Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:28]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:28]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:12]2[C:11]3[CH:20]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=[CH:9][C:10]=3[S:14][N:13]=2)=[O:38])=[CH:40][CH:41]=1)[CH2:29][CH2:30][CH3:31]
Reactant: NCCCNc1nsc2ccc(-c3ccccc3)cc12
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)NCCCNc2nsc3ccc(-c4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
The crude N1-(5-Phenylbenzo[d]isothiazol-3-yl)propane-1,3-diamine mixture (˜100 mg, 0.20 mmol) was dissolved in anhydrous methylene chloride with triethylamine (0.3 mL, 0.24 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of 4-butoxybenzoyl chloride (51 mg, 0.24 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield 4-butoxy-N-(3-(5-phenylbenzo[d]isothiazol-3-ylamino)propyl) benzamide (13 mg). 1H NMR (300 MHz, DMSO-d6): 8.23 (s, 1H), 8.17 (t, 1H), 7.98 (d, 1H), 7.76-7.82 (m, 4H), 7.50 (t, 3H), 7.37-7.40 (m, 1H), 6.97 (d, 2H), 4.00 (t, 2H), 3.50 (q, 2H), 3.39 (q, 2H), 1.90-2.00 (m, 2H), 1.62-1.78 (m, 2H), 1.40-1.49 (m, 2H), 0.96 ppm (t, 3H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH:6]([NH:9][CH2:10][CH2:11]O)([CH3:8])[CH3:7].C1(C)C=CC=CC=1>O>[S:1]([O:3][CH2:11][CH2:10][NH:9][CH:6]([CH3:8])[CH3:7])([OH:2])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CC(C)NCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)NCCOS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50-ml three-necked flask, 1.01 g (10 mmol) of sulfuric acid (97%) was diluted with 1 g of water, and the resulting dilution was ice-cooled. A mixture of 1.03 g (10 mmol) of 2-isopropylaminoethanol and 1 g of water was slowly dropped into the cooled dilution. After completion of the dropping, the resulting mixture was warmed to room temperature and 10 ml of toluene was added thereto. The mixture thus obtained was dehydrated by heating with vigorous stirring after attaching a Dean-Stark trap to the flask. The mixture was heated and stirred for 4 hours until a theoretical amount of water was removed. Then, the reaction was continued for another 1 hour. After a large portion of the toluene was removed by decantation, the residual toluene was distilled off under reduced pressure to obtain a crude product of 2-isopropylaminoethyl hydrogensulfate, the desired compound, quantitatively.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].C([O-])(=[O:33])C.[Na+]>CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:33])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)nc(Cl)c21
Agent: [Na+]
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Temperature: 120 °C
Reaction time: 7 h
Yield: 75.5 %

Procedure:
A mixture consisting of 580 mg of t-butyl N-[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate, 315 mg of sodium acetate and 6 ml of dimethyl sulfoxide was stirred in an oil bath at 120° C. for 7 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered through a small amount of silica gel. The filtrate was concentrated, and the residue was crystallized with ethyl acetate-hexane to give 420 mg of t-butyl N-[1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate. A mixture consisting of an 100 mg aliquot of the compound obtained above, 0.17 ml of methyl iodide, 48 mg of anhydrous potassium carbonate and 0.5 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. Then, the organic layer was concentrated, and the residue was purified by silica gel column chromatography using 50% ethyl acetate/hexane to give 104 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][C:46]([CH:49]3[CH2:51][CH2:50]3)=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:52].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:52])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][C:46]([CH:49]7[CH2:50][CH2:51]7)=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2cnc(C3CC3)cn2)cc(C)c1Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnc(C7CC7)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-5-cyclopropyl-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.31 min; Mass spectrum (ESI+): m/z=565 [M+H]+.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[C:4]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1I)([CH3:7])([CH3:6])[CH3:5].C(OCC)(=O)C.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:4]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:1]#[C:2][CH3:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CC
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#Cc1cnccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Propyne (6.3 mL, 124 mmol) was condensed in a pressure tube at −78° C. A solution of (3-iodopyridin-4-yl)carbamic acid tert-butyl ester (7.98 g, 24.9 mmol) in 15 mL of DMF, 60 mL of triethylamine, dichlorobis(triphenylphosphine)palladium (II) (877 mg, 1.25 mmol), and CuI (472 mg, 2.49 mmol) were added, and the tube was sealed and stirred at room temperature overnight. 200 mL of ethyl acetate and 100 mL of saturated aqueous ammonium chloride solution were added, the phases were separated and the aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (25% to 40% ethyl acetate in hexanes, gradient) afforded 5.65 g of (3-prop-1-ynylpyridin-4-yl)carbamic acid tert-butyl ester (98% yield).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][C:43]([F:46])([F:45])[F:44].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:42][C:43]([F:46])([F:45])[F:44])[N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(F)(F)F)c4cc(F)ccc34)nc12
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a mixture of N-tert-Butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 0.12 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 10 mL of DMF was added 2-iodo-1,1,1-trifluoroethane (0.5 mL, 5.07 mmol). The reaction mixture was heated to 80° C. for 3 hours. After cooling to room temperature, 50 mL of water were added, and the mixture was extracted with ethyl acetate (2×50 mL), combined organics dried with sodium sulphate, filtered and concentrated to give N-tert-butyl-2-(6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, crude). LCMS: (M+H)+=565; (M+Na)+=587. Crude material used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].CN([Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])C.CNC>>[C:4]1([S:2]([CH2:1][Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Agent: CNC
Product: CCCC[Sn](CCCC)(CCCC)CS(=O)c1ccccc1
Yield: 65 %

Procedure:
Phenyl methyl sulfoxide (7.0 g.; 0.05 moles) and dimethylamino tributyltin (16.7 g.; 0.05 moles) were admixed in a 50 ml round bottom flask, under a positive pressure argon atmosphere, for 20 hours at 100° C. During the reaction, liberated dimethylamine gas exited from the reaction flask through an open port with the moving argon gas. The crude product was distilled through a semi-micro distillation apparatus. The main fraction (13 g; 65% yield) distilled at 160°-170° C at 0.05 mm Hg. The product was identified by 'H NMR and infra red spectra as (phenylsulfinylmethyl) tributyltin.
Reaction SMILES: CN(C)CCN(C)C.[CH:9]([Mg]Cl)([CH3:11])[CH3:10].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][CH2:22][C:23]#[C:24][C:25]([O:27][CH3:28])=[O:26].[NH4+].[Cl-]>O1CCCC1.[Cu](I)I>[CH3:10][CH:9]([CH3:11])[C:23]([CH2:22][CH2:21][O:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)=[CH:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C#CCCOC1CCCCO1
Reactant: CC(C)[Mg]Cl
Agent: I[Cu]I
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)C=C(CCOC1CCCCO1)C(C)C
Temperature: 25 °C
Yield: 85 %

Procedure:
Freshly purchased copper iodide (CuI, approximately 1.97 g, approximately 12.2 mmol) was placed under N2 in a four-neck flask. Dry tetrahydrofuran (THF) (about 35 ml) was added, followed by N,N,N′,N′-tetramethylethylenediamine (about 2.76 ml). The mixture was stirred at room temperature until a green-yellow solution was obtained and then cooled to about −70° C., upon which a green suspension was formed. Isopropylmagnesium chloride solution (approximately 12.3 mmol; about 6.1 ml of approximately 2.0 M in tetrahydrofuran (THF) was added slowly, whereupon a green suspension became colorless then turned brown. The mixture was stirred at about −70° C. for about 1 h, then methyl 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynoate (approximately 1.3 g, approximately 6.1 mmol) dissolved in dry THF (about 5-10 ml) was added. The resultant mixture was stirred at about −70° C. for about 3 h and quickly poured into an ice-cold mixture of saturated NH4Cl and hexanes/ether, approximately 5:1. The organic layer was separated, and the aqueous layer was extracted with hexanes/ether, approximately 5:1. The combined organic extracts were thoroughly washed with saturated NH4Cl solution until no blue color was seen. The organic extract was dried and concentrated. Flash chromatography with hexanes/ethyl acetate, approximately 5:1, afforded methyl 4-methyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2-pentenoate (approximately 1.3 g, approximately 85%) as an approximately 92:8 mixture of E and Z isomers as judged from GC-MS analysis. GC-MS (E isomer, m/z, relative intensity): 172 (2), 171 (3), 155 (32), 142 (8), 141 (6), 139 (6), 95 (17), 85 (100), 67 (16), 57 (10), 55 (11), 43 (11), 41 (16). GC-MS (Z isomer, m/z, relative intensity): 172 (4), 155 (3), 154 (8), 142 (8), 141 (2), 139 (4), 123 (6), 95 (23), 85 (100), 67 (17), 57 (10), 55 (12), 43 (11), 41 (17). 1H NMR (400 MHz, C6D6, δ): 0.86 (d, J=8.0 Hz, E isomer), 0.86 (d, J=8.0 Hz, Z isomer), 1.20-1.42 (m, 4H), 1.55-1.62 (m, 2H), 1.70-1.82 (m, 1H), 2.18-2.31 (m, 1H), 3.02-3.18 (m, 2H), 3.41 (s, OCH3), 3.67-3.73 (m, 1H), 3.81-3.88 (m, 1H), 4.04-4.11 (m, 1H), 4.39 (septet, J=8.0 Hz, H-4, Z isomer), 4.52 (t, J=4.0 Hz, OCHO, Z isomer), 4.66 (t, J=4.0 Hz, OCHO, E isomer), 5.83 (br. s, H-2, E isomer), 5.86 (br. s, H-2, Z isomer). 13C NMR (101 MHz, C6D6, δ, E isomer): 20.0, 21.7 (two carbons), 26.3, 31.4, 32.9, 37.3, 50.9, 61.9, 67.3, 98.8, 115.1, 167.2, 167.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[C:22]([C:27](O)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:59][N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([N:63]2[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccccc2-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
Charge a vial with 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-2-carboxylic acid (example 6) (70 mg, 0.17 mmol), EDCl (65 mg, 0.34 mmol) and HOBt (23 mg, 0.17 mmol). Dissolve in DMF (0.1 M) and add triethylamine (95 μL, 0.68 mmol) and N-methyl piperazine (34 mg, 0.34 mmol). Stir at room temperature overnight. Pour into water and extract with ether. Dry over sodium sulfate, filter and concentrate. Purify over silica gel. Dissolve the residue in methylene chloride and acidify with 4N HCl in dioxane. Concentrate in vacuo which affords 57 mg (63%) of the title compound: Mass spectrum (apci) m/z=494.3 (M+H-HCl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:34](=[O:35])[C:28]3[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=3)[C:37]2=[O:36])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-phenylbenzoxazole (420 mg, 1.42 mmol) and 1,2,4-benzenetricarboxylic anhydride (273 mg, 1.42 mmol) the title compound was obtained, (460 mg, 66%). 1H NMR (DMSO) δ 13.85(s, 1H), 8.51(dd, 1H), 8.41(s, 1H), 8.29(d, 1H), 8.16(m, 2H), 7.95(d, 1H), 7.81(m, 4H), 7.58(m, 2H), 7.54(d, 1H), 7.48(d, 1H), 4.12(s, 3H). MS 491 m/z (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([C:22](=[O:24])[CH3:23])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C(C)=O)cc3)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=1[F:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1(B(O)O)[CH2:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1ccc(I)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1ccc(C2CC2)cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
To (S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.5 g, 9.0 mmol) and cyclopropylboronic acid (1.0 g, 11.7 mmol) in a mixture of toluene (40 mL) and water (2 mL) were added potassium phosphate tribasic (6.68 g, 31.5 mmol), tricyclohexylphosphine (0.50 g, 1.8 mmol) and palladium acetate (0.20 g, 0.89 mmol). The mixture was heated to 100° C. for 3 hours then additional tricyclohexylphosphine (0.25 g, 0.89 mmol) and palladium acetate (0.10 g, 0.45 mmol) were added. Heating at 100° C. was continued for an additional 3 hours before adding cyclopropylboronic acid (0.2 g, 2.33 mmol) and heating at 100° C. for a final period of 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), brine (once), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted with 9:1 v/v dichloromethane in hexanes to afford (S)-[1-(4-cyclopropyl-2-fluoro-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester as a colorless solid (2.0 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[CH:50][CH:49]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:29]=1)=[O:6]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (76 mg, 0.339 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.420 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) was added to the solution, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (129 mg, 81%) as a white powder.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].F[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>CN(C)C=O.Cl.C(OCC)(=O)C>[C:1]([CH:3]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 174.4 %

Procedure:
Ethyl 2-cyanoacetate (10.9 mL, 102 mmol) was slowly added to a 60% suspension of sodium hydride (4.10 g, 102 mmol) in N,N-dimethylformamide (125 mL) at 0° C. to give a gray suspension. The mixture was stirred at 0° C. for 15 minutes and methyl 4-fluoro-3-nitrobenzoate (10.2 g, 51 mmol) in N,N-dimethylformamide (125 mL) was added. The resulting deep red mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was diluted with 1N HCl (40 mL) and ethyl acetate (40 mL). The separated aqueous layer was extracted with ethyl acetate (3×50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue (26 g) which was purified by flash-chromatography (started with 100% hexanes and gradually added ethyl acetate increments to complete with 100% ethyl acetate) to afford 14.9 g of the title compound. LCMS m/z 291.0 (M−H)−, retention time (on analytical HPLC)=1.76 minutes.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([N:16]2[CH2:20][CH2:19][O:18]C2=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH2:20][CH2:19][OH:18])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1c1nn(Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cn(Cc2ccccc2)nc1NCCO

Procedure:
1 00 g (0.35 mmoles) of N-(1-benzyl-4-nitropyrazolyl) oxazolidine-2-one is heated in 10 ml 5 normal sodium hydroxide solution for 4 hours at 70° C. The solvent is distilled off in the rotary evaporator in vacuum and the residue is separated by means of column chromatography using silica gel with a mixture of chloroform and methanol (10:1).