiv.) and THF (18 ml), to give (2R,3R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-3-ethynyl-tetrahydrofuran-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:25]([NH2:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[CH3:29][C:30]1[NH:34][N:33]=[C:32]([C:35](O)=[O:36])[CH:31]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C@H:25]([NH:26][C:35]([C:32]4[CH:31]=[C:30]([CH3:29])[NH:34][N:33]=4)=[O:36])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C(=O)N[C@@H]2CC(C)(C)Oc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc32)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Step B (300 mg, 0.69 mmol), 5-methylpyrazole-3-carboxylic acid (105 mg, 0.83 mmol), PyBOP (540 mg, 1.04 mmol), and NEt3 (0.19 mL, 1.38 mmol) in 20 mL of CH2Cl2 was stirred at rt. After 16 h, the reaction mixture was diluted with Et2O (50 mL), washed with saturated aq NaHCO3 (3×50 mL) and brine (3×50 mL). The organic layer was separated, dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 1:1 v/v EtOAc/Hexanes as the eluant afforded the title compound: 1H NMR δ 1.44 (s, 3H), 1.51 (s, 3H), 1.94 (t, J=12.5, 1H), 2.26-2.30 (m, 4H), 5.62 (m, 1H), 6.58 (s, 1H), 6.96 (d, J=8.5, 2H), 7.12-7.29 (m, 5H), 7.69 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCOCC.CCCCC>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: O=C1Cc2ccccc2N1Cc1ccccc1
Temperature: 125 °C
Yield: 78.2 %

Procedure:
N-benzylisatin (13.0 g, 55 mmol) was mixed with hydrazine hydrate (60 mL) and placed in an oil bath. The mixture was heated in stages to 125° C., becoming first a green sludge, then yellow with clumps of a sticky solid. After a total of 5 h at 125° C., the mixture was cooled and extracted with EtOAc (2×100 mL). The combined organic portions were washed twice with 1.0 M aq. H2SO4, and once each with half-saturated brine then brine, dried over MgSO4, filtered and concentrated to afford a pale yellow solid. Re-precipitation from ether/pentane gave the title compound as an off-white solid (9.6 g, 75%). Spectral data matches literature values (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.[Si]([C:14]#[N:15])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]#[N:15])[CH:4]=1
Reactant: COc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
To a stirring mixture of 1.2 g (9.67 mmol) of 4-methoxypyridine-N-oxide in 18 mL of CH2Cl2 at r.t. was added 1.6 mL (12.0 mmol) of TMSCN. After 5 min. 0.9 mL (9.8 mmol) of dimethylcarbamoyl chloride. The solution was stirred at r.t. for 13 h and CHCl3 and 20 mL of 10% K2CO3 was added. The aqueous layer was extracted with CHCl3 3 times, and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (38-44% EtOAc/hexanes) provided 949 mg of 4-methoxypicolinonitrile as a colorless solid in 73% yield.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([NH:12][C:13]2[C:14]([N:19]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]3=[O:26])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:27]1COCC1>C(OCC)(=O)C.O>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][N:19]([C:14]2[C:13]([NH:12][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([OH:3])([CH3:27])[CH3:2])[N:9]=3)=[O:11])=[CH:17][N:16]([CH3:18])[N:15]=2)[C:20]1=[O:26]
Reactant: CC(=O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(NC(=O)c2cccc(C(C)(C)O)n2)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-acetyl-N-(3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide (35 mg) and THF (3.0 mL) was added 3M methylmagnesium bromide diethyl ether solution (0.33 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with ethyl acetate, and water was added thereto. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (14 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+].[OH2:24]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:19])=[O:24])=[CH:11][N:10]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(-c2ccccc2C(F)(F)F)nc1
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)nc1

Procedure:
A suspension of 2-(2-Trifluoromethylphenyl)-5-methylpyridine (0.40 g, 1.68 mmol) and potassium permanganate (1.60 g, 10.1 mmol), in water (10 mL) was heated at reflux for 16 hours. The reaction was filtered hot through celite to remove the solids. Acetic acid was added to the colourless filtrate to yield a pH of 5 and the resulting suspension was extracted with CH2Cl2, washed with water (10 mL), dried, (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.O>ClCCl>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:31]([NH:14][C:10]2[CH2:11][O:12][CH2:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)([CH3:15])[N:9]=2)([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:43][CH:42]=1
Reactant: CC1(c2cccc(Br)c2)COCC(N)=N1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=NC(C)(c3cccc(Br)c3)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of (RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (3.7 g, 13.8 mmol) and triethylamine (1.5 g, 1.1 eq) in dichloromethane (20 ml) was cooled to 0° C. and 4,4′-dimethoxytriphenylmethyl chloride (5.12 g, 1.1 eq) was added. The reaction mixture was stirred at room temperature overnight. Thereafter, water was added to the mixture and the organic phase was separated, dried over sodium sulphate and concentrated at reduced pressure. The crude was purified by chromatography on silica gel to yield the (RS)-[bis-(4-methoxy-phenyl)-phenyl-methyl]-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine as a yellow oil (7.0 g, 99%). Mass (calculated) C3H31BrN2O3 [571.52]; (found) [M+H]+=571.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[S:11][C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C.O.C(OCC)C>[Cl:20][C:19]1[C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[C:18]=1[Cl:21]
Reactant: CCOC(=O)COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C)Cc1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Yield: 93.7 %

Procedure:
To 9.6 g of ethyl[ (6,7-dichloro-2-isobutylbenzo[b]thien-5-yl)oxy]acetate in 75 ml of 95% ethanol is added 175 ml of a 6 N sodium hydroxide solution and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated in vacuo to give a slurry which is diluted with 500 ml of water and 500 ml of diethyl ether. With stirring and cooling, the mixture is acidified with 6 N hydrochloric acid. The acidic mixture is extracted with diethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the solid from diethyl ether and hexane gives 8.3 g of [(6,7-dichloro-2-isobutylbenzo[b]thien-5-yl)oxy]acetic acid, mp 164°-165°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1>ClCCl.CCOCC>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][O:17][C:19](=[O:21])[CH3:20])[CH2:12][CH2:11]1)=[O:18])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC[C@H]1CC[C@H](CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1CC[C@H](CCNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 27.9 g (86.7 mmol) trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-carbamic acid tert-butyl ester, 41 ml (434 mmol) acetic anhydride and 35 ml (434 mmol) of pyridine in 140 ml of dichloromethane was stirred at room temperature for 16 hours. The reaction-mixture was then taken up in ether and washed with 1N hydrogen chloride solution, sodium hydrogen carbonate solution and water. Then, the ether-phase was dried over magnesium sulfate and concentrated to yield 26.0 g crude trans-acetic acid 4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester as colorless viscous oil, MS: 200 [(M-(tert-butoxycarbonyl))H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)(=[O:10])=[O:9])[CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[S:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:10]
Reactant: NCc1cccc(F)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Product: O=C(NCc1cccc(F)c1)c1ccccc1S(=O)(=O)Nc1cccnc1
Yield: 84 %

Procedure:
The title compound was prepared according to procedures described above, using methyl 2-[(pyridin-3-ylamino)sulfonyl]benzoate and 3-fluorobenzylamine. The title compound was further purified by dissolving 25 g in EtOH (300 mL) and gently heating using water bath to 80° C. The resulting solids material were then slowly dissolved and more EtOH (50 mL) was added to completely dissolve all the solids. The solution left at room temperature to crystallize for 1 h. The resulting crystals were collected and dried under high vacuum for 16 h to afford the title compound as a crystalline solid (21 g, 84%). 1H NMR (400 MHz, DMSO-D6) δ 9.76 (s, 1H) 9.32 (t, 1H) 8.31 (d, 1H) 8.25 (d, 1H) 7.66-7.78 (m, 2H) 7.50-7.65 (m, 3H) 7.39 (q, 1H) 7.23-7.29 (m, 3H) 7.09 (t, 1H) 4.54 (d, 2H).
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1SC(Cc2ccc(OCCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCCc3cn4ccccc4n3)cc2)S1

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 0.94 g of 5-[4-{2-(imidazo[1,2-a]pyridin-2-yl)ethoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 27), 4 ml of methylene chloride and 1 ml of trifluoroacetic acid were used, to give the title compound as a crude product. This product was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate and subsequently a 1:2 by volume mixture of ethyl acetate and tetrahydrofuran, as the eluents, to give 287 mg of the title compound, melting at 205.9-207.0° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1
Yield: 78 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-trifluoromethyl-phenylamine provided the title compound (78% yield). 1H NMR (DMSO-d6) δ 1.40 (t, 3H, J=6.9 Hz, CH3), 4.15 (q, 2H, J=6.9 Hz, CH2), 6.45 (s, 2H, NH2), 6.84 (s, 1H, Ar), 7.16 (d, 1H, J=8.9 Hz, Ar), 7.43 (dd, 1H, J=8.8 Hz, 2.8 Hz, Ar), 7.61 (d, 2H, J=8.9 Hz, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar), 7.99 (d, 2H, J=8.9 Hz), 9.59 (s, 1H, NH).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10](C)=[C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:8]=[C:7]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[N:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:9]1[N:8]=[C:7]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1nc(-c2cncc(C(F)(F)F)c2)nc(NCc2ccc(F)cc2F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(NCc2ccc(F)cc2F)nc(-c2cncc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.44 %

Procedure:
A solution of methyl 6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid methyl ester (1 g, 0.0023 mol) in THF (10 ml), MeOH (10 ml) and H2O (10 ml) was added LiOH (0.198 g, 0.0047 mol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuum, reaction mass was diluted with water and neutralized with 5% citric acid solution. The obtained precipitate was filtered and washed with water, dried well under vacuum to get the title compound as a white solid.
Reaction SMILES: [C:1](SC#N)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1.[S-:21][C:22]#[N:23].[NH4+].[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[Cl:35]>CC(C)=O.CC#N>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:22]([NH:23][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[S:21])=[CH:30][C:29]=1[Cl:35]
Reactant: N#CSC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(NC(=S)NC(=O)c2ccccc2)cc1Cl

Procedure:
Benzoyl thiocyanate was generated by refluxing a solution of benzoyl chloride (0.31 mL) and ammonium thiocyanate (0.20 g) in acetone (15 mL) for 30 min. To this solution was added a solution of 4-amino-2-chlorobenzoic acid methyl ester (0.5 g) in CH3CN (10 mL) and the mixture was refluxed for 5 h. The solvent was removed and the residue was partitioned between CH2Cl2 and water. The organic layer was separated, washed with brine, dried and evaporated. The residue was purified by column chromatography to yield 2-chloro-4-(3-benzoylthioureido)benzoic acid methyl ester (0.71 g). ESMS: 349 (MH+).