Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.S(Cl)([Cl:20])=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[ClH:20].[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:37]2[CH2:38][CH2:39][N:40]([C:7](=[O:9])[CH:6]=[CH:5][C:4]3[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:3]=3[O:2][CH3:1])[CH2:41][CH2:42]2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Product: Cl
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
In 10 ml of chloroform was suspended 2.5 g (10.5 millimoles) of 2,3,4-trimethoxycinnamic acid, and under ice cooling, 3.5 ml (about 48 millimoles) of thionyl chloride was added dropwise. The mixture was stirred for 30 minutes under ice cooling, and the excess of thionyl chloride and chloroform were distilled off under reduced pressure. The residue was diluted with 20 ml of methylene chloride and added dropwise under ice cooling to 30 ml of a methylene chloride solution of 2.7 g (9.4 millimoles) of bis(4-fluorophenyl)methylpiperazine and 2 g (19.8 millimoles) of triethylamine. The mixture was stirred for 30 minutes under ice cooling. Thereafter, a 10% aqueous solution of sodium bicarbonate was added, and the mixture was shaken. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting oily product was diluted with 20 ml of ethanol. One milliliter of concentrated hydrochloric acid was added and then ether was added. The crystals that precipitated were collected by filtration. Recrystallization from methanol gave 1.4 g (yield 27.3%) of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxycinnamoyl)piperazine hydrochloride as colorless crystals.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([OH:21])[C:9]([C:14]2[C:15]([OH:20])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH3:22][O:23][CH2:24]Cl.C1[CH2:30][O:29][CH2:28]C1>>[CH3:22][O:23][CH2:24][O:21][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:28][O:29][CH3:30]
Reactant: COCCl
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1-c1ccccc1OCOC
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a 250 mL of three-necked bottle was added NaH (content 50%, 3.5 g, 72 mmol), anhydrous THF (60 mL) and anhydrous DMF (20 mL), after the temperature was lowered to 0° C., a solution of biphenol (5.6 g, 30 mmol) in THF (15 mL) was added, stirred at this temperature for 10 minutes. Methoxymethyl chloride (6 mL, 78 mmol) was added dropwise, and the mixture was stirred for 8 h at room temperature, quenched by adding 100 mL of water, extracted with ethyl acetate (100 mL×3), the combined organic phase was washed with brine (60 mL×2), dried over MgSO4, after filtration, the solvent was removed to give a yellow oil. Purification through chromatography give 8 g (97% yield) of the product as a light yellow oil. 1HNMR (300 MHz, CDCl3) δ (ppm) 3.39 (s, 6H), 5.12 (s, 4H), 7.13 (m, 2H), 7.30–7.37 (m, 6H). Physical data of the compound was consistent with that reported in literature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[C:16]=1[CH3:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[C:16]([CH3:25])[C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1sc2c(c1C)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: Cc1sc2c(c1C)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2
Yield: 57 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,3,4-Trimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30][CH3:31])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[S:32](=[O:36])(=O)(O)[OH:33].S(Cl)([Cl:39])=O.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Cl:39][S:32]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:18]([C:17]1[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=1)=[CH:14][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][CH:11]=3)[CH2:19][CH2:20][CH2:21]2)(=[O:36])=[O:33]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccccc43)nc2c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)Cl)ccc43)nc2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (300 mg, 0.73 mmol) in chloroform (50 mL) was added sulfuric acid (213.6 mg, 2.18 mmol) and thionyl chloride (514 mg, 4.36 mmol) dropwise with stirring at 85° C. for 3 h in an oil bath. The reaction was then quenched by the addition of ice-water, extracted with dichloromethane (3×80 mL). The organic layers combined and dried over magnesium sulfate, concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2% ethyl acetate in petroleum to afford methyl 3-[6-(chlorosulfonyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (260 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C1C(=O)N([I:17])C(=O)C1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([I:17])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Product: Oc1c(Cl)cc(I)cc1Cl
Yield: 59.2 %

Procedure:
A solution of 2,6-dichlorophenol (10 g, 61.35 mmol, 1.00 equiv) and NIS (27.6 g, 245.33 mmol, 2.00 equiv) in methanol (100 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was redissolved in 50 mL of ethyl acetate and washed with 3×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether (100%) to give 10.5 g (59%) of 2,6-dichloro-4-iodophenol as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.83 (s, 1H), 7.27 (s, 2H) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (69 mg, 84%), MS (ISP) m/z=331.5 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=2)[C:23]([F:38])=[CH:22][N:21]=1.C(Cl)(Cl)Cl.CO>C(O)CCC>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=3)[C:23]([F:38])=[CH:22][N:21]=2)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(N)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)ncc2F)c1
Yield: 11.6 %

Procedure:
A solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)aniline (4.02 g) and N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)acrylamide (4.0 g) in 1-butanol (10 mL) was heated to 135° C. for 3 hr. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, butanol was removed under reduced pressure and water was added. The mixture was extracted with ethyl acetate. Organic layer was dried over sodium sulfate and solvent was removed under reduced pressure. Crude material was purified by Combiflash chromatography eluting with 2.5% methanol in CHCl3 to give 0.828 g of N-(3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)acrylamide. 1H NMR: DMSO-d6 (400 MHz) 0.036 (s, 6H), 0.844 (s, 9H), 3.859-3.895 (d, 4H), 5.737-5.767 (dd, 1H, J=1.6, 8.4), 6.245-6.292 (dd, 1H, J=2, 15.2), 6.437-6.505 (m, 1H), 6.737-6.760 (d, 2H, J=9.2), 7.252-7.293 (t, 1H, J=8), 7.415-7.542 (m, 4H), 7.944-7.956 (d, 1H, J=4.8), 8.065-8.074 (d, 1H, J=3.6), 8.896 (s, 1H), 8.896 (s, 1H), 9.379 (s, 1H), 10.1190 (s, 1H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:12]1([C:10]2[N:2]=[C:3]3[CH2:7][CH2:6][CH2:5][N:4]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C1CCCN1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
Combine 2-iminopyrrolidine hydrochloride (6.98 g, 57.8 mmol) (Callahan, et al., J. Med. Chem. 45, 999-1001 (2002)), 2-bromoacetophenone (3.8 g, 19.3 mmol), and sodium carbonate (8.2 g, 77.2 mmol) in dry dimethylformamide (25 mL). Heat at 80° C. for 18 hours. Cool to room temperature, add water (60 mL), and extract with ethyl acetate (3×100 mL). Concentrate the combined organic layers under reduced pressure. Dilute the residue with diethyl ether (100 mL), wash with cold water (3×80 mL), and concentrate under reduced pressure to provide the desired compound as a white solid (3.2 g, 89%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:4][CH:3]=1.[CH2:21]([C:23]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:23]1[C:30]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C(F)(F)F
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 130 °C
Yield: 48.3 %

Procedure:
To a solution of 5-bromo-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazole (D67) (120 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (77 mg) and tripotassium phosphate (157 mg) in 1,2-dimethoxyethane (DME) (3 mL) and water (0.750 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (34.1 mg) in one charge. The reaction vessel was sealed and heated under microwave at 130° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (60 mg). MS (ES): C22H20F3NO2S requires 419. found 420.0 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[CH3:52][O:53][CH2:54][CH2:55][CH2:56][NH2:57]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH:57][CH2:56][CH2:55][CH2:54][O:53][CH3:52])=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(C(=O)O)s3)nc12
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCNC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=O)c3n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (30 mg, 0.091 mmol), EDCI (19 mg, 0.10 mmol), Et3N (14 μL, 0.10 mmol), and HOBt (14 mg, 0.10 mmol) in 2 mL of DMF pre-stirred for 5 minutes was added 3-methoxypropylamine (10 μL, 0.10 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate, washed with H2O, brine, dried over MgSO4, filtered, and evaporated to dryness to provide 30 mg of 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide (83%). LCMS (M+1=400)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9]C)=O)=[CH:3][N:2]=1.O.[NH2:12][NH2:13]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:12][NH2:13])=[O:9])=[CH:3][N:2]=1
Reactant: COC(=O)c1ccnnc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccnnc1
Yield: 98.6 %

Procedure:
To a solution of methyl 4-pyridazinecarboxylate (400 mg, 2.9 mmol) in MeOH (5 ml) was added hydrazine monohydrate (23 mmol). The solution was heated to reflux for 12 h. Volatiles were evaporated in vacuo to give 395 mg of the title compound as a yellow pale foam, which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[NH:16]1[CH2:20][CH:19]=[CH:18][CH2:17]1.C1COCC1>C([O-])(O)=O.[Na+]>[N:16]1([C:1]([O:2][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[O:14])[CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: C1=CCNC1
Reactant: O=C(Cl)OCc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccc2ccccc2c1)N1CC=CC1
Reaction time: 12 h
Yield: 75 %

Procedure:
Naphthalen-2-ylmethyl carbonochloridate (31.93 g, 144.7 mmol) was added to a solution of 2,5-dihydro-1H-pyrrole (10 g, 144.7 mmol) in a 1:1 mixture of saturated NaHCO3 (400 mL) and THF (400 mL). The reaction was stirred for 12 hours, condensed to a small volume, diluted with saturated NaHCO3, extracted with CH2Cl2, wash with 1 N HCl, dried over sodium sulfate, filtered and condensed to afford 27.5 g of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1[C:16](F)=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10]>C1COCC1>[C:9]([C:11]1[C:16]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10]
Reactant: N#Cc1ncccc1F
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ncccc1OCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A stirred solution of 680 mg (6.80 mmol) of 2,2,2-trifluoroethanol in 25 mL of THF was added 273 mg (6.83 mmol) of sodium hydride (60% dispersion). After 30 min at room temperature, 822 mg (6.73 mmol) of 2-cyano-3-fluoropyridine in 5 mL THF was added via syringe. The reaction was quenched after 1 h, by the addition of 15% K2CO3 aqueous solution. Concentration gave an oil that was partitioned between water and EtOAc. The layers were separated, the aqueous phase was backwashed with EtOAc (2×), and the combined organic layers were dried (MgSO4) and concentrated to an orange oil. The resultant crude residue was chromatographed on SiO2 using 25:75 EtOAc-hexanes to afford the title compound as a yellow oil: 1H NMR (CDCl3) δ8.43 (d,1H, 4.6 Hz), 7.55 (dd, 1H, 4.6, 8.7 Hz), 7.42 (d, 1H, 8.7 Hz), 4.55 (q, 2H, 7.8 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=1.CN(C)[CH:30]=[O:31]>C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:8]([O:15][C:30]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=1)=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: OCc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1F
Temperature: 120 °C
Yield: 61 %

Procedure:
Palladium diacetate (4.5 mg, 0.02 mmol), 1,4-(bisdiphenylphosphino)butane (8.5 mg, 0.02 mmol), triethylamine (55.8 μL, 0.4 mmol) and benzyl alcohol (1 mL) were added to a solution of methyl 4-bromo-2-fluorobenzoate (46.6 mg, 0.2 mmol) in dimethylformamide (1 mL). In this solution, bubbling was carried out for a few minutes with carbon monoxide, and then this solution was heated at 120° C. for 12 hours under carbon monoxide atmosphere. After completion of the reaction, ethyl acetate was added, and the resultant product was washed with a saturated ammonium chloride aqueous solution, and purified with a silica gel column chromatography (hexane/ethyl acetate=19/1) to obtain 35.4 mg of the desired product as a yellow viscous liquid (yield 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][C:12](OC(C)=O)=[O:13]>>[C:12]([C:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[S:6][CH:7]=1)(=[O:13])[CH3:11]
Reactant: Cc1ccc2sccc2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1csc2ccc(C)cc12
Reaction time: 8 h
Yield: 50 %

Procedure:
1 g of 5-methylbenzo(b)thiophene (6.75×10−3 moles) was stirred at 55° C. with 0.8 ml of Ac2O (8.10×10−3 moles). 0.83 ml of BF3 Et2O were added and stirring was continued for 8 hours.11 The solvent was removed in the rotary evaporator and the residue was extracted with AcOEt and H2O. It was decanted and washed with NaHCO3 and H2O. It was dried with Na2SO4, the solvent was removed and the product was purified in successive columns of AcOEt/hexane (1:1) and toluene respectively. A product was obtained which was a mixture of the substitution isomers in positions 2- and 3- of the benzo(b)thiophene ring in a proportion of approximately 20/80 (determined by the ratios of the areas of the NMR signals), which was passed to the following reaction. Yield: 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[C:35]5[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][C:3]=1[O:38][CH2:39][CH2:40]SC.O[O:44][S:45]([O-:47])=O.[K+].[CH3:49]O.O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[C:35]5[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][C:3]=1[O:38][CH2:39][CH2:40][S:45]([CH3:49])(=[O:47])=[O:44]
Reactant: CO
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(Cl)c(OCCSC)c5)c5ccccc45)cc3)ccnc2c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(Cl)c(OCCS(C)(=O)=O)c5)c5ccccc45)cc3)ccnc2c1
Reaction time: 3 h

Procedure:
4-(4-Chloro-3-(2-(methylthio)ethoxy)phenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (150 mg, 252 μmol) and oxone (464 mg, 755 μmol) were combined in 3:1 MeOH/water (20 ml) and stirred for 3 h. The mixture was then concentrated to remove methanol, then extracted with DCM, dried with sat. sodium bicarb., and concentrated. The crude material was then purified by chromatography using 0 to 100% 90/10/1 in DCM, followed by reverse phase chromatography to provide the titled compound. MS: M+H+=628.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH3:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Reaction time: 2 h
Yield: 105.7 %

Procedure:
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 1.25 equiv), Pd(dppf)Cl2.CH2Cl2 (19 mg, 10% mol), 2M aq Na2CO3 (1 mL), 1,4-dioxane (3 mL) was degassed, refilled with N2 gas for 3 times before being put into microwave oven for 2 h at 130° C. LC-MS found the reaction was completed. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel column, eluted with a 0 to 10% MeOH in CH2Cl2 gradient to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (112 mg, quant yield). LC-MS Method 1 tR=1.66 min, m/z=461 (M+1).
Reaction SMILES: F[B-](F)(F)F.[H+].[F:7][C:8]1[C:9]([CH3:15])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[N:16]([O-])=O.[Na+]>O>[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:10]2[C:9]=1[CH:15]=[N:16][NH:11]2
Reactant: Cc1c(N)cccc1F
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Fc1cccc2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tetrafluoroboric acid (8.2 ml, 48 wt % in water) was added 3-fluoro-2-methylaniline (2.27 ml). The mixture was cooled to 0° C. when a precipitate formed which was redissolved by the addition of water (8 ml). A solution of sodium nitrite (1.38 g) in water (2.7 ml) was then added dropwise and the mixture was then allowed to warm to ambient temperature and then stirred for a further 1 hour. The precipitated solid was filtered, then washed with diethyl ether, and then dried under suction for 30 minutes. The resulting tetrafluoroborate salt was added to a suspension of potassium acetate (3.92 g) and 18-crown-6 (0.264 g) in chloroform (45 ml). After stirring for 3 hours at ambient temperature the bright orange mixture was filtered and the insoluble material was washed with dichloromethane, then subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (3:1 v/v) to give 4-fluoro-1H-indazole (0.675 g) as an off-white solid. LC-MS (METHOD B): RT=2.70 minutes; 137 (M+H)+. (c) 4-Chloro-1H-indazole