Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2=[N:16][O:17][C:13]3=[C:14]2[C:5]([C:6](=[O:18])[C:7]2[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:3]=1.[CH:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CC(OC)(C)C.CO>CS(C)=O>[CH:29]1([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:15]4=[N:16][O:17][C:13]5=[C:14]4[C:5]([C:6](=[O:18])[C:7]4[C:12]5=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:4]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH:3]=3)[CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(Nc2cc(Br)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: CO
Product: O=C(O)c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
About 70 g of 4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid was dissolved in 950 mL of DMSO. About 50 mL of TEA and 50 g of 1-cyclohexyl piperazine were added to the reaction. Temperature was raised to 60-70° C. After 2-3 hours, slowly added 500 mL of MTBE and MeOH (10:1) solution and adjusted the temperature to 40-50° C. The solid was centrifuged and washed by 100 mL of MTBE and MeOH solution and followed by 100 mL of MeOH. Solid was dried under reduced pressure at 25-30° C. for 12-24 hours to obtain the 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid at about 98% purity and about 91% yield.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:2]
Reactant: C1COCCN1
Reactant: C=CS(=O)(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Solvent: CC#N
Product: CCn1c(-c2ccc(NS(=O)(=O)CCN3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH3CN (1.5 mL) is heated at reflux for 1.5 h. After cooling to room temperature, the reaction is concentrated and the residue is purified by flash chromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg (100%) of 2-morpholin-4-yl-ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a tan foam.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCOCC1>ClCCl>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:7]
Reactant: O=C1NCC[C@@H]1O
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1[C@@H](O)CCN1c1ccccc1
Temperature: 25 °C

Procedure:
A Schlenk flask is initially charged with 0.123 g of 3(S)-hydroxy-pyrrolidin-2-one, 0.453 g of caesium carbonate, 0.032 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex and 0.052 g of 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthane under argon. 0.110 ml of bromobenzene and 2 ml dioxane are added and the reaction mixture is heated to reflux over 14 hours. The reaction mixture is subsequently cooled to room temperature, diluted with dichloromethane and filtered through Hyflo, and the filtrate is concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.24 (4:1 EtOAc-heptane); Rt=2.50.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29]C(=O)C)[C@@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[C:9]=2[N:10]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].C1COCC1.C(Cl)(Cl)Cl>CO>[NH2:4][C:5]1[N:6]=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:21]([OH:22])[C@H:16]3[OH:17])[C:9]=2[N:10]=1
Reactant: CC(=O)Nc1nc(OC(C)C)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)Oc1nc(N)nc2c1sc(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 18 h

Procedure:
Compound 27 (600 mg, 1.14 mmol) was dissolved in methanol (15 ml) under a dry nitrogen atmosphere. K2CO3 (31.5 mg, 0.2 mmol) was added and the mixture was stirred for 18 h periodically being monitored by TLC (1:1 THF:Chloroform). The reaction mixture was concentrated under vacuum and purified by flash column chromatography (3% methanol in chloroform). The isolated solid was triturated with ethyl ether yielding 210 mg (51%) of pure 28 as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 6.83 (s, 2H), 5.86 (d, J=5.2 Hz, 1H), 5.34 (m, 1H), 5.26 (d, J=5.6 Hz, 2H), 4.95 (d, J=5.6 Hz, 1H), 4.77 (m, 1H), 4.67 (m, 1H), 4.09 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 3.43 (m, 1H), 1.29 (d, J=6.4 Hz, 6H); MS (+)-ES [M+H]+ m/z 359, [2M+H]+ m/z 717.3. Rf=0.2 (50% THF—CHCl3). Elemental analysis for C13H18N4O16S: calc'd: C, 43.57; H, 5.06; N, 15.63; S, 8.95. Found: C, 43.39; H, 5.07; N, 15.45; S, 8.82.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:5]([C:14]([OH:16])=O)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C1C=C[C:29]2N(O)N=[N:32][C:30]=2C=1.[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37](CCN)=[CH:38][CH:39]=[CH:40][CH:41]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH:4]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:5]([C:14](=[O:16])[NH:32][CH2:30][CH2:29][C:48]1[CH:47]=[CH:46][C:45]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:50][CH:49]=1)[CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8]
Reactant: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccccc1-c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)NCCc1ccc(-c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 53 (590 mg, 1.68 mmol) and HOBt (272 mg, 2.016 mmol) in anhydrous DMF was stirred in an ice bath for 10 minutes. Biphenyl ethylamine (404 mg, 2.02 mmol) was added followed by the addition of DIC (320 μL, 2.01 mmol). After 20 minutes, the ice bath was removed and stirring was continued at room temperature. After 24 h of stirring, the reaction mixture was partitioned between ethyl acetate and HCl (1M, excess). The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was extracted with brine, saturated sodium hydrogen carbonate, and brine. The solvent was evaporated following drying over sodium sulfate and filtration. The crude was flashed using 25% EtOAc in hexanes. 1H-NMR(CDCl3, 300 MHz: 1.41(s, 9H); 1.82(m, 2H); 2.23(m, 1H); 2.55(t, J=8.1 Hz, 2H); 2.75(m, 5H); 3.54(m, 1H); 3.70(s, 3H); 6.09(t, J=5.7 Hz, 1H); 7.13-7.36, 7.41-7.49, 7.55-7.58(m, 14H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C[O:13][C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([CH:15]([CH3:21])[C:14]([OH:22])=[O:13])[C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C(=O)O)C(=Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
After careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (60% in mineral oil, 16 g, 0.40 mol) in anhydrous toluene (200 mL), a solution of 4-chloro-benzaldehyde (28 g, 0.20 mol) and 2-methyl-succinic acid dimethyl ester (48 g, 0.30 mol) in anhydrous toluene (100 mL) was added dropwise at room temperature under a stream of nitrogen. After being stirred at room temperature for 2 hours, the resulting mixture was diluted by adding 2 N sodium hydroxide (200 mL) dropwise, then heated to 80° C., and stirred at the same temperature for 2 hours. After being cooled to room temperature naturally, the aqueous layer was separated, washed with ethyl acetate (100 mL×3), then acidified with 2 N hydrochloric acid to pH 2, and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated from ethyl acetate/petroleum ether (10:1) to give 2-(4-chloro-benzylidene)-3-methyl-succinic acid (13.4 g, 26%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH2:38])=[S:37])[CH3:28].[C:39]([O-])(=[O:41])C.[Na+]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:38][C:39]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=1)=[O:41])=[S:37])[CH3:28]
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(=O)[O-]
Reactant: CCc1ccccc1NC(N)=S
Agent: [Na+]
Product: CCc1ccccc1NC(=S)NC(=O)NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(2-ethylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.175 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.07 (s, 1H), 9.40 (s, 1H), 8.13-8.04 (m, 2H), 8.02-7.93 (m, 2H), 7.65-7.59 (m, 2H), 7.55 (dt, J=6.5, 3.7 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 7.31-7.24 (m, 1H), 7.21 (dd, J=5.8, 3.5 Hz, 2H), 7.15-7.06 (m, 1H), 3.18 (q, J=6.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 1.90-1.74 (m, 2H), 1.12 (t, J=7.5 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 569 ([M+H]+), 567 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19]([CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])[CH3:17]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(=O)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.8 %

Procedure:
To a stirred suspension of 2-chloro-5-(chloromethyl)pyridine (2.0 g, 12 mmol) in acetonitrile (60 mL) was added potassium carbonate (1.5 mL, 25 mmol) followed by 1-(ethoxycarbonylmethyl)piperazine (2.0 mL, 12 mmol). The resulting mixture was stirred at room temperature for 19 h. The mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was subjected to combi-flash column chromatography (methanol/DCM with Et3N) to give compound 348 (1.1 g, 30% yield) as a colorless liquid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.31 (1 H, d, J=2.0 Hz), 7.66 (1 H, d, J=6.1 Hz), 7.28 (1 H, d, J=8.1 Hz), 4.18 (2 H, q, J=7.1 Hz), 3.50 (2 H, br. s.), 3.21 (2 H, s), 2.36-2.77 (8 H, m), 1.27 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 298.1.
Reaction SMILES: [CH2:1]([N:8]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([N:8]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:9][C@H:10]([O:11][C:39](=[O:41])[CH3:40])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(N(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2C1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2ccccc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(R)-2-[Benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol (2.75 g) is dissolved in pyridine (15 mL). Acetic anhydride (1.66 g) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 18 hours. Water (10 mL) is added to quench the reaction. Ethyl acetate (250 mL) is added and the solution is washed with 1M KHSO4 (3×100 mL), saturated NaHCO3 (100 mL), water (100 mL) and brine (100 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 4:1 Rf=0.40).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Si:1]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CCC(CO)CC1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CCC(C=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of (4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)methanol (7.38 g) and triethylamine (8.37 mL) in DMSO (50 mL) was added sulfur trioxide pyridine complex (9.56 g). The reaction mixture was stirred at room temperature for 3 hr and extracted with diethyl ether and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (5.83 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:7]1[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1Cl
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2Cl)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-chloro phenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C21H19ClNO3 (M+H): 368.1048. Found 368.1015
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([N+:12]([O-])=O)[CH:3]=1>C(O)C.O>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([NH2:12])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: Cc1cc(N)c(N)c([N+](=O)[O-])c1
Temperature: 28 °C
Yield: 76.8 %

Procedure:
The procedure of Gillespie et al., J. Org. Chem. 25:942 (1960) was adopted as follows. A dark black solution of 4-methyl-2,6-dinitroaniline (0.100 g, 0.561 mmol, Aldrich, used as received) in 6.66% aq. (NH4)2S (3.3 mL, prepared from 20% aq.(NH4)2S solution supplied by Aldrich) and ethanol (3.5 mL) was refluxed for 45 min. It was then cooled to 28° C. and the solvents were removed as much as possible under vacuum (inside the hood to avoid the stench of ammonium sulfide). The slurry so obtained was diluted with water (10 mL) and the resulting red solid was filtered and dried under vacuum to obtain 0.072 g (85%) solid as a red powder, which was used as such for the next reaction. 1H NMR (acetone-d6): 2.205 (s, 3H), 6.342 (br s, 2H), 6.622 (s, 1H), 7.571 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:25])([F:26])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH:17]([F:28])[CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1c2ccc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)cc2CC1F
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure and diluted with CH2Cl2. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M−H]−); IR (thin film) 1728, 1114, 817 cm−1.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[CH2:30][C:29]5[C:24](=[C:25]([N+:31]([O-])=O)[CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:34])=[CH:20][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl>[NH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[C:23](=[O:34])[N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=4)[N:14]=3)[NH:19][CH:20]=1)[CH2:30]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cccc([N+](=O)[O-])c4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5cccc(N)c5C4=O)c3n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-7-nitro-isoindolin-1-one (148 mg, 0.2056 mmol) suspended in EtOH (5 mL) and mixture heated to 70° C. SnCl2.2H2O (232.0 mg, 1.028 mmol) added and the mixture heated at reflux. After 1 h a further ˜200 mg SnCl2.2H2O added. After 1 h reaction mixture cooled, diluted with DCM and sat NaHCO3 added. Mixture stirred vigorously for 30 mins then passed through a phase separator cartridge. Org phase concentrated to a yellow solid (158 mg). This material deprotected using Method E Step 2 to give the title compound after purification using hplc; 1H NMR (400 MHz, DMSO) δ 1.21 (6H, d), 3.49 (1H, sep), 5.35 (2H, s), 6.22 (2H, s), 6.65 (1H, d), 6.81 (1H, d), 7.31 (1H, dd), 7.99 (2H, d), 8.43 (1H, s), 8.50 (2H, d), 9.07 (1H, s), 12.27 (1H, brs) ppm; MS (ES+) 448.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[O:17]CC([O-])=O)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([OH:17])[CH:22]=[CH:23][CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])COc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the acetate from Step 2 (550 mg) in THF (5 mL) and methanol (5 mL) was added milled potassium carbonate (414 mg) and the mixture stirred at room temperature for 2.5 hours. The mixture was poured into pH 7 buffer solution and extracted with ethyl acetate. The organic layer was dried, filtered and filtrate evaporated to afford the title product as yellow-solid: m.p. 197°-199° C.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].COC(OC)[N:14]([CH3:16])C.O.[NH2:20]N>C(O)C>[CH2:8]([C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:16][NH:14][N:20]=1)[CH2:9][CH3:10]
Reactant: NN
Reactant: CCCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: O
Product: CCCc1n[nH]cc1C(=O)OC
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-oxohexanoate (2.1 g) and dimethylformamide dimethylacetal (2.1 mL) was stirred at 100° C. for 12 hr, and the mixture was allowed to cool. To the reaction mixture were added ethanol (50 mL) and hydrazine monohydrate (0.75 mL). In the same manner as in Example 1(3), a crude product of methyl 3-propyl-1H-pyrazole-4-carboxylate was obtained. This was dissolved in dimethylformamide (20 ml), potassium carbonate (3.0 g) and 2-chloro-5-trifluoromethylpyridine (2.7 g) were added, and the mixture was stirred at 100° C. for 2 hr. In the same manner as in Example 1(4), the title object compound (3.3 g, 71%) was obtained as a white solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.Cl.[CH2:16](O)[CH3:17]>O1CCOCC1>[CH2:16]([O:9][C:8](=[O:10])[CH2:7][C:3]1[CH:2]=[C:1]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=1)[CH3:17]
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(CC(=O)O)c1

Procedure:
A solution of the diester from preparation 16 (44.3 g, 177 mmol) and 2,2′-(1,3-phenylene)diacetic acid (59.2, 308 mmol) in ethanol (24 ml) and dioxan (290 ml) was treated dropwise with 12M hydrochloric acid (4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry filtered. The filtrate was concentrated in vacuo and the residue taken up in water and basified with sodium bicarbonate until pH neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5×30 ml) and brine (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3×30 ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The residue was triturated with pentane giving the title compound as a colourless solid 10.8 g.