Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[N:13]=1.C(Cl)Cl>C(OCC)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:13][C:12]=2[CH:14]=1
Reactant: COC(=O)N=C=O
Reactant: Nc1nc2cc(Cl)ccc2s1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
One part by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution of 2 parts by weight of 2-amino-5-chlorobenzothiazole in 100 parts by weight of methylene chloride and 50 parts by weight of ethyl ether. After stirring the reaction mixture at room temperature overnight, a product was isolated by filtration giving an 85% yield of methyl 4-(5-chlorobenzothiazol-2-yl)allophanate having a melting point of 395°.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH2:11][CH3:12])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:7]2[N:23]=[CH:24][C:25]([C:26]#[N:27])=[C:6]12)=[O:4].[CH2:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:36][CH2:37]2)[C:6]2[N:7]([N:23]=[CH:24][C:25]=2[C:26]#[N:27])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=1)[CH3:12]
Reactant: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3)CC2)C1

Procedure:
A mixture of 3.8 g of 4-chloroacetyl-4,5-dihydro6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.8 ml of 1-benzyl piperazine and 1.1 g of sodium carbonate in 128 ml of toluene was reacted as described in Example 146, giving 3.7 g of the desired product, mp 97°-99° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11]C(OCC)C.C([Li])CCC.C[O:23][B:24](OC)OC.Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[B:24]([OH:23])[O:11][CH2:10][C:3]=2[CH:4]=1
Reactant: COB(OC)OC
Reactant: CCOC(C)OCc1cc(OC)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)COB2O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-methoxy-benzene (3.0 g, 10.3 mmol)in THF (100 mL) and cool to −78° C. Add 2.5M butyllithium in hexanes (4.6 mL, 11.4 mmol), dropwise and stir for 15 min. Add trimethylborate (2.1 g, 20.6 mmol) to the reaction mixture and warm to room temperature. Add 1N HCl (100 mL) and stir at room temperature for 2 hours. Extract three times with methylene chloride, dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo to yield a crude product. Triturate with methylene chloride/hexanes to yield 680 mg (40%) of the title compound. 1H NMR (CDCl3) δ 7.65 (d, J=8.2 Hz, 1H), 6.93 (dd, J=8.2, 2.1 Hz, 1H), 6.85 (d, J=1.4 Hz, 1H), 5.06 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:24]=[CH:23][C:12]2[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:16]O)=[N:15][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:28])=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:24]=[CH:23][C:12]2[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:16][Cl:28])=[N:15][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCn1c(CO)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)CCn1c(CCl)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of [2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (146 mg, 0.42 mmol) in DCM (5 mL) was added thionyl chloride (46 μL, 0.63 mmol). The solution was stirred at 0° C. for 15 min. and concentrated in vacuo to give [2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester; HCl salt (176 mg, 100%) as a white solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(F)c2ccccc12
Reaction time: 72 h
Yield: 48.4 %

Procedure:
21.7 g of 4-Fluoro-naphthalen-1-ol were dissolved in 250 ml acetone. 39.0 g of potassium carbonate and 14.6 ml dimethyl sulfate were added at room temperature. The reaction was placed under nitrogen and stirred for 72 h. The mixture was filtrated, the solid washed with acetone, and the filtrate was concentrated to a viscous oil, which was taken up in ethyl acetate. This was washed with water and with brine, dried over sodium sulfate, filtered through celite and concentrated. The resulting oil was distilled using a Kugelrohr-apparatus, yielding 11.4 g of 4-fluoro-1-methoxynaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([OH:14])=[O:13].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([C:12]([O:14][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:3][CH:4]=2)=[O:13])=[N:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2[nH]nc(C(=O)O)c2c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C(=O)OCc1ccccc1)nn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A suspension of 5-methoxy-1H-indazole-3-carboxylic acid (21.5 g; 0.11 mol) and 60% NaH (10.5 g; 0.44 mol) in N,N-dimethylformamide (DMF) (200 ml) was stirred at 70° C. for 1 hour. Benzyl chloride (32.9 g; 0.26 mol) was then added slowly to the suspension and the mixture was stirred at 70° C. for 4 hours. The reaction was stopped by cooling the mixture to room temperature and pouring the mixture into water and ice. The product was extracted with ethyl acetate (3×250 ml). The combined organic phases were concentrated under reduced pressure. The crude residue thus obtained was purified by successive crystallizations from 95° ethanol, to give 18 g of benzyl 1-benzyl-5-methoxy-1H-indazole-3-carboxylate with a melting point of 107-109° C.
Reaction SMILES: [CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:20][C:9](=[O:11])/[C:8](=[N:7]/[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: O=C(O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 67 %

Procedure:
(E)-Cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid (prepared as in Example 18, 100 mg, 0.33 mmol), 2-aminobenzothiazole (50 mg 0.33 mmol) and N,N-diisopropylethylamine (173 μL, 0.99 mmol) were combined in methylene chloride (1.6 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-cyclopentyloxyimino-2-(3,4-dichloro-phenyl)-acetamide (96 mg, 67%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H17Cl2N3O2S [M+] 433.04, found 434 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 4.93 (m, 1 H, OCH), 7.34 (ddd, Jo=8.0, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.40 (dd, Jo=8.4, Jm=2.0 Hz, 1 H, Ar), 7.47 (ddd, Jo=8.3, Jo=7.3, Jm=1.3 Hz, 1 H, Ar), 7.53 (d, Jo=8.4 Hz, 1 H, Ar), 7.67 (d, Jm=2.0 Hz, 1 H, Ar), 7.83 (m, 2H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: [F:1][C:2]1([F:29])[CH:10]([F:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[C:3]21[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=O)[NH:15][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[N:13]2.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:16]1[NH:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:13][C:3]2([C:4]3[C:9](=[CH:8][C:7]([F:12])=[CH:6][CH:5]=3)[CH:10]([F:11])[C:2]2([F:29])[F:1])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C1C(=O)NC(c2ccccn2)=NC12c1ccc(F)cc1C(F)C2(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)C1=C(Cl)NC(c2ccccn2)=NC12c1ccc(F)cc1C(F)C2(F)F
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Compound 165 (10.2 g, 23.1 mmol), pyridine-2-carboximidamide hydrochloride (6.37 g, 40.4 mmol), sodium bicarbonate (7.76 g, 92.4 mmol) and dioxane (200 mL) were heated and stirred at 60° C. during 6 hours and stirred further overnight at 40° C. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were combined and concentrated yielding methyl 2,2,3,5-tetrafluoro-6′-oxo-2′-(pyridin-2-yl)-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidine]-5′-carboxylate (6.1 g) as a light yellow amorphous powder. A solution of methyl 2′,2′,3′,5′-tetrafluoro-6-oxo-2-(2-pyridyl)spiro[1,5-dihydropyrimidine-4,1′-indane]-5-carboxylate in phosphorus oxychloride (50 g) equipped with a CaCl2 drying tube was heated at 110° C. during 210 minutes. The reaction mixture was concentrated, the residue dissolved in CH2Cl2 (200 mL), poured in saturated NaHCO3 (200 mL) solution and stirred 30 minutes. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. methyl 6′-chloro-2,2,3,5-tetrafluoro-2′-(pyridin-2-yl)-2,3-dihydro-1′H-spiro[indene-1,4′-pyrimidine]-5′-carboxylate was isolated as two separate diastereoisomers: and compound 167A (1046 mg after second purification) and compound 167B (1705 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:15]([C:17]1[O:21][C:20]([C:22](Cl)=[O:23])=[CH:19][CH:18]=1)#[N:16].CCN(C(C)C)C(C)C>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([NH:8][C:22]([C:20]2[O:21][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N1CCCCC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)c2ccc(C#N)o2)c1N1CCCCC1
Yield: 12 %

Procedure:
Using a procedure similar to example 3, step (d), 3-methyl-2-piperidin-1-yl-phenylamine (68 mg, 0.35 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (65 mg, 0.42 mmol) in the presence of DIEA (134 μL, 0.77 mmol) to afford 13 mg (12%) of the title compound as a waxy yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 10.7 (br s, 1H), 8.33 (d, 1H, J=8.0 Hz), 7.27 (d, 1H, J=3.7 Hz), 7.22 (dd, 1H, 3.7 Hz), 7.12 (t, 1H, J=7.9 Hz), 6.87 (dd, 1H, J=0.7, 7.7 Hz), 3.22-3.28 (m, 2H), 2.88-2.91 (m, 1H), 2.41 (s, 3H), 2.01-2.04 (m, 1H), 1.80-1.86 (m, 4H), 1.43-1.47 (m, 1H); Mass spectrum (ESI, m/z): Calcd. for C18H19N3O2, 310.1 (M+H), found 310.2.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCOc1ccccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1ccccn1
Temperature: 90 °C
Yield: 7.4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.63 mmol), 2-(2-chloroethoxy)pyridine hydrochloride (120 mg, 0.61 mmol) and potassium carbonate (260 mg, 1.9 mmol) in DMF (25 ml) was heated at 90° C. for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol mixtures (100/0 increasing to 90/10) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)quinazoline (20 mg, 7%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 3.99(s, 3H); 4.35(t, 2H); 4.42(t, 2H); 6.22(t, 1H); 6.40(d, 1H); 7.42(s, 1H); 7.55(d, 2H); 7.71(d, 1H); 7.85(t, 1H); 8.55(d, 1H); 9.62(s, 1H) MS-ESI: 441 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cncc(F)c4)c3)c2cc1OC
Yield: 50.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (159 mg, 0.45 mmol), described in the previous step, to afford 1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (84 mg, 50%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 9H), 3.97-3.99 (m, 6H), 6.42 (s, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.34-7.40 (m, 2H), 7.54 (d, J=5.1 Hz, 2H), 7.98 (d, J=10 Hz, 1H), 8.55 (s, 1H), 8.61-8.71 (m, 3H), 9.24 (s, 1H); LC-MS (ESI) m/z 558 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:15]2[CH:52]=[CH:51][CH:50]=[CH:49][C:16]=2[CH2:17][CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[N:20]=2)[CH2:14][CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:39]1[CH2:40][CH2:41][CH:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:21]3[N:20]=[C:19]([CH2:18][CH2:17][C:16]4[CH:49]=[CH:50][CH:51]=[CH:52][C:15]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:14][CH2:13][CH2:12]4)[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=3)=[CH:35][CH:34]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CCC4)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of TFA (0.5 mL) and tert-butyl 4-(4-((4-(2-(1-carbamoylcyclobutyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A57 (6.0 mg, 9.6 μL) in DCM (5 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo before 2 M aq. NaOH (5 mL) was added to form a precipitate. The solid was collected by filtration and washed with cyclohexane (10 mL) to give the title compound 52 as a tan solid (1.5 mg, 30%). LCMS-A: rt 4.994 min; m/z 524.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[N:5][N:6]=1.[C:22]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:27])[CH2:23][C:24]([O-])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][C:22]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:27])=[N:6][N:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: CCCc1c(CSc2nnc(N)s2)ccc(C(C)=O)c1O
Reactant: COc1ccc(COC(=O)CC(=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(NC(=O)CC(=O)OCc3ccc(OC)cc3)s2)ccc(C(C)=O)c1O
Yield: 17.4 %

Procedure:
To a solution of 0.14 g of 2-amino-5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole obtained in Example 5 and 0.15 g of mono-p-methoxybenzyl malonate in 3 ml of pyridine were added 0.15 g of dicyclohexylcarbodiimide and a catalytic amount of p-toluenesulfonic acid. The resultant mixture was stirred at room temperature for 6 hours. During the stirring, 0.15 g each of mono-p-methoxybenzyl malonate and dicyclohexylcarbodiimide were supplemented to the system. After completion of the reaction, ethyl acetate was added to the system. After insoluble matters were filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform. The solution was washed with, in sequence, 1N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and water and then, dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The resultant residue was subjected to silica gel column chromatography followed by elution with a mixture of chloroform-methanol (4:1). The eluate was recrystallized from isopropyl alcohol to give 0.04 g of p-methoxybenzyl 3-[[ 5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-3-oxopropionate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=1)[C:25]#[N:26]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1C
Product: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 3,4-dimethyl-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:46][CH2:47]Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>CN(C=O)C>[C:41]([O:46][CH2:47][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.4 mmol) in DMF (1 mL) was added chloromethyl isobutyrate (34 mg, 0.25 mmol) at rt. The reaction was stirred at rt for 16 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as a white solid (45 mg, 37.5%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][Cl:22]>CC(C)=O>[Cl:22][CH2:21][CH2:20][O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=2[CH:11]=1
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCCCl)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.8 %

Procedure:
A suspension of 2-cyano-6-hydroxybenzothiazole (1.0 g, 5.68 mmol) in acetone (5 mL) was prepared in a 50-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (1.57 g, 11.3 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then 1-bromo-2-chloroethane (1.06 g, 0.56 mL, 7.38 mmol) was added by syringe and the reaction mixture was heated at reflux using a heated stir plate and oil bath. The reaction was monitored periodically by RP HPLC. After 5 hours the reaction appeared to be about 30% complete. Additional 1-bromo-2-chloroethane was added (2.84 mmol, 0.21 mL) and the reaction was refluxed overnight. HPLC analysis indicated the reaction was about 50% complete. Additional 1-bromo-2-chloroethane (2.84 mmol, 0.21 mL) and potassium carbonate (0.60 g, 4.37 mmol) were added and the reaction was refluxed for the rest of the day (about 7 h). The reaction was about 64% complete, and it was refluxed overnight. The next morning the reaction was found to be about 84% complete. Additional 1-bromo-2-chloroethane (2.84 mmol, 0.21 mL) and potassium carbonate (0.60 g, 4.37 mmol) were added and the reaction was refluxed for the rest of the day (about 7 h). At this point the reaction was about 92% complete. The reaction mixture was allowed to cool to room temperature and it was then filtered through glass fiber paper and rinsed with acetone. The filtrate was concentrated to give a yellow-brown solid. The crude solid (1.3 g) was purified on silica gel (100 g) using 4:1 heptane-ethyl acetate. Fractions containing product were pooled and concentrated to give 1.0 g (74%) of the desired product as an off-white solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.