Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:13]1([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-Nitrophenol (5.0 g, 35.9 mmol) was added to a suspension of (bromomethyl)cyclopropane (10.7 g, 79.07 mmol) and K2CO3 (19.9 g, 143.76 mmol) in DMF (80 mL), and the reaction was stirred at 40° C. overnight. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc/PE) to give 6.77 g (98%) of the title compound as a colorless oil. [M+H] Calc'd for C10H11NO3, 194. Found, 194.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](N(C)C)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.26 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 481 [M+H]
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.O>[CH2:16]([O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cc(Br)cnc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 2,5-dibromopyridin-3-ol (200 mg, 0.791 mmol) in dry N,N-dimethylformamide (8 mL) was added potassium carbonate (164 mg, 1.19 mmol) and benzyl bromide (0.11 mL, 0.949 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1→3/2) to give the title compound as a white crystal (211 mg, yield 78%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.[Br-]>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:12]3[CH:13]=[CH:14][C:9]([N:8]([CH3:17])[CH3:7])=[CH:10][CH:11]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-N,N-dimethylanilinemagnesium bromide. Yield: 52 mg of a yellow solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]+=462.0, 464.0; HPLC retention time: 2.6 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16]>>[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([NH:17][C:18]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=1)=[O:19])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
A portion of 5-trifluoromethyl-2-aminopyridine is reacted with 2-chloro-6-fluorobenzoyl isocyanate as described in Example 1. The reaction mixture is evaporated under vacuum and the product is recrystallized to obtain the product named above.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[S:23][C:24]=3[CH3:25])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:25][C:24]1[S:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:32])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1sc(-c2ccccc2)nc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {6-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-indol-1-yl}-acetic acid as colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:48][C:49]([F:69])([F:68])[C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]([C:58]2[C:63]([C:64]([F:67])([F:66])[F:65])=[CH:62][CH:61]=[CH:60][N:59]=2)[NH2:57])=[CH:52][CH:51]=1>CN(C=O)C.C1COCC1.CO.[Li+].[OH-]>[F:68][C:49]([F:48])([F:69])[C:50]1[CH:51]=[CH:52][C:53]([C@H:56]([NH:57][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=2)=[O:13])[C:58]2[C:63]([C:64]([F:65])([F:66])[F:67])=[CH:62][CH:61]=[CH:60][N:59]=2)=[CH:54][CH:55]=1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(methoxycarbonyl)picolinic acid (70.7 mg, 0.390 mmol) and DIPEA (0.20 mL, 1.148 mmol) in DMF (2 mL) were added HATU (223 mg, 0.586 mmol) and (S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methanamine hydrochloride (Intermediate 1) (125 mg, 0.390 mmol). The resulting mixture was stirred at rt 16 h. The mixture was then diluted with THF (10 mL), MeOH (3 mL), and 1M LiOH (2 mL). After a further 16 h, the reaction was concentrated in vacuo, taken up in a minimum of DMF and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini™ column (5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with a linear gradient of 20% to 90% MeCN (0.1% TFA) in H2O (0.1% TFA) over 10 minutes to give the title compound as a white solid after lyopholization. 1H NMR (CDCl3, 300 MHz) δ ppm 9.74 (d, J=8.2 Hz, 1H), 9.25 (s, 1H), 8.97 (d, J=4.0 Hz, 1H), 8.47 (dd, J=8.0, 2.1 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.46 (dd, J=7.5, 5.0 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H). MS (ESI pos. ion) m/z: 469.9 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([S:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1.[Cl-].[NH4+]>C1COCC1>[C:24]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([S:9][CH2:10][CH2:11][N:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[CH3:8])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(SCC(=O)N1CCCc2c(O)cccc21)(c1ccccc1)c1ccccc1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(SCCN1CCCc2c(O)cccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
1-((1,1-diphenylethylthio)acetyl)-5-hydroxy-1,2,3,4-tetrahydroquinoline (136 mg) was dissolved in THF (5 ml), and the resultant solution was stirred at 0° C. A borane THF complex (1.0N in THF) (2.0 ml) was added to the solution, and the mixture was stirred at room temperature. After disappearance of the raw materials was confirmed, the reaction solution was added to a saturated ammonium chloride aqueous solution (20 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and a concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=5/1) to obtain the object compound (60 mg, yield 46%).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[Br:21])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[Br:19][C:18]1[CH:17]=[C:16]([F:20])[CH:15]=[C:14]([Br:21])[C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)Nc1c(Br)cc(F)cc1Br)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=S)Nc1c(Br)cc(F)cc1Br
Temperature: 23 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 1-benzoyl-3-(2,6-dibromo-4-fluoro-phenyl)-thiourea (1.37 g, 3.17 mmol) in MeOH (12 mL) was added dropwise a sodium methoxide solution (5.4M in MeOH, 1.29 mL, 6.96 mmol) at 0° C. The mixture was warmed to 23° C. and stirred for 16 hours. MeOH was concentrated under reduced pressure. The residue was dissolved in water, cooled to 0° C., and acidified to pH 4 with 1M HCl. The resulting precipitate was collected by filtration and washed with hexanes to yield titled compound (1.04 g, 99%). MS (ESI/CI): mass calcd. for C7H5Br2FN2S, 325.9; m/z found, 326.9 [M+H]+. 1H NMR (400 MHz, CD3OD-d4): 8.05-8.01 (m, 2H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1cc(Br)oc1C
Product: COC(=O)c1cc(-c2ccc(F)cc2C)oc1C
Yield: 84.2 %

Procedure:
An operation similar to that in Example 49 (2) was performed using methyl 5-bromo-2-methyl-3-furoate (4.4 g) and 4-fluoro-2-methylphenylboronic acid (3.7 g) to give the title compound (4.2 g, 85%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.Cl>C(O)(C)C>[ClH:1].[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7(3-(pyrrolidin-1-yl)propoxy)quinazoline (61 mg, 0.19 mmol), (prepared as described for the starting material in Example 9), and 5-aminoindole (30 mg, 0.23 mmol) in isopropanol (2 ml) containing 6.2 N hydrogen chloride in isopropanol (33 μl) was heated at 80° C. for 6 hours. After cooling, the precipitate was filtered, washed with ether and dried under vacuum to give 4-(indol-5-ylamino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline hydrochloride (80 mg, 72%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:14])[C:10]([Cl:13])=[N:11][CH:12]=1.CN([CH:18]=[O:19])C.CCOC(C)=O>CCOCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([CH:18]=[O:19])=[CH:8][C:9]=1[F:14]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cnc1Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyl lithium (2.5 M in hexane, 2.5 mL, 6.3 mmol) was added to 5-bromo-2-chloro-3-fluoro-pyridine (1 g, 4.75 mmol) in 10 mL of ether at −78° C. After 10 minutes, DMF (5 mL) was added and the mixture was warmed to room temperature over 1 h. The mixture was poured into 20 mL of EtOAc and the mixture was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to afford the crude 53a (0.92 g) as a brown oil: LC-MS160.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:19]([O:21][CH3:22])=[O:20])=[N:10][C:11]([OH:18])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([C:19]([O:21][CH3:22])=[O:20])=[N:10][C:11]([O:18][CH2:23][CH3:24])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(O)c(C(F)(F)F)cc1-n1c(C)ccc1C
Reactant: CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOc1nc(C(=O)OC)c(-n2c(C)ccc2C)cc1C(F)(F)F

Procedure:
Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl)picolinate (62 mg, 0.168 mmol) in 1,4-dioxane (1.5 ml) (dry) was treated with EtOH (0.020 ml, 0.335 mmol) and triphenylphosphine (88 mg, 0.335 mmol) and the solution stirred. DEAD (0.053 ml, 0.335 mmol) was added dropwise and the reaction mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound;
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](C2C=CC([N+]([O-])=O)=C(Cl)C=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[ClH:25]>[Fe].C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)cc1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Cl)cc1

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of 4-(4-acetamidophenyl-sulphonyl)-2-chloro-nitrobenzene (Method 13) (0.67 g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol (10 ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×15 ml). The organic extracts were combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-2% methanol/DCM to give the title compound (0.18 g) as a solid. NMR: 2.05 (s, 3H), 6.4 (s, 2H), 6.8 (d, 1H), 7.5 (d, 1H), 7.6 (d, 1H), 7.8 (q, 4H), 10.3 (brs, 1H); MS (ESP−): 323.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].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.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)c1cc2ccc(Br)cc2c(=O)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Part 2, Step A: A mixture of 5-bromo-2-iodobenzoic acid (12.6 g, 38.5 mmol), but-3-yn-2-ol (3.1 mL, 2.96 g, 42.4 mmol), ZnCl2 (5.2 g, 38.5 mmol), Pd(Ph3P)4 (2.23 g, 1.9 mmol), Et3N (16.0 mL, 11.7 g, 115.5 mmol) and DMF (80 mL) was stirred under argon at 80° C. for 2 hours. After removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-100%) to provide the intermediate 7-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (7.5 g, 72%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38-8.45 (1H, m), 7.81 (1H, dd, J=8.35, 2.05 Hz), 7.32 (1H, d, J=8.51 Hz), 6.52-6.59 (1H, m), 4.66 (1H, qd, J=6.52, 0.95 Hz), 1.54-1.60 (3H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:21]([CH3:23])[CH3:22])[S:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])=O)C.C([NH2:26])=O.C[O-].[Na+].CO.C(O)(C(F)(F)F)=O.[NH4+].[Cl-]>CN(C=O)C.O.C(#N)C>[CH:21]([C:8]1[S:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[C:6]([C:4]([NH2:26])=[O:3])[N:7]=1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1nc(C(C)C)sc1Nc1ccccc1[N+](=O)[O-]
Reactant: NC=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)c1nc(C(N)=O)c(Nc2ccccc2[N+](=O)[O-])s1
Yield: 84.3 %

Procedure:
Stir 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester (68.6 g, 204 mmol) at rt under N2 as a slurry in DMF (205 mL). Add formamide (32.4 mL, 816 mmol, 4.0 eq.) in one portion, and heat the thick red slurry to 100° C.; a dark red/purple solution is formed. Add dropwise over 20–30 min, 25% NaOMe in MeOH (32.6 mL, 143 mmol, 0.7 eq.) Increase the temperature 120° C. and stir the dark solution was stirred at 120° C. overnight until complete (<2% Me ester+SM) by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). After cooling the reaction to rt, add aqueous 5% NH4Cl (410 mL) at such a rate as to maintain the temperature below 35° C. with no external cooling. Precipitate the product, cool the slurry to 0–5° C., filter by vacuum filtration and dry in a vacuum oven at 60° C. to afford 52.7 g (84% yield) crude title compound as a purple solid that was used without further purification. An aqueous workup may result in bad emulsions/slow separations. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (bs, 1H), 8.21 (d, 1H, J=7.69 Hz), 7.78 (m, 2H), 7.59 (bs, 1H), 7.53 (bs, 1H), 7.15 (m, 1H), 3.23 (dq, 1H, J=6.95 Hz), 1.35 (d, 6H, J=6.95 Hz). 13C NMR (75 MHz, DMSO-d6) δ 165.53, 161.44, 144.58, 137.12, 136.31, 135.72, 128.90, 126.58, 121.08, 116.28, 32.32, 22.35(2). IR (CHCl3) 3520, 3400, 3004, 2967, 2925, 2866, 1658, 1611, 1578, 1513, 1427, 1342 cm−1. HRMS(ES) M/z calculated for C13H14N4O3S1 329.0684, found 329.0667.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>O1CCOCC1>[F:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Yield: 84.4 %

Procedure:
Using a method similar to Preparation 13, using 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol), dioxane (20 mL), and 2,4-difluorobenzoyl chloride (1.46 g, 8.3 mmol) gives the title intermediate (1.6 g, 84% yield): mass spectrum (ion spray): m/z=297.0 (M+1).
Reaction SMILES: [OH-].[Li+].[C:3]1([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25]C)=[O:24])=[C:21]3[C:16]([C@H:17]4[CH2:29][CH2:28][O:27][C@H:18]4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)=O>O1CCOCC1.O>[C:3]1([S:9]([NH:12][C:13]2[C:22]([C:23]([OH:25])=[O:24])=[C:21]3[C:16]([C@H:17]4[CH2:29][CH2:28][O:27][C@H:18]4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 24.6 %

Procedure:
Lithium hydroxide (0.048 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 1, 0.08 g) in a mixture of dioxane (10 mL) and water (5 mL) and the resultant mixture was irradiated in the microwave at 110° C. with air cooling for 20 minutes. Further lithium hydroxide (0.2 g) was added and the mixture was irradiated in the microwave at 110° C. with air cooling for a total of 80 minutes. After cooling, the solution was acidified by addition of aqueous formic acid solution (10%) and the resultant mixture was extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was dissolved in a mixture of methanol (10 mL) and water (5 mL) and treated with lithium hydroxide (0.2 g) then irradiated in the microwave at 110° C. with air cooling for 40 minutes. After cooling, the solution was acidified by addition of formic acid (10%) and the resultant mixture was extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 30-50% to give cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (0.019 g) as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([O-:20])(=O)=[O:18])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([Cl:2])(=[O:20])=[O:18])=[CH:11][CH:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])CCc1ccc(F)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(Cl)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Phosphorus pentachloride (5.6 g, 27 mmol) was added portionwise over 10 minutes to a stirred suspension of 2-(4-fluorophenyl)ethanesulfonic acid sodium salt (9 mmol, contaminated with sodium bromide, total weight 2.87 g) in dry toluene (15 ml) at room temperature. The reaction mixture was heated under reflux for 90 minutes and was then stirred at room temperature overnight. The reaction mixture was diluted with water (20 ml) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 ml) and the organic extracts were combined, dried over magnesium sulfate and concentrated under vacuum to give the title compound as an oil, (0.7 g) Rf 0.92 (dichloromethane).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[CH:29]=[CH:30][CH:31]=2)O1>>[CH3:17][C:15]1[N:16]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:30]4[CH:29]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[CH:27]=[CH:26][CH:31]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[N:12]=[N:13][CH:14]=1
Reactant: Cc1cnnc(-c2ccn3c(I)cnc3c2)n1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Product: Cc1cnnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1

Procedure:
3-Iodo-7-(5-methyl-[1,2,4]triazin-3-yl)-imidazo[1,2-a]pyridine (120 mg, 0.4 mmol, 1 equiv) and 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea were coupled according to procedure D4 to furnish the title compound as a yellow solid (85 mg). 1H NMR (400 MHz, DMSO-d6): 9.34 (1H, s), 8.99 (1H, s), 8.74 (1H, d), 8.67 (1H, s), 7.98 (1H, d), 7.93 (1H, s), 7.79 (1H, s), 7.55-7.43 (2H, m), 7.31 (1H, d), 6.87 (1H, t), 3.99-3.88 (2H, m), 2.65 (3H, s). MS: [M+H]+428