Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([O:33][C:34]1[CH:35]=[C:36]([CH:40]([NH:55][CH3:56])[CH2:41][N:42]2[CH2:46][CH2:45][CH:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:43]2)[CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH:5]1[O:1][C:2]([CH2:10][C:11]([N:55]([CH:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:35]=2)[CH2:41][N:42]2[CH2:46][CH2:45][CH:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:43]2)[CH3:56])=[O:13])=[C:3]2[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: CNC(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Reactant: O=C(O)Cc1cc2ccccc2o1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1occ2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 3-benzofuran acetic acid (1.446 g, 8.01 mmol) in THF (5 mL) at room temperature was added carbonyldiimidazole (1.31 g, 8.09 mmol). After stirring for 2 hours, a solution of Example 5 (2.68 g, 6.09 mmol) in THF (10 mL) was added. After stirring for 16 hours, all volatiles were removed in vacuo and the residue dissolved in ethyl acetate (300 mL). This solution was washed with saturated sodium hydrogencarbonate solution, then water, then saturated NaCl solution (50 mL of each). After drying (MgSO4) and concentration in vacuo, column chromatography (60:40 ethyl acetate:heptane) gave the desired product, 3.04 g, 83%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([Cl:10])=[C:4](Cl)[C:3]=1[Cl:12].[NH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[Cl:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Cl:1])=[C:3]([Cl:12])[C:4]=1[NH:13][NH2:14]
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: NN
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)c(NN)c1Cl
Temperature: 45 °C

Procedure:
To a reaction flask was added 400 milliliters of 95 percent ethanol and 24.2 grams (0.10 mole) of tetrachloropicolinonitrile. The mixture was heated to 45°C. with stirring and 3.7 grams (0.11 mole) of 95 percent hydrazine and 10.1 grams (0.10 mole) of triethylamine was added thereto. The mixture was heated under reflux for 1 hour and the reaction mixture thereafter cooled to 40°C. To this mixture was added 400 grams of an ice-water mixture and the solid 3,5,6-trichloro-4-hydrazinopicolinonitrile product which precipitated was recovered by filtration, water washed and dried. The product was recovered in a yield of 20.6 grams (87 percent of theoretical) melting at 178°-181°C.
Reaction SMILES: Cl.[CH2:2]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[S:4][CH2:3]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]>>[CH2:2]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[S:4][CH2:3]1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCS2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCS3)c1ccc(F)cc1
Yield: 31.5 %

Procedure:
The 4-((6bR,10aS)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indol-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone (349 mg, 25%) was prepared from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indolehydrochloride (750 mg, 2.79 mmol) with 4-chloro-1-(4-fluorophenyl)-1-butanone (3.0 mL, 15.24 mmol) using the procedure described in Example 456 Step A.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(C1C=CC(C)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+].[N-:48]=[N+:49]=[N-:50].[Na+]>CN(C)C=O.O>[N:48]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[N+:49]=[N-:50]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCC#Cc2cccc(C(=O)OCc3ccccc3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of benzyl 3-(1-(tosyloxy)-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (35.4 g, 59.30 mmol, 1.00 equiv) in N,N-dimethylformamide (400 mL), sodium bicarbonate (10 g, 119.05 mmol, 2.00 equiv), sodium azide (11 g, 169.23 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of NaHCO3 aq. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 25 g (90%) of benzyl 3-(1-azido-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[C:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([OH:28])=[O:1]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1CCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1CCC(=O)O
Yield: 74 %

Procedure:
A solution of 1.01 g of 3-(hydroxypropyl)-4-pivaloyloxybenzophenone in 40 ml of acetone was treated with 1.5 ml of 8N Jones' Reagent at 0° C. for 1 h. The reaction mixture was treated with 5 ml of isopropyl alcohol and filtered to remove inorganic material. The filtrate was evaporated and the residue was taken up with toluene. The toluene phase was extracted with 3% KHCO3 solution and the aqeuous extract was acidified to pH 2. The acidic product was extracted with ethyl acetate. The ethyl acetate extact was washed with brine, dried (MgSO4), and concentrated to give 0.784 mg (74%) of product.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25][CH3:26])=[C:17]2[C:27](=[O:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=[O:30])[C:16]=12)([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.CO.[BH4-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25][CH3:26])=[C:17]2[CH:27]([OH:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=[O:30])[C:16]=12)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2O
Reaction time: 1 h
Yield: 30.3 %

Procedure:
5-Benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 246 (10 mg, 0.019 mmol, 1 equiv.) was dissolved in CH2Cl2 (0.2 mL) and MeOH (0.5 mL) under a nitrogen atmosphere at 0° C. Sodium borohydride (NaBH4) was added (115 μL, 0.057 mmol, 3 equiv., 0.5 M). The reaction was allowed to stir for 1 hour and then quenched with water (5 mL) and extracted with ethyl acetate (2×5 mL). The organic layer was washed several times with water (2×10 mL), brine solution (10 mL). It was dried over Na2SO4, filtered and concentrated in vacuo and purified by preparatory thin-layer chromatography (PTLC) using 3/2 Hexanes/Ethyl acetate to obtain 5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 247a (34%, 3 mg) and reduced species: 5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-1,2,3,4,7,8-hexahydro-pyrrolo[3,4-g]quinoxalin-6-one 247b (21%, 2 mg) and 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-1,2,3,4-tetrahydro-pyrrolo[3,4-g]quinoxaline-6,8-dione 247c (34%, 3.4 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1>[Fe].C(Cl)(Cl)Cl>[Br:1][C:13]1[C:5]([O:4][CH3:3])=[CH:6][C:7]([CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Bromine (3.87 mL, 0.076 mol) was added dropwise at 5° C. to a mixture of 4-methoxy-2-methylbenzoic acid (10 g, 0.060 mol), Fe (0.20 g, 3.61 mmol) and chloroform (10 mL). After the reaction mixture was warmed to room temperature, it was stirred overnight. After chloroform (600 mL) was added, this suspension was washed with 10% sodium hydrogensulfate (200 mL×2) and brine, and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the pale yellow powder obtained by evaporating the solvent under reduced pressure was recrystallized from methanol twice to obtain 5-bromo-4-methoxy-2-methylbenzoic acid (4.96 g, 34%).
Reaction SMILES: C([Mg]Cl)(C)C.[N:6]1[C:11]2[S:12][C:13]([C:15]([O:17]C)=O)=[CH:14][C:10]=2[CH:9]=[N:8][CH:7]=1.[CH3:19][O:20][N-:21][CH3:22]>C1COCC1>[CH3:19][O:20][N:21]([CH3:22])[C:15]([C:13]1[S:12][C:11]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:14]=1)=[O:17]
Reactant: COC(=O)c1cc2cncnc2s1
Reactant: C[N-]OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc2cncnc2s1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
iPrMgCl (2M in THF, 1.1 mL) was added dropwise to a solution of methyl thieno[2,3-d]pyrimidine-6-carboxylate (intermediate 11) (138 mg) and N-methoxy-N-methylamide (104 mg) in THF at −20° C. maintaining the internal temperature below −5° C. The reaction was allowed to stir at −10° C. for 30 minutes and then quenched with NH4Cl (sat. aq). The solution was diluted with EtOAc and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×15 mL) and then the combined organics dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (1:1 to 1:4) afforded the title compound as a pale yellow solid (107 mg, 67%);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCCC1.C(OCC)(=O)C>[CH:18]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1)=[CH2:19]
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Temperature: 150 °C
Yield: 66.2 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1 Steps 1 and 2, 410 mg, 1.52 mmol), tributyl(vinyl)tin (535 mg, 1.69 mmol) and tetrakis-(triphenylphosphine)palladium(0) (87 mg) were combined in tetrahydrofuran (10 mL) in three batches in 5 mL microwave vials. The vials were heated to 150° C. for 10 minutes in a Smith synthesiser microwave reactor. The combined reactions were diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10-20% ethyl acetate/isohexane gave 2-vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine as a colourless solid (265 mg, 66%). δH (500 MHz, d6 DMSO): 9.03 (1H, s), 8.30 (1H, dd, J=1.4, 8.3 Hz), 7.51 (1H, td, J=7.9, 0.85 Hz), 7.43 (1H, dd, J=9.1, 10.6 Hz), 6.92 (1H, dd, J=10.7, 17.4 Hz), 6.43 (1H, dd, J=1.2, 17.4 Hz), 5.70 (1H, dd, J=1.2, 10.7 Hz); m/z (ES+) 364 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[CH3:17]>>[Cl:16][C:12]1[C:11]([CH3:17])=[C:10]([C:9](=[O:18])[CH2:6][C:2]#[N:1])[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1cccc(Cl)c1C
Product: Cc1c(Cl)cccc1C(=O)CC#N
Yield: 74 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 3-Chloro-2-methyl-benzoic acid methyl ester (3.1 g, 16.8 mmol, 1.0 eq). The crude product was precipitated form water and used in the following step without further purification (2.4 g, yield: 74%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:19]([C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)=O.[OH-].[K+]>CCO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])/[CH:17]=[CH:19]/[C:21]3[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-(4-acetyl-piperazin-1-yl)-phenyl]-ethanone (prepared following the procedure described in Example 16 STEP A, 533 mg, 2.16 mmol), 4-formylcinnamic acid (381 mg, 2.16 mmol) and 1.7 M KOH (2.54 ml) in EtOH (15 ml) and water (3 ml) was stirred overnight at room temperature. The resulting precipitate was filtered to get 260 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its potassium salt. The mother liquors were acidified with 10% HCl and the resulting green precipitate was filtered to give 240 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride. The mixture of both, the potassium salt and of the hydrochloric salt, was used in the next step without any further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.C(O)C>[ClH:41].[CH3:24][O:23][C:20]1[N:19]=[CH:18][C:17]([S:14]([N:13]2[CH:12]=[C:11]([CH2:25][NH:26][CH3:27])[CH:10]=[C:9]2[C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2C#N)cn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
tert-Butyl ({5-(2-cyanopyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (235 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 161 mg, 79%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14]>C(NCC)C>[CH3:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6]
Reactant: C#CCCCO
Reactant: Cc1ccccc1I
Solvent: CCNCC
Product: Cc1ccccc1C#CCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
A mixture of 4-pentyn-1-ol (1 g, 12.1 mmol), 2-iodotoluene (2.53 g, 11.6 mmol), dry diethylamine (20 ml), bis-triphenyl-phosphine palladium (II) chloride (150 mg) and cuprous iodide (60 mg) was stirred at room temperature under dry nitrogen for 24 hours). The solvent was removed and the residue extracted with ether. The organic phase was washed with brine and dried and the solvent removed. The crude product was purified by dry column chromatography (alumina, 9:1 hexane:ether 1:1 hexane:ether) to give 1.2 g (60% of theory) of 5-(2'-methylphenyl)-4-pentyn-1-ol as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1([CH3:38])[CH2:36][O:35][C:34](=[O:37])[O:33]1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:32]3([CH3:38])[CH2:36][O:35][C:34](=[O:37])[O:33]3)[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CC1(Cl)COC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(C3(C)COC(=O)O3)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution 3.2 g of the compound of Example 1 in 20 ml of dimethylformamide are added 2 g of potassium carbonate and 1.6 g of 4-chloro-4-methyl-2-oxo-1,3-dioxolane, and the mixture is stirred at 60° C. for 6 hours. The reaction mixture is poured into ice-cold water and the precipitate is extracted with ethyl acetate. After the extract is washed with water, dried and concentrated, the residue is recrystallized from a mixed solvent of hexane and toluene to give 3 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(4-methyl-2-oxo-1,3-dioxolan-4-yl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 190°-191° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:20]([Mg]Br)=[CH2:21].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)([CH:9]([F:10])[F:11])[CH:20]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N=C(c1cccc(Br)c1)C(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=CC(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)F
Temperature: -20 °C
Reaction time: 1.25 h

Procedure:
[1-(3-Bromo-phenyl)-2,2-difluoro-ethylidene]-carbamic acid tert-butyl ester (9.09 g, 27.2 mmol) was dissolved in toluene and cooled to −20° C. under N2. Using a syringe pump, vinylmagnesiumbromide (42.5 ml, 34.0 mmol) was added (1 eq. per hour). After 1.25 hrs no starting material was left and 218 ml half-saturated NH4Cl solution was added to the reaction. The product was extracted with TBME. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated column chromatography (cyclohexane/TBME) to yield the title compound as a yellowish oil. 1H-NMR (600 MHz, DMSO-d6): 7.81 (br, 1H, NH), 7.52 (m, 2H), 7.35 (m, 2H), 6.48 (t, 1H, CHF2), 5.45 (d, 1H), 5.15 (d, 1H), 1.32 (s, 9H); MS: 362 [(M+H)+].
Reaction SMILES: Cl.[CH2:2]([CH:5]1[C:9](OC(=O)C)([CH3:10])[CH:8]=[CH:7][C:6]1=[O:15])[CH:3]=[CH2:4].[O:16]1CCOCC1>>[CH2:2]([C:5]1[C:6](=[O:15])[CH2:7][CH:8]([OH:16])[C:9]=1[CH3:10])[CH:3]=[CH2:4]
Reactant: C1COCCO1
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Agent: Cl
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 2 h

Procedure:
In the same flask as in Example 1, 10% aqueous hydrochloric acid (10 ml) and dioxane (10 ml) were charged, and 2-allyl-3-acetoxy-3-methyl-4-cyclopentenone (1.94 g) was dropwise added thereto in 2 hours while keeping the inner temperature at 0° to 10° C. After completion of the dropwise addition, the resultant mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was subjected to post-treatment and purification as in Example 1 to give 1.37 g of 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone. Yield, 90%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1C#CCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperazine-1-carboxylate (0.0625 g, 0.121 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)-methylene]-6-methoxy-7-[3-(piperazin-1-yl)prop-1-ynyl]benzofuran-3(2H)-one (0.0453 g, 90%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.S([CH2:31][N+:32]#[C-:33])(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[CH3:14][N:10]([CH2:11][CH2:12][CH3:13])[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([CH:17]=[C:16]([C:18]2[O:19][CH:33]=[N:32][CH:31]=2)[CH:15]=1)[C:4]([OH:3])=[O:20]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2cnco2)c1
Yield: 65.2 %

Procedure:
Heat a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (300 mg, 1.08 mmol), tosylmethyl isocyanide (254 mg, 1.3 mmol), and sodium methoxide (193 mg, 3.57 mmol) in methanol (3.1 mL) at 40° C. for 1 h. Add water to the hot solution and extract with dichloromethane and ethyl acetate. Acidify the aqueous with 5 N HCl, extract with dichloromethane, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 4:96 methanol:dichloromethane) to give the title compound (203 mg, 65%).
Reaction SMILES: Br[C:2]1[O:14][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]([CH3:13])[CH3:12])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1(C)C(C)(C)OB([C:29]2[CH:42]=[CH:41][C:32]([O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[CH:11]([NH:10][C:9]1[C:4]2[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:41][CH:42]=3)[O:14][C:5]=2[N:6]=[CH:7][N:8]=1)([CH3:13])[CH3:12]
Reactant: CC(C)Nc1ncnc2oc(Br)c(-c3ccccc3)c12
Reactant: CC1(C)OB(c2ccc(OCCN3CCCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Nc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 75 °C

Procedure:
Into a 16×100 mm vial sparged with argon was placed 6-bromo-N-isopropyl-5-phenylfuro[2,3-d]pyrimidin-4-amine (100 mg, 0.301 mmol), 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine (120 mg, 0.361 mmol), palladium tetrakistriphenylphosphine (17 mg, 0.015 mmol), potassium carbonate (125 mg, 0.903 mmol), DME (4 mL), and water (1 mL). The vial was sealed and heated to 75° C. for 24 hours.