Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](=[N:9][OH:10])[NH2:8].Cl[C:22](OCC)=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]1[NH:8][C:22](=[O:23])[O:10][N:9]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=NO)c1Cl
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2noc(=O)[nH]2)c1Cl
Yield: 46.4 %

Procedure:
To a room temperature solution of 2-(2,6-dichloro-3-methylanilino)benzamide oxime (585 mg, 1.89 mmols) in 5 mL of pyridine is added ethyl chloroformate (250 μL, 2.62 mmols). The solution is heated at reflux for 1 hour, cooled, and concentrated in vacuo. Flash chromatography eluting with 2:1 hexane: ethyl acetate provides 295 mg (47%) of 3-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,2,4-oxadiazol-5(4H)-one as a white solid;
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.CC([O-])=O.[K+].C(#N)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>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[O:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3o2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[2,3-d]pyrimidine (1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.7 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M KOAc aqueous solution (3 eq) and an equal volume of acetonitrile (3 eq) was heated to 140° C. in a sealed microwave reactor for 12 min. Upon completion, the reaction mixture was concentrated and crude mixture was purified by reverse phase HPLC to yield 34 mg of 165. MS (Q1) 476 (M)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.O>CN(C)C=O>[CH3:14][C:12]1[N:13]=[C:9]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:10][C:11]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1sc(Cl)nc1C
Reactant: Sc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(Sc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Thiophenol (1.90 ml) was dissolved in N,N-dimethylformamide (10 ml) Sodium hydride (60% oil suspension, 740 mg) was added by portions under ice-cooling, and the mixture was stirred at room temperature for 15 min. Thereafter, a solution of ethyl 2-chloro-4-methylthiazole-5-carboxylate (3.05 g) in N,N-dimethylformamide (10 ml) was added dropwise, and the mixture was stirred at the same temperature for 20 min. Water (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed twice with water (50 ml) and then with saturated brine (30 ml), and dried (Na2SO4). Ethyl acetate was evaporated under reduced pressure and the obtained residue was purified by column chromatography to give ethyl 4-methyl-2-phenylsulfanylthiazole-5-carboxylate (3.85 g).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)CCCc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCCc1cccs1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
2-(4-Oxopentyl)thiophene (3.30 g, 19.6 mmol) was dissolved in 10 ml of 95% ethanol and the solution was added to a stirred solution of sodium borohydride (0.38 g, 10 mmol) in 20 ml of ethanol at room temperature. The mixture was stirred overnight and the excess reducing agent destroyed by the dropwise addition of 1N HCl. The solvents were evaporated and the residue partitioned between water and ether. The organic phase was washed with water and brine and dried (Na2SO4) Evaporation of the solvents gave 3.13 g of product as a yellow oil, which was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][C:11]1[C:6]2([CH2:18][C:19]#[N:20])[CH2:7][CH2:8][C:9](=[O:17])[CH:10]=1.C1C=CC=CC=1.[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH2:27]1[CH2:28][O:29][C:9]2([CH2:8][CH2:7][C:6]3([CH2:18][C:19]#[N:20])[C:11](=[CH:12][CH2:13][C:14]4[C:5]3=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=4)[CH2:10]2)[O:17]1
Reactant: OCCO
Reactant: COc1ccc2c(c1)C1(CC#N)CCC(=O)C=C1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C1(CC#N)CCC3(CC1=CC2)OCCO3

Procedure:
A mixture of the crude enone III, benzene (2.5 l), ethylene glycol (150 ml) and p-toluenesulphonic acid (4.0 g) was refluxed with water separation (Dean-Stark trap) for 17 hrs. cooled and evaporatd at reduced pressure to approximately 500 ml. Dichloromethane (2.5 l) was added; the mixture worked up, the organic solution was evaporated to approximately 700 ml and diluted with ether (1.5l). The ketal IV was obtained in two crops as colorless needles (249 g, 80%); m.p. 174°-175° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNC(C)C
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CC(C)N(C)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-Isopropylmethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-isopropyl-methyl-amine, MS: 389 (MH+, 1Cl).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O>C(O)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:12]2[N:11]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)=[C:18]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:19]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3cccnc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3cccnc3)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (389) (45 mg, 0.088 mmol) in acetic acid (2 mL), concentrated H2SO4 (0.001 mL, 0.018 mmol) was added and the reaction mixture was stirred for 4 h at room temperature (monitored by LC-MS). From the reaction, volatiles were removed and the residue was quenched with ice col d water (5 mL). Aqueous saturated NaHCO3 was added to adjust the pH up to 8. The quenched mass was extracted with ethyl acetate (2×15 mL), the combined organic part was dried, concentrated and purified by preparative HPLC to get 6-(4-chloro-2-pyridin-3-yl-benzyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (390) (12.0 mg, 32.26%) as an off-white solid.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:38][N:39]([CH3:44])[CH2:40][C:41](O)=[O:42].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CCN(CC)CC>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:41](=[O:42])[CH2:40][N:39]([CH3:44])[CH3:38])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 in DMF (2.0 ml), Et3N (25.1 μl ) was added, N,N-dimethylglycine hydrochloride (16.7 mg) and WSC.HCl (23 mg) were added thereto and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC. The obtained compound was dissolved in ethyl acetate, washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried, and then the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)#[CH:16].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]3([OH:25])[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A mixture of 4-bromo-4'-hydroxybiphenyl (747 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis(triphenylphosphine)-palladium (II) chloride (105 mg), copper (I) iodide (55 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 4 hours. The reaction mixture was cooled and the dimethylformamide and triethylamine were removed by evaporation. The residue was purified by flash column chromatography on alumina (ICN - Alumina N32-63) using a gradient of 10% methanol in ethyl acetate to 20% methanol in ethyl acetate as eluent to give 3-[(4'-hydroxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (220 mg) as a solid, m.p. 230-233° C.; microanalysis, found C, 76.7; H, 6.6, N, 4.4%; C21H21NO2 0.5H2O requires C, 76.8; H, 6.7; N, 4.26%; NMR (DMSO-d6): 1.2-1.42(1H, m), 1.5-1.72(1H, m), 1.8-2.0(3H, m), 2.65-2.8(4H, t), 2.8-3.2(2H, d of d), 5.6-5.7(1H, br), 6.8-6.9(2H, d) and 7.48-7.63(6H, m); m/z 320 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc(C)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
To a solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20 g, 80 mmol), prepared as described in Example 361B, and 4-methylphenylboronic acid (13 g, 96 mmol) in toluene (300 mL) at RT under argon was added (Ph3P)4Pd (1.85 g, 1.8 mmol) and 2 M aqueous Na2CO3 solution (160 mL, 320 mmol). The resulting suspension was heated at 100° C. for 5 h with stirring. HPLC/MS indicated complete reaction. After cooling the reaction mixture to room temperature, it was extracted with CH2Cl2 (200 mL×2), then dried (Na2SO4), filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc to give the title compound, 2-benzyl-4-methoxy-5-p-tolylpyridazin-3(2H)-one, (21.9 g, 89%) as a white foam. MS [M+H]+ 307; HPLC retention time=3.78 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:28]1[N:35]=[CH:34][CH:33]=[C:32]([I:36])[C:29]=1[CH:30]=[O:31].[NH4+].[Cl-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:28]1[C:29]([CH:30]=[O:31])=[C:32]([I:36])[CH:33]=[CH:34][N:35]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1c(I)ccnc1F
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ccc2c1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a solution of 6-tert-butyl-8-fluoroisoquinolin-1(2H)-one (225 mg, 1.03 mmol, Eq: 1.00) in THF (11.1 ml) was added lithium bis(trimethylsilyl)amide in THF (1 M) (1.13 ml, 1.13 mmol, Eq: 1.1) at room temperature. The reaction mixture was stirred for 20 min. at the same temperature. Then 2-fluoro-4-iodonicotinaldehyde (335 mg, 1.33 mmol, Eq: 1.3) in THF (5 mL) was added. The reaction mixture was heated to 65° C. and stirred for 3 h. Then the reaction was poured into an aqueous-saturated solution of NH4Cl (30 mL) and product was extracted with EtOAc (2×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated under vacuum. Crude was diluted with CH2Cl2 (2 mL) and purified by chromatography (SiO2, Hex:AcOEt, 100% to 70% in 25 min) to afford the desired product (350 mg) as a light yellow powder. LC/MS, m/z 451[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9 H) 6.65 (dd, J=7.58, 2.02 Hz, 1 H) 7.21 (dd, J=13.64, 1.77 Hz, 1 H) 7.31 (d, J=1.77 Hz, 1 H) 7.55 (d, J=7.58 Hz, 1 H) 7.91 (d, J=5.05 Hz, 1 H) 8.28 (d, J=5.31 Hz, 1 H) 9.94 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.CS(C)=O.CO.CO>[NH2:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Nc1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
To a solution of 3-amino-2-pyridinecarboxylic acid (56 mg, 0.40 mmol, available from Apollo Scientific) in DMF (2 ml) was added HATU (150 mg, 0.40 mmol) and DIPEA (0.211 ml, 1.21 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was added to the top of a 20 g aminopropyl cartridge that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The solvent was removed in vacuo to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (9 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32]Br.C[N+]1([O-])CC[O:38]CC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH:32]=[O:38]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(Cl)c(C=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene (2.0 g) in acetonitrile (20 mL) is added N-methylmorpholine-N-oxide (0.47 g). The resulting solution is stirred at ambient temperature for 2 h before more N-methylmorpholine-N-oxide (0.20 g) is added. After stirring at ambient temperature overnight, the solvent is removed under reduced pressure and the residue is filtered over silica gel eluting with dichloromethane.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc2scc(Br)c2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1sc2ccc(F)cc2c1Br
Yield: 26 %

Procedure:
A solution of 5.12 ml of fuming nitric acid and 4.5 ml of acetic acid was added dropwise, with stirring, to a cooled (5°-10° C.) mixture of 3-bromo-5-fluorobenzo[b]thiophene (5.35 g, 23.15 mmol) and 28.5 ml of acetic anhydride. The reaction mixture was stirred for 2 hours and poured onto ice water (350 ml) and extracted with CH2Cl2 (4×50 ml). The organic phases were combined, washed with water and dried over MgSO4. The solvent was evaporated and the residue was recrystallized from 90% ethanol to yield 1.7 g (26%) of 3-bromo-5-fluoro-2-nitrobenzo[b]thiophene. M.p. 129°-130° C. 1H-NMR(CDCl3): δ7.40 (ddd, 1H), 7.68 (ddd, 1H), 7.78 (dd, 1H).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[F:32][C:33]1[CH:34]=[C:35]([Mg]Br)[CH:36]=[CH:37][CH:38]=1.CCCCCC.C(OCC)(=O)C>C1COCC1.CO>[F:32][C:33]1[CH:38]=[C:37]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[O:9])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)sc2c1
Yield: 67.9 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.5 g, 3.4 mmol) in THF (13 mL) was treated with a 1.9 M THF solution of 3-Fluorophenylmagnesium bromide (9.0 mL, 17 mmol) to provide, after chromatography (silica gel, 1:1 hexane:ethyl acetate, 0-10% MeOH) 1.13 g (68%) of the title compound as an off-white solid: 1H NMR d 1.44 (m, 2H), 1.58 (m, 4H), 2.47 (m, 4H), 2.73 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 4.08 (t, J=6.0 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.87-6.93 (m, 1H), 6.97 (dd, J=2.3, 8.9 Hz, 1H), 7.11-7.20 (m, 3H), 7.33 (d, J=2.3 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H); 13C NMR d 24.2, 25.9, 55.1, 55.7, 57.7, 66.3, 104.3, 104.5, 114.3, 115.15, 115.22, 115.4, 124.4, 124.6, 124.8, 130.3, 132.2, 132.4, 133.7, 140.4, 158.1, 160.9, 163.3, 164.2, 192.8; IR (CHCl3) 1648, 1599 cm-1 ; MS (FD) m/e 489 (M+); Anal. calc'd. for C29H28FNO3S: C, 71.14; H, 5.76; N, 2.86. Found: C, 70.89; H, 5.83; N, 2.85.
Reaction SMILES: C1(C(C2C=CC=CC=2)[C:8]([OH:10])=[O:9])C=CC=CC=1.C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:37][Si:38]([CH3:46])([CH3:45])[C:39]1[S:40][CH:41]=[CH:42][C:43]=1[Cl:44].C(=O)=O>O1CCCC1.CCCCCC>[Cl:44][C:43]1[CH:42]=[C:41]([C:8]([OH:10])=[O:9])[S:40][C:39]=1[Si:38]([CH3:46])([CH3:45])[CH3:37]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1sccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1sc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A small (4 mg) sample of diphenylacetic acid was dissolved in 50 mL of tetrahydrofuran and stirred at room temperature. To this solution was slowly added dropwise n-butyllithium as a 2.5M hexane solution until the solution turned light yellow from the diphenylacetic acid dianion. This protocol ensures that the solution is dry. At this point the solution was cooled to -72° C. (acetone/dry ice). Once at this temperature 4.62 mL (11.542 mmol) of a 2.5M hexane solution of n-butyllithium was added followed by 1.76 mL (12.592 mmol) of diisopropylamine. For formation of lithium diisopropyl amide the reaction solution was raised to 0° C. (ice bath) for 20 minutes and then lowered again to -72° C. To the cold reaction solution was added 2.0 g (10.493 mmol) of 2-trimethylsilyl-3-chlorothiophene as a 5 mL tetrahydrofuran solution over a 20 minute period. Reaction pot temperature was maintained below -70° C. to ensure regioselective deprotonation. After 30 minute reaction time carbon dioxide gas was slowly bubbled through the yellow solution. During the bubbling the reaction temperature was kept below -55° C. Total carbon dioxide treatment lasted 10 minutes. Following carbon dioxide addition the solution was gradually warmed to 0° C. at which point the reaction was quenched with 50 mL of 1N hydrochloric acid causing some gas evolution. On addition of the acidic solution the reaction was brought to room temperature. A 50 mL volume of brine was also added. The organic layer was separated and the aqueous was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with brine (1×50 mL), dried (sodium sulfate), filtered, and evaporated to 2.38 g of a white solid. Recrystallization of the crude product with heptane gave 1.67 g of pure title compound as small white needles, mp=206°-210° C.