Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH:13](OCC)(OCC)OCC.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(O)=O>[F:12][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]1[CH:13]=[N:25][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(CC(=O)O)cc1F
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(-n2cnnn2)c(F)c1
Temperature: 100 °C

Procedure:
A solution of (4-amino-3-fluorophenyl)acetic acid (450 mg, 2.66 mmol) and triethyl orthoformate (1.18 g, 7.98 mmol) in HOAc (10 mL) was added sodium azide (208 mg, 3.19 mmol), and the mixture was heated to 100° C. for 3 hours. After the reaction was completed, the reaction mixture was cooled to ambient temperature. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was directly used in next step.
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11].[OH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28].C([O-])(=O)C.[NH4+]>C(O)C>[CH3:28][C:27]1[NH:29][C:3]2[CH2:4][CH2:5][CH2:6][S:1](=[O:9])(=[O:8])[C:2]=2[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[C:26]=1[C:25]([O:24][CH2:23][CH2:22][OH:21])=[O:30]
Reactant: C/C(N)=C/C(=O)OCCO
Reactant: O=C1CCCS(=O)(=O)C1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1=C(C(=O)OCCO)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCS2(=O)=O)N1
Temperature: 25 °C

Procedure:
A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (2.80 g, 0.0189 moles), 3-nitrobenzaldehyde (2.85 g, 0.0189 moles), 2-hydroxyethyl-3-aminocrotonate (3.28 g, 0.0226 moles), ammonium acetate (0.291 g, 0.0038 moles) and ethanol (35 mL) was refluxed for 16 hours. After cooling to room temperature the resulting solid was isolated by filtration, washed with ethanol and diethyl ether. The product was dried under vacuum for 16 hours at room temperature affording the product; mp 233°-235° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[CH2:31][CH2:30]1)[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:35][C:36]([CH3:38])=[O:37].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:36]([OH:37])([CH3:38])[CH3:35])[CH2:30]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
15.81 ml (25.3 mmole) of butyllithium (as a 1.6M solution in hexane) were added, at -78° C. and under an atmosphere of nitrogen, to a solution of 3.55 ml (25.3 mmole) of diisopropylamine in 30 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. A solution of 3.58 g (11.5 mmole) of (5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]dihydrofuran-2(3H)-one in 10 ml of anhydrous tetrahydrofuran was then added to the mixture, and the mixture was stirred at -78° C. for 1 hour. 1.86 ml (25.3 mmole) of acetone purified by distillation was added to the mixture, after which the mixture was stirred for a further 2 hours. At the end of this time, the reaction mixture was mixed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed, in turn, with a 10% w/v aqueous solution of citric acid, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure and the residue was purified by medium pressure column chromatography through silica gel (using a 1:1 by volume mixture of hexane and diethyl ether as the eluent). The title compound, obtained from the less polar fractions, was isolated as white crystals, melting at 123°-125° C., and the amount obtained was 3.65 g (yield 86%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:16])[C:14]#[CH:15])=[CH:9][CH:8]=1.I[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:29]/[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])/[C:22](=[O:28])[NH:23]2>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.CN(C=O)C.CCN(CC)CC>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([OH:16])[C:14]#[C:15][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2/[C:21](=[CH:29]/[C:30]2[NH:31][CH:32]=[CH:33][C:34]=2[O:35][CH3:36])/[C:22](=[O:28])[NH:23]3)=[CH:11][CH:12]=1
Reactant: C#CC(O)c1ccc(OCCCN(C)C)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCCCN(C)C)cc3)c21

Procedure:
Using Method C above, 3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propyne (201 mg, 0.86 mmol) (from Example 22 above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (34 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, to yield rac-(Z)-1,3-dihydro-4-[3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 151 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14](I)=[CH:13][N:12]=[CH:11][N:10]=2)[C:5]([F:16])=[CH:4][C:3]=1[NH2:17].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)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>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)=[CH:13][N:12]=[CH:11][N:10]=2)[C:5]([F:16])=[CH:4][C:3]=1[NH2:17]
Reactant: Nc1cc(F)c(Oc2ncncc2I)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cncnc2Oc2cc(F)c(N)cc2F)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a degassed solution of 2,5-difluoro-4-(5-iodopyrimidin-4-yloxy)benzenamine (0.23 g, 0.659 mmol) in DMF (5 mL) was added 1-methyl-pyrazole-4-boronic acid pinacol ester (0.206 g, 0.988 mmol), cesium carbonate (0.644 g, 1977 mmol) in water (2 mL) and Pd(PPh3)4 (0.076 g, 0.066 mmol) and the mixture was stirred at 80° C. under an argon atmosphere for 1 hour. Water was added and the solution was extracted with EtOAc (3×). The organics were washed with 5% aqueous lithium chloride solution and brine, and then dried over MgSO4. The organics were filtered and concentrated under reduced pressure. The residue was treated with small amount of EtOAc and Et2O. The solid was collected by filtration to obtain 2,5-difluoro-4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yloxy)benzenamine (0.18 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.21 (m, 1H), 6.69 (m, 1H), 5.42 (s, 2H), 3.89 (s, 3H); MS (ESI) m/z: 304.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)[NH2:6])[CH3:2].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:17](=[O:18])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1cc(N)cc(-c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2cccnc2)c1

Procedure:
The title compound (0.276 g, 0.87 mmol) was prepared by the methodology of description 67, using 3-ethyl-5-(pyrid-3-yl)aniline, phenyl chloroformate (0.13 ml, 0.96 mmol) and triethylamine (0.13 ml, 0.96 mmol) in dichloromethane (10 ml)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:29]=[N:28][C:4]2[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=2[CH:16]=1
Reactant: NN
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1F)OC
Solvent: O
Product: CC1(C)Cc2cc(-c3ccc(F)cc3F)nnc2C1

Procedure:
yellow solid. MS (EI): 260.1 (M+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [[2-(2,4-difluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1([N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8](=[O:25])[O:9][CH2:10][C:11]2([OH:24])[CH2:17][CH2:16][CH2:15][C:14]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]2[OH:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.CCOC(C)=O>[C:26]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:9][CH2:10][C:11]2([OH:24])[CH2:17][CH2:16][CH2:15][C:14]3[C:18]([O:22][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]2[OH:23])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCC1(O)CCCc2c(O)cccc2C1O)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of [(5SR,6SR)-1,5,6-trihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (461 mg) and potassium carbonate (304 mg) in DMF (8 ml) was added ethyl bromoacetate (0.244 ml) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 4:5) to give ethyl {[(5SR,6SR)-6-(N,N-diphenylcarbamoyloxy)methyl-5,6-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1 -yl]oxy}acetate (459.6 mg) as an amorphous solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[OH:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)C(C)(C)CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
tert-Butyl 4-aminocyclohexylcarbamate (4:1 cis:trans mix of isomers, 1.00 g, 4.67 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (0.60 g, 5.13 mmol) and triethylamine (1.30 ml, 9.33 mmol) were dissolved in dimethylformamide (20 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (984 mg, 5.13 mmol) and 1-hydroxybenzotriazole (694 mg, 5.13 mmol) were added. The reaction was stirred under nitrogen at room temperature for 18 h then partitioned between water and ethyl acetate. The organic phase was washed with water, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane:methanol:0.880ammonia (95:5:0.5) as eluant to give tert-butyl 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate (840 mg) as a white foam as a ca. 4:1 mixture of diastereoisomers.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:38](Cl)=[O:39])=[N:29][N:30]([C:32]2[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=2)[CH:31]=1)[CH3:25]>>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=3)[N:29]=2)=[O:39])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2ccn(C)n2)nc1C(=O)Cl
Product: CCOc1cn(-c2ccn(C)n2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X20 was prepared from A2 and 4-ethoxy-1′-methyl-1′H-[1,3′-bipyrazole]-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.36 (t, J=7.0 Hz, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 4.02 (s, 3H), 4.06 (q, J=7.0 Hz, 2H), 6.57 (d, J=2.1 Hz, 1H), 6.88 (d, J=6.2 Hz, 1H), 7.52 (s, 1H), 7.56 (m, 2H), 7.71 (s, 1H), 7.76 (d, J=8.9 Hz, 1H), 8.08 (dd, J=2.1 Hz, J=13.1 Hz, 1H), 8.17 (s, 1H), 8.75 (d, J=6.2 Hz, 1H), 10.34 (s, 1H). MS (ES) C27H25FN6O5 requires: 532. Found: 533 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>CN(C=O)C.O>[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:19][N:18]=2)=[O:21])[CH2:70][CH2:69]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes 4-(2-chloro-phenylamino)-piperidine dihydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using basic alumina (50% ethyl acetate in hexane) afforded 0.142 g (78%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45](Br)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=3)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C(N)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C(=O)OCc4ccccc4)c3c2)c1
Yield: 30.9 %

Procedure:
3-carbamoylphenyltri-n-butylstannane (3.076 g, 7.50 mmol) (see Preparation 9) and 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (2.81 g, 6.80 mmol) (see Preparation 35B) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as a pale yellow foam (954 mg). Found: C,68.45; H,5.92; N,8.10; C28H27N3O3. 7/12CH2Cl2 requires: C,68.24; H,5.64; N,8.35%.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:9]=[C:8]([NH:10]C(=O)C(C)(C)C)[CH:7]=[CH:6][CH:5]=1)[CH3:3].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[NH2:10][C:8]1[N:9]=[C:4]([CH:2]([OH:1])[CH3:3])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(N)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To a solution of N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (2.0 g, 9.6 mmol) in dioxane (20 mL) was added 9 N aqueous HCl (10 mL). The reaction mixture was warmed to 100° C. for 24 h. After cooling to 25° C., the solution was neutralized with solid NaOH until pH=9 and diluted with EtOAc (50 mL). The resulting mixture was washed with saturated aqeuous NaHCO3(2×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was dissolved in dichloromethane (10:1, 5 mL). Diethyl ether (10 mL) was added, and the solution was allowed to stand for 24 h. The resulting crystals were filtered and rinsed with diethyl ether (2×10 mL) to afford the above-titled intermediate as a white solid (0.65 g, 49%). 1H NMR (400 MHz, CDCl3), δ: 7.43 (t, J=7.5 Hz, 1H), 6.59 (d, J=7.3 Hz, 1H), 6.39 (d, J=8.1 Hz, 1H), 4.72 (q, J=6.3 Hz, 1H), 4.43 (bs, 2H), 4.21 (bs, 1H), 1.45 (d, J=6.3 Hz, 3H); LRMS (ESI): m/z: 139.1.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[CH:8]=[C:7]([C:9](Cl)=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[N:5]1>O>[CH3:1][NH:2][C:9]([C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[N:5][N:4]([CH3:3])[CH:8]=1)=[O:10]
Reactant: Cn1cc(C(=O)Cl)c([N+](=O)[O-])n1
Reactant: CN
Solvent: O
Product: CNC(=O)c1cn(C)nc1[N+](=O)[O-]

Procedure:
Fifty ml. of water was cooled in an ice bath and saturated with monomethylamine. To the solution was added 2 gm. of 1-methyl-3-nitro-4-pyrazolecarbonyl chloride in portions, and the mixture was heated until the solid dissolved. Upon cooling a solid precipitated which was recrystallized from water and identified as 1.3 gm. of N,1-dimethyl-3-nitro-4-pyrazolecarboxamide, m.p. 163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=2)[N:10]=1
Reactant: COc1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Yield: 65.1 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (2.0 g, 4.23 mmol), TFA (30 mL) and DCM (5 mL) to afford 1.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 4.47 (d, J=5.4 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.67-7.74 (m, 3H), 7.93 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 10.11 (m, 1H), 12.86 (br s, 1H); MS (m/z): 471.88 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.[CH:29]([NH2:31])=O>CCOC(C)=O.O>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[CH:5]=[N:4][C:3]4[C:2]3=[N:1][CH:29]=[N:31][C:20]=4[C:21]3[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccc(S)cc2)c1N
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(S)cc3)ncnc21
Temperature: 180 °C
Yield: 59 %

Procedure:
The mixture of 3-[5-Amino-4-(4-mercapto-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide (33 mg, 0.09 mmol), formamide (0.5 mL, excess), and p-tolunesolfonic acid (10 mg) was heated in the microwave at 180° C. for 30 min. After cooling, the mixture was diluted with EtOAc and water, and the EtOAc layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparatory HPLC to provide the title compound (20 mg, 59%) as a white solid: HPLC tR=2.47 min; MS m/z 416.27 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:9].[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)CC>[F:13][C:2]1[N:7]=[C:6]2[C:8]([O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:9]
Reactant: [F-]
Reactant: O=C1OC(=O)c2nc(Cl)ccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCC#N
Product: O=C1OC(=O)c2nc(F)ccc21
Reaction time: 10 h

Procedure:
A mixture of 36.7 g (0.2 mol) of 6-chloropyridine-2,3-dicarboxylic anhydride, 17.4 g (0.3 mol) of potassium fluoride and 1 g of 18-crown-6 in 200 ml of propionitrile were stirred for 10 hours while refluxing. After cooling, the reaction mixture was filtered with suction and the residue was washed with methylene chloride. The filtrate was evaporated down under reduced pressure and stirred with a 2:1 methyl tert-butyl ether/pentane mixture, and the product was filtered off with suction and dried. 25.3 g (76% of theory) of the title compound of melting point 106° C. (decomposition) were obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.[C:23]1([CH3:29])C=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:14]3[CH2:29][CH2:23][O:1][CH2:2][CH2:13]3)=[O:12])[S:7][C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1ccccc1
Reactant: COc1cc2cc(C(=O)O)sc2c([N+](=O)[O-])c1O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2cc(C(=O)N3CCOCC3)sc2c([N+](=O)[O-])c1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid (2.7 g) was dissolved in toluene (45 ml). Thionyl chloride (1.2 ml) and N,N-dimethylformamide (4 drops) were added. The solution was stirred at 80° C. for two hours and after that it was evaporated. The residue was dissolved into dichloromethane (45 ml) and morpholine (1.4 ml) and triethylamine (1.2 ml) added. The reaction solution was stirred at room temperature overnight. The solution of water and 2M HCl was added to the solution. The solid was washed with water and dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](F)=[C:6]([CH3:8])[CH:7]=1.CN(C)C=O.[CH3:16][S-:17].[Na+]>O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([S:17][CH3:16])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(C)cc(Br)cc1C
Temperature: 50 °C
Yield: 14.2 %

Procedure:
Add 5-bromo-2-fluoro-1,3-dimethyl-benzene (3.5 g, 17.2 mmol) to dimethylformamide (DMF, 30 mL) at ambient temperature followed by sodium thiomethoxide (1.32 g, 17.9 mmol). Heat at 50° C. for 8 hours and dilute with water (10 mL) and diethyl ether (100 mL). Separate the layers, wash the organics with brine, and dry with magnesium sulfate before concentrating to a residue. Chromatograph the residue on a SiO2 column eluting with diethyl ether (20%) in hexane to give 566 mg (14%) of 5-bromo-1,3-dimethyl-2-methylsulfanyl-benzene.