Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:17]2[O:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O.C(Cl)(Cl)Cl>[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][O:7][C:8]3[C:17]4[O:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13](=[O:23])[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:37][CH:36]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)c1cc(=O)c2cccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2cccc(OCc3ccc(OCCCCc4ccccc4)cc3)c2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
A solution of potassium carbonate (330 mg, 2.39 mmol) in dry N,N-dimethylformamide (15 ml) was added with ethyl 8-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (520 mg, 2.39 mmol) stirring at room temperature for 10 min. After that the reaction mixture was added with 4-(4-phenylbutoxy)benzyl chloride 595 mg, 2.17 mmol) and left under stirring at 60° C. for 18 h, subsequently was added with water (25 ml), extracted with ethyl ether (3×50 ml), dried and the solvent was evaporated off under reduced pressure, to obtain a residue which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 7:3, recovering 740 mg of the title compound (66% yield).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([NH:48][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1csc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a stirred solution of 5-bromo-3-thiophenecarboxylic acid (0.50 g, 2.42 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (1.30 mL, 7.46 mmol), 1-hydroxybenzotriazole (0.49 g, 3.61 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g, 3.62 mmol). Benzylamine (0.26 mL, 2.41 mmol) was added 5 minutes later. The reaction mixture was stirred at ambient temperature for 16 h, then diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (25 mL), saturated aqueous sodium bicarbonate (2×25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound as a colorless solid (0.57 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=1.6 Hz, 1H), 7.37-7.31 (m, 6H), 6.14 (br s, 1H), 4.59 (d, J=5.7 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([F:30])[CH:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)C.C(C1OC(CCN)=NC=1)C.CC1OC(CCN)=NC=1.Cl.C(C1OC(CCN)=NC=1)C.NCC(O)CC.NCC(O)C>>[F:30][C:22]1[CH:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[O:7][C:3]([CH3:1])=[CH:4][N:5]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)o1
Agent: CC(O)CN
Agent: CCC(O)CN
Agent: CCc1cnc(CCN)o1
Product: Cc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)o1

Procedure:
The title compound is prepared by the same procedure as 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(5-methyl-oxazol-2-yl)ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2-yl)ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 1-amino-2-propanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH3:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.CN(C)[C:32](=O)[O:33]CC.[NH4+].[Cl-]>CCOCC.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:11]3[CH:12]=[C:13]([CH3:16])[S:14][C:15]=3[C:32](=[O:33])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N(C)C
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)cs1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc2c(s1)C(=O)c1cc(C(C)(C)C)ccc1-2
Temperature: -40 °C

Procedure:
A solution of 2.23 g (0.01 mol) of 4-[4-(tert-butyl)phenyl]-2-methylthiophene, 2.97 mL (0.02 mol) of TMEDA in 30 mL of ether was treated with 13 mL (0.02 mol) of 1.6M BuLi in hexane under stirring at −40° C. Then the reaction mixture was allowed to warm up to r.t. and stirred for 3 h. The reaction mixture was cooled −40° C. and treated with 1.17 g (0.01 mol) of ethyl N,N-dimethylcarbamate in 10 mL of ether. Then the reaction mixture was allowed to warm up to r.t. and was stirred overnight. Resulting mixture was treated with 10% aqueous NH4Cl, organic layer was separated, washed with 10% aqueous NH4Cl and then dried over anhydrous Na2SO4. Solvent was evaporated, the residue was washed with methanol. Yield 2.4 g (about 100%) of red oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]2=[O:51].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]3=[O:51])=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=2)[CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
1-Ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-yl)urea (0.171 g, 0.39 mmol, Intermediate 17), ethyl 6-iodo-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.155 g, 0.39 mmol, Intermediate 20), cesium carbonate (0.214 g, 0.66 mmol, Aldrich) and tris(dibenzylideneacetaone)palladium (0) (0.035 g, 0.04 mmol, Aldrich) or tetrakis(triphenylphosphine)palladium (0) (5 mol %, Strem) were combined in dioxane (2 mL)/water (0 mL) and heated to 100° C. The reaction mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and then placed in an ice-bath. The resulting precipitate was collected by filtration and dried under vacuum to provide the desired product (0.090 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(=O)(OC)O[CH2:12][CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCOC(=O)OC
Reactant: Cc1cccc(C)c1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOc1c(C)cccc1C
Temperature: 70 °C
Yield: 98.7 %

Procedure:
A mixture of 2,6-dimethylphenol (1.22 g, 10 mmoles), allyl methyl carbonate (1.40 g, 12 mmoles), 5 percent palladium on charcoal (26 mg, 0.0125 mmole paladium) and triphenyl phosphine (20 mg, 0.0375 mmole) is heated at 70° C. for 45 minutes. Filtration of the catalyst and bulb-to-bulb distillation of the residue at 120° C., 10 mm Hg gives 1.60 g of substantially pure allyl 2,6-dimethylphenyl ether, 98.7 percent yield.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][S:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([NH:29][C:30]([NH:19][C:15]1[CH:14]=[C:13]([C:11]2[O:12][C:8]([S:7][CH2:6][C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][N:10]=2)[CH:18]=[CH:17][N:16]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2nnc(SCc3ccc(Cl)cc3)o2)ccn1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1cc(-c2nnc(SCc3ccc(Cl)cc3)o2)ccn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
A suspension of 4-[5-[(4-chlorobenzyl)thio]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (90 mg, 0.282 mmol) and benzyl isocyanate (187 mg, 1.41 mmol) in tetrahydrofuran (5 mL) was stirred at 70° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/chloroform/diethyl ether to give the title compound (72 mg, yield 56%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[F:27][C:28]1[C:36]2[O:35][C:34]([CH3:38])([CH3:37])[CH2:33][C:32]=2[CH:31]=[C:30](B(O)O)[CH:29]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:27][C:28]1[C:36]2[O:35][C:34]([CH3:38])([CH3:37])[CH2:33][C:32]=2[CH:31]=[C:30]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])[CH:29]=1
Reactant: CC1(C)Cc2cc(B(O)O)cc(F)c2O1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(-c2cc(F)c3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.22 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.20 g, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2].C([N-]C(C)C)(C)C.[Li+].[F:26]N1C(C)(C)C2C=CC=CC=2S1(=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([F:26])([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2]
Reactant: CC1(C)c2ccccc2S(=O)(=O)N1F
Reactant: N#Cc1ccc2c(c1)CCCC2c1ccns1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CCCC2(F)c1ccns1
Temperature: 25 °C

Procedure:
6-Cyano-1-(5-isothiazolyl)-1,2,3,4-tetrahydronaphthalene (Example 26) is converted into the carbanion by treatment with lithium diisopropylamide in THF at -78° and then reacted with N-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzothiazole-1,1-dioxide. The reaction mixture is allowed to warm to room temperature and is worked up in aqueous medium, yielding the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1CCc2cc([N+](=O)[O-])cnc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(N)cnc21

Procedure:
A mixture of ethyl 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (4.2 g, 17.8 mmol) and Pd/C (0.5 g, 10%) in 80 mL of ethanol was stirred at room temperature under 50 psi of hydrogen for 2 hours then filtered. The filtrate was concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19](/[CH:24]=[CH:25]/[O:26]C)[C:18]=3[O:28][CH3:29])=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:28][CH3:29])=[C:19]([CH2:24][CH:25]=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CO/C=C/c1cc(F)cc(-c2cnc(-c3ccc(OC(C)C)c(Cl)c3)s2)c1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(CC=O)cc(F)cc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 70 °C
Yield: 93 %

Procedure:
To a mixture of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D79) (100 mg) in tetrahydrofuran (THF) (20 mL) under nitrogen was added HCl (0.5 mL). The reaction was heated to 70° C. for 2 h. The mixture was filtered and the filtrate was concentrated to give the crude product [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]acetaldehyde (D80) (90 mg) as a brown oil. MS (ES): C21H19ClFNO3S requires 419. found 420.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[N:7]([CH2:15][C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]3[CH:28]=[C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)[CH:26]=[CH:25][C:24]=3[NH:34]C(=O)OC(C)(C)C)=[O:21])=[CH:18][CH:17]=1)[CH2:6]2.C(ONC(=O)CCCCCNC(OC(C)(C)C)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:34][C:24]1[CH:25]=[CH:26][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:7]2[CH2:6][C:5]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]=3[C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[C:8]2=[O:14])=[CH:43][CH:42]=1
Reactant: COc1cc2c(c(-c3cccnc3)c1OC)CN(Cc1ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cc1)C2=O
Agent: CC(C)(C)OC(=O)NCCCCCC(=O)NOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(c(-c3cccnc3)c1OC)CN(Cc1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cc1)C2=O
Reaction time: 3 h
Yield: 99 %

Procedure:
The procedure of the Step 1 in Example 39 was repeated except that tert-butyl 2-(4-((5,6-dimethoxy-1-oxo-4-(pyridin-3-yl)isoindolin-2-yl)methyl)benzamido)-4-(thiophen-2-yl)phenylcarbamate in the Step 2 of Example 48 instead of N-(benzyloxy)-6-(BOC-amino)hexanamide and a mixture of CH2Cl2 and trifluoroacetic acid (mixture ratio=1:1 (v/v)) were used, and the reaction was performed for 3 hrs, to obtain the title compound (99%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([OH:15])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([NH:37][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15]
Reactant: NCCc1ccccc1
Reactant: O=C(O)CC1Nc2ccccc2NC1=O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1Nc2ccccc2NC1=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the solution of (3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetic acid (510 mg, 2.48 mmol) in THF (18 mL) was added triethylamine (0.38 ml, 2.74 mmol) and ethyl chloroformate (0.24 ml, 2.74 mmol). The mixture was stirred at rt for 1.5 hours and then phenethylamine (0.34 ml, 2.74 mmol) was added. The resulting mixture was again stirred at rt for 4.5 hours. The precipitate was filtered off and washed with small amount of THF a few times. The solvent was removed under the reduced pressure to give the title compound as a yellow solid: 1H NMR (DMSO-d6) δ=10.24 (bs, 1H), 8.03 (t, 1H, J=5.4 Hz), 7.30-7.15 (m, SH), 6.75-6.70 (m, 3H), 6.61-6.56 (m, 1H), 5.79 (bs, 1H), 4.08-4.04 (m, 1H), 3.30-3.24 (m, 2H), 2.71 (t, 2H, J=7.8 Hz), 2.60 (dd, 1H, J=3.9, 15.3 Hz), 2.31 (dd, 1H, J=8.7, 15.3 Hz).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:1])([F:14])[F:13])[CH3:27]
Reactant: CCNCC
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccccc1OC(F)(F)F
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a stirring solution of 2-trifluoromethoxybenzoic acid (3.6 g, 17.5 mmol, Avocado) in dry CH2Cl2 (150 mL) with DMF (0.5 mL) was added a 2M solution of oxalyl chloride in CH2Cl2 (17.5 mL) dropwise over 30 min. The reaction was stirred for 4 h and then conc. in vacuo to a white solid. The solid was dissolved in CH2Cl2 (150 mL) and reacted with diethylamine (3.2 g, 43.8 mmol, Aldrich) the reaction was stirred for 16 h and then conc. in vacuo to a yellow solid. The solid was purified by radial chromatography (SiO2, 1:5, EtOAc:hexanes) to yield 4.3 grams (94%) of the product as a colorless oil. MS (ESI) 262 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[P:5]([O:12]CC)([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>>[Br:1][CH2:2][CH2:3][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: CCOP(OCC)OCC
Reactant: BrCCBr
Product: CCOP(=O)(CCBr)OCC

Procedure:
Commercially available 1,2-dibromoethane (1.0 equiv.) and triethyl phosphite (1.0 equiv.) were heated with microwave irradiation at 160° C. for 20 minutes. The resulting residue was purified by reverse phase high performance liquid chromatography (HPLC) (0.035% TFA in ACN: 0.05% TFA in H2O, C18 column) to give diethyl 2-bromoethylphosphonate as a colorless liquid.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=2)[CH2:4][CH2:3]1.[NH2:17][C@@H:18]([CH3:34])[CH2:19][N:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[CH:26]=2)=[N:21]1>>[Cl:33][C:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][N:20]([CH2:19][C@@H:18]([NH:17][C:14]([C:12]3[N:13]=[C:9]([CH2:8][N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)[S:10][CH:11]=3)=[O:16])[CH3:34])[N:21]=2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: O=C(O)c1csc(CN2CCOCC2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CN2CCOCC2)n1
Yield: 68.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(morpholinomethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(morpholinomethyl)thiazole-4-carboxylic acid hydrochloride (260 mg, 0.982 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (218 mg, 0.818 mmol). The product was purified by washing the organic phase with 1M HCl, 1M Na2CO3, brine and water. Yield 68.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.23 (d, 3H), 2.50 (t, 4H; overlap with DMSO), 3.61 (t, 4H), 3.85 (d, 2H), 4.32 (dd, 1H), 4.40 (dd, 1H), 4.43-4.50 (m, 1H), 6.96 (d, 1H), 7.84 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.02 (dd, 1H), 8.16 (s, 1H), 8.46 (d, 1H). m/z [471.0+1].
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][C:26](Cl)=[CH:27][C:28]=2[C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[C:18]([C:36]#[N:37])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=2)=[CH:27][C:28]=1[C:29]1[CH:34]=[N:33][CH:32]=[N:31][CH:30]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2cnc(Cl)cc2-c2cncnc2)c(C#N)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cncnc1
Reaction time: 0.17 h
Yield: 753.9 %

Procedure:
10 mg (0.02 mmol) of tert-butyl((4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-3-cyanophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.5 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 80 mg (70% yield) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:8][O:9][N:10]([C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(=O)NOC
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N(OC)C(=O)OC
Temperature: 25 °C

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with tetrahydrofuran (14.0 mL), triethylamine (2.13 g, 1.5 eq) and N-methoxynonanamide (1.96 g, 1 eq). The reaction is cooled in an ice bath and methyl chloroformate (1.88 g, 1.4 eq) is added dropwise. The reaction is allowed to warm to room temperature overnight. The tetrahydrofuran is removed under vacuum and the residue is diluted with methylene chloride (25 mL). The reaction is washed with 0.1 M hydrochloric acid solution (1×20 mL), saturated aqueous sodium bicarbonate (3×20 mL)and brine (1×20 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.