Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[OH:34][C@:30]([C:27]1[CH:26]=[C:25]([CH3:24])[O:29][N:28]=1)([CH3:31])[C:32]#[C:33][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (5 g) was subjected similar to as described in Example 6 to yield 4.2 g of methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. Methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (0.52 g) was subjected to lithium hydroxide water/THF to give 0.44 g of 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.44 g) was reacted with Methylamine hydrochloride similar to as described in Example 2 to afford 314 mg 10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following triteration from water. 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 43.9 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 436 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (q, J=4.3 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 6.36 (s, 1H), 5.04-4.91 (m, 2H), 4.57-4.44 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][CH:5]3[N:6](C(OC(C)(C)C)=O)[C:7]=2[CH:8]=[CH:9][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:38]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39]1.N#N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[O:38]1[CH:42]=[CH:41][C:40]([C:2]2[C:3]3[C@@H:4]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:5]4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:39]1
Reactant: CC(C)(C)OC(=O)N1CCC2c3c(Br)cccc3N(C(=O)OC(C)(C)C)C2CC1
Reactant: OB(O)c1ccoc1
Agent: [Pd]
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc2c(c(-c3ccoc3)c1)[C@@H]1CCNCC[C@@H]1N2
Temperature: 80 °C
Yield: 69.8 %

Procedure:
A 30-mL shaker vial was charged with di(tert-butyl) 10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol), furan-3-boronic acid (0.072 g, 0.642 mmol), and DMF (2 mL). The vial was purged with N2, and tetrakis(triphenylphosphine)-palladium (0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPM with heating at 80° C. overnight. The mixture was filtered through Celite, washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial was then purged with N2, capped and agitated at 250 RPM with heating at 65° C. for 72 h. The mixture was filtered through a scintered funnel and the resin was washed 1:1 methylene chloride/methanol and then consecutively washed with MeOH and THF to ensure that all excess reagent was removed from the resin (the methanol and THF washes are alternated to swell and then shrink the resin to help expel reagents from inside the resin). The resin was then washed with 4M ammonium hydroxide in methanol (4×2 ml) and THF (2×2 ml) into an accurately weight round-bottomed flask. The filtrate was concentrated to give 0.038 g (70%) of a pink oil: MS (EI) m/z 255 (MH+); HPLC rt=2.51 min (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C[O:24]B(OC)OC.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[OH:24]
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(O)c(F)c2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
In a nitrogen atmosphere, 10.00 g of 3,5-difluoro-1-(4-propylphenyl)benzene was dissolved in 50 mL of THF, and the resultant solution was cooled to −40° C. Then, 30 mL of butyl lithium (1.6 mol/L, hexane solution) was added at such a rate that the inside temperature did not exceed −35° C. After stirring at −40° C. for 1 hour, 5.37 g of trimethoxyborane was added at such a rate that the inside temperature did not exceed −35° C. After stirring at −40° C. for 1 hour, the inside temperature was increased to room temperature, and 10% hydrochloric acid was added until the reaction system became acidic. Then, an organic layer was separated from the mixture, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and cooled with ice, and 11.71 g of a 15% aqueous hydrogen peroxide solution was added to the mixture, followed by stirring at room temperature for 15 hours. Further, an organic layer was separated from the mixture, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and washed with a 10% aqueous sodium sulfite solution and saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to yield 10.24 g of 2,6-difluoro-4-(4-propylphenyl)phenol.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][C:3](=[O:13])[CH2:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+]>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][CH2:2][C:3]1=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1CNc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CNc2ccccc2C(=O)N1CCCCBr
Yield: 64 %

Procedure:
A solution of 84.2 mg of 2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione dissolved in 10 ml of dimethylformamide was ice-cooled, and then 0.0874 ml (1.5 equivalents) of 1,4-dibromobutane and 23.0 mg (1.2 equivalents) of 60% sodium hydride were added, followed reaction treatment and purification were conducted in the desired compound (yield 64%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([NH:11]C(OC(C)(C)C)=O)([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)Cl)=[CH:43][CH:42]=1>C(OCC)C.CCO>[C:1]([O:5][C:6](=[O:19])[C:7]([NH:11][CH:47]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[C:44]1[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COc1ccc(C(NC(C)(CO)C(=O)OC(C)(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol 9 (100 mg, 0.36 mmol) in 2 mL of diethyl ether was added 1 eq of p-toluenesulfonic acid monohydrate (69 mg) dissolved in 6 mL of EtOH. The reaction mixture was concentrated under reduced pressure at 40° C., and the residue was dissolved in 6 mL of EtOH and concentrated again. This process was repeated 4 times, at which time no starting material was present on TLC analysis. The resulting white solid was suspended in 3 mL of CH2Cl2, and treated with 4.5 eq of triethylamine (0.23 mL) followed by 1 eq of bis(4-methoxyphenyl)chloromethane (95 mg). The reaction mixture was stirred for 1 hour at room temperature. The solution was then partitioned between 10 mL of EtOAc and 10 mL of H2O. The aqueous layer was extracted with 10 mL of EtOAc followed by the usual work up of the combined organic layers. Purification by silica gel column chromatography (20% EtOAc in hexane) provided the amino ester 12a as a colorless oil (107 mg, 73% from 9): 1H NMR (CDCl3) δ 1.17 (3H, s), 1.46 (9H, s), 3.35 (1H, d, J=11.2), 3.44 (1H, d, J=11.2), 3.76 (3H, s), 3.77 (3H, s), 4.82 (1H, s), 6.80-6.84 (4H, m), 7.27-7.31 (4H, m). Anal. (C23H31NO5)C,H,N.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]([Cl:18])=[CH:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[Na+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[Cl:6][C:7]([Cl:18])=[CH:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH2:3][CH2:4][OH:5])=[CH:13][CH:12]=1
Reactant: Oc1ccc(OCC=C(Cl)Cl)cc1
Reactant: OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCOc1ccc(OCC=C(Cl)Cl)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
A mixture of 1.40 g of 3-bromopropanol, 10.0 g of toluene and 0.14 g of tetra-n-butylammonium bromide was heated to 60° C. Thereto was added dropwise a mixed solution of 2.0 g of 4-(3,3-dichloro-2-propenyloxy)phenol, 10.0 g of water and 1.49 g of a 27% aqueous sodium hydroxide solution with stirring over 6 hours. After completion of the addition, the mixture was further stirred for 11 hours at 60° C. In this period, 0.20 g of 3-bromopropanol and 0.20 g of a 27% aqueous sodium hydroxide solution were further added at the time point of 7 hours. Then, the reaction mixture was cooled to 20° C. After 4.0 g of a 20% aqueous sulfuric acid solution and 5.0 g of toluene were added thereto, the mixture was stirred and then separated. The obtained organic layer was washed once with 10.0 g of a 1% aqueous sodium hydroxide solution and once with 10.0 g of water, and concentrated under reduced pressure to give 2.5 g of 3-(4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 93%, yield: 93%).
Reaction SMILES: [Mg].C([Mg])CCC.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][CH:8]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CCCC[Mg]
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1c[nH]c2ccccc12
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
Magnesium (2.08 g), toluene (40 ml), triethylamine (10.4 g) were put into a 3″ diameter flask, and the internal temperature was raised to 30 to 45° C. A solution of 1-iodebutane (18.9 g) in toluene was added under stirring at an internal temperature of 30 to 45°C. After stirring for two hours at the same temperature, the temperature was lowered to 0 to 5° C., thereby preparing a solution of iode n-butylmagnesium in toluene. To this prepared Grignard reagent, indole (10.0 g) dissolved beforehand in toluene (25 ml) was added at an internal temperature of 0 to 10° C., and a reaction was carried out for about one hour at the same temperature to synthesize iodeindole-1-ylmagnesium. Then, benzoyl chloride (12.0 g) and toluene (60 ml) were put into another 3″ diameter flask, and the internal temperature was lowered to below −15° C. The slurry of the iodeindole-1-ylmagnesium prepared previously was added to the solution of this acid chloride while keeping the internal temperature at −15 to −10° C., and the mixture was stirred for more one hour at the same temperature. The internal temperature was then raised further to 20 to 25° C., and the mixture was stirred for one hour. After this reaction, the mixture was added to an aqueous ammonium chloride solution (16 g, 60 ml) prepared beforehand in another 3″ diameter flask at 10° C. or less to carry out quenching. Acetone (220 ml) was added thereto, the internal temperature was raised to 50 to 65° C., and dissolution was carried out, followed by separation. The organic layer of the upper layer was then collected and cleaned with an aqueous 5% sodium hydrogencarbonate solution at the same temperature. The solvent was evaporated so as to be concentrated. Methanol (20 ml) was added thereto and refluxed. After cooled to an internal temperature of 2 to 10° C., a precipitated crystal was filtered. The filtered crystal was cleaned with cooled methanol (5 ml) and dried to obtain a crystal of 3-benzoylindole (13.7 g) (72.2% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)=[CH:7][N:6]=2)=[O:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of N-(5-bromopyridin-2-yl)-4-methanesulfonylbenzamide (287 mg, 0.81 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (305 mg, 0.97 mmol) in dry N,N-dimethylformamide (10 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with dichloromethane) (33 mg, 0.040 mmol) and cesium carbonate (527 mg, 1.6 mmol). The mixture was stirred at 90° C. overnight under N2, allowed to cool to room temperature, 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=1/2) to give the title compound as a white crystal (83 mg, yield 22%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:15](C)(C)[C:16]([O-])=O.[K+].C(I)C.O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)C(=O)[O-]
Reactant: N#CCc1ncc(C(F)(F)F)cc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(C#N)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
199 g (0.9 mol) of 3 of [3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile are dissolved in 3 L of THF at −5° C. A solution of 106 g (0.945 mol) of potassium terbutanoate in 0.6 L of THF is slowly added to the reaction medium. After 2H, 147 g (0.945 mol) of ethyl iodide is added dropwise to the reaction mixture which is stirred overnight at room temperature. 3 L of water and 2 L of ethyl acetate are added to the reaction mixture, after separation, the aqueous phase is extracted twice with 500 mL of ethyl acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[C:19]2[N:18]=[CH:17][NH:16][C:15]=2[C:14](=[O:20])[NH:13][C:12]1=[S:21].[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:32]=O)=[CH:24]1>>[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][NH:8][CH2:9][CH2:10][N:11]2[C:19]3[N:18]=[CH:17][NH:16][C:15]=3[C:14](=[O:20])[NH:13][C:12]2=[S:21])=[CH:24]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: NCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(CNCCn2c(=S)[nH]c(=O)c3[nH]cnc32)c2ccccc21
Yield: 197.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 26(c) by using 3-(2-aminoethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate (98 mg, 0.3 mmol, obtained from Example 26(b)) and 1-methylindole-3-aldehyde (51 mg, 0.03 mmol) which yielded 0.021 g (20% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH2:8][S:9][C:10]2[N:19]=[C:18]([NH:20][C@H:21]([CH3:31])[CH2:22][NH:23]C(=O)OC(C)(C)C)[C:17]3[N:16]=[CH:15][C:14](=[O:32])[NH:13][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.Cl.O>[ClH:1].[NH2:23][CH2:22][C@H:21]([NH:20][C:18]1[C:17]2[N:16]=[CH:15][C:14](=[O:32])[NH:13][C:12]=2[N:11]=[C:10]([S:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:33])[N:19]=1)[CH3:31]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CN)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12
Reaction time: 2 h
Yield: 175.2 %

Procedure:
A two-phase mixture of the product from Example 9 (76 mg) in 1,4-dioxane (3 ml) and conc. HCl (0.3 ml) was stirred for 2 hours, then diluted with water (10 ml) and lyophilised. The residue was dissolved in water (10 ml), washed with ethyl acetate (5 ml), and lyophilised to give the titled compound as a pale yellow solid (58 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:16][CH2:15][CH2:14][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOCc1ccccc1
Reactant: OCc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1COCCOCc1ccccc1
Yield: 50.5 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanol (5 g, 24.509 mmol) in DMF (50 mL) at 0° C. NaH (60% suspension in mineral oil, 1.96 g, 49.018 mmol) was added in portions. To the resulting suspension ((2-bromoethoxy)methyl)benzene (6.32 g, 29.41 mmol) was added at 0° C., and the reaction mixture was allowed to stir at RT for 16 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was quenched with MeOH (5 mL), diluted with ice cold water (50 mL) and was extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water (50 mL), brine (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 1-((2-(benzyloxy)ethoxy)methyl)-4-bromo-2-fluorobenzene (4.2 g, 51%) as yellow liquid (TLC solvent system: 30% EtOAc in PE; Rf: 0.6).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Yield: 90.4 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (3.67 g, 30 mmol), 2,4-thiazolidinedione (3.51 g, 30 mmol) and benzoic acid (4.40 g, 36 mmol) in toluene (100 mL) was added piperidine (4.5 mL, 45 mmol) and the mixture was equipped with a Dean Stark apparatus and brought to a vigorous reflux. After 45 min the mixture was cooled in an ice bath and the supernatant was decanted. The bright yellow solid was made into a suspension by the addition of glacial acetic acid (100 mL) and filtered through a Buchner funnel to yield a pale yellow solid (6.00 g, 90%). 1H NMR: (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 10.30 (s, 1H), 7.70 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Br:13]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:13][C:10]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]([Cl:1])=[C:3]2[S:12][CH:11]=1
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2c(Br)csc2c1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.1 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (100 mg, 0.51 mmol) and N-bromosuccinimide (118 mg, 0.66 mmol) in 0.63 mL of dimethylformamide is stirred at room temperature for 4 days. Additional N-bromosuccinimide (118 mgs) is added and the reaction mixture is heated at 40° C. for 17 hours. Additional N-bromosuccinimide (118 mgs) is added and the reaction mixture is heated at 40° C. for 24 hours. Additional N-bromosuccinimide (118 mgs) is added and the reaction mixture is heated at 60° C. for 24 hours. The mixture is cooled to room temperature and treated with ice water and neutralized with aqueous saturated sodium bicarbonate. The resultant solid is purified by flash column chromatography eluting with 10% hexane in dichloromethane to provide 35 mg of 3-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 176–178° C.; 1H NMR (DMSO-d6) δ 8.79 (s, 1H), 9.23 (s, 1H); MS 272.9, 274.8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24](Br)[CH:25]=[C:7]2[C:6]=1[OH:27])=[O:4].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[C:7]2[C:6]=1[OH:27])=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(O)c2cc(Br)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(O)c2cc(-c3ccccc3)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Temperature: 120 °C
Yield: 13.3 %

Procedure:
A mixture of 6-bromo-4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (446 mg), phenyl boronic acid (366 mg), PEPPSI-IPr (34 mg; Total Synthesis Ltd./Sigma-Aldrich), and sodium carbonate solution (1.0 mL, 2 M in water) in DMA (10 mL) was heated at 120° C. for 5 h; the mixture was then cooled, diluted with EtOAc, washed with water, diluted HCl solution and sat. NaCl solution respectively; subsequently, the organic phase was dried over sodium sulfate, filtered, concentrated, and the residue was column purified (eluent: DCM/MeOH) to give the desired product (59 mg). ESI (m/z): 443 (M+H)+.