Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])=[N:15][CH:16]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[S:7][C:6]=2[CH:30]=1.[OH-].[Li+]>C1COCC1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[N:15][CH:16]=3)=[C:8]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[S:7][C:6]=2[CH:30]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
To a solution of (E)-methyl 3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (0.118 g, 0.28 mmol) in THF (2.00 mL) and water (2.00 mL) was added lithium hydroxide (1.0 M aq., 0.844 mL, 0.84 mmol) and the reaction was stirred at room temperature for 2 h. Upon completion the reaction was quenched with water, diluted with DCM and acidified to pH 1 with 1 N HCl. The mixture was extracted with DCM (3×) and the combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O) to afford (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid (14 mg, 0.03 mmol, 9% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=6.66 (d, J=15.66 Hz, 1H), 6.77-6.81 (m, 2H), 6.84 (dd, J=8.59, 2.02 Hz, 1H), 7.17 (d, J=8.59 Hz, 1H), 7.22 (dd, J=8.59, 3.03 Hz, 1H), 7.31 (d, J=2.02 Hz, 1H), 7.44-7.49 (m, 2H), 7.52 (d, J=15.66 Hz, 1H), 7.64 (d, J=8.59 Hz, 1H), 8.45 (d, J=2.53 Hz, 1H). LC/MS (m/z, MH+): 406.2.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[C:19]=3[F:33])[CH2:14][CH2:13]2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:19]1[C:20]([CH2:24][OH:25])=[CH:21][CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)Oc1cc(N2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(N2CCN(c3cccc(CO)c3F)CC2)cc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
1-(2-tert-Butoxypyridin-4-yl)-4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (3.14 g) was mixed with CH2Cl2 (50 ml), and TFA (5.1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with MeOH (2 ml). A 8 M NH3/MeOH solution (10 ml) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The solid in the reaction mixture was collected by filtration, washed with MeOH, and dried at 50° C. under reduced pressure to obtain 4-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (1.76 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCOC.O.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]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@@H:10]4[CH2:9][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:38]6[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=6)=[CH:7][N:6]=5)[CH2:13][CH2:12][O:11]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCOC
Solvent: O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCN(C(=O)OC(C)(C)C)CC6)cn5)CCO4)c3n2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 500 mg (1.09 mmol) was dissolved in dimethoxymethane 8 ml, and then tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate 406 mg (1.31 mol) was added. Potassium carbonate 453 mg (3.28 mmol) was dissolved in distilled water 2 ml, which was then added to the reaction solution. PdCl2(dppf)2 45 mg (0.0547 mmol) was added, and the mixture was purged with N2 (g), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate and brine, and the organic layer was dried over Na2SO4. 3% MeOH/MC chromatography gave a product 478 mg (78%).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:21]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCSc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCSc2ccccc2)cc1
Yield: 90 %

Procedure:
A mixture of alpha-oxo-4-[[2-(phenylthio)ethyl]oxy]benzeneacetic acid methyl ester (0.5 g) in methanol and 0.5N sodium hydroxide (6 mL) was treated as in Example 19. Extraction provided material which was crystallized from benzene-hexane to give 0.43 g of colorless alpha-oxo-4-[[2-(phenylthio)ethyl]oxy]benzeneacetic acid, mp 72°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH:6]([NH:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH3:7].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH:6]([N:8]([CH2:9][CH:10]([O:11][CH3:12])[O:13][CH3:14])[S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(C(C)NCC(OC)OC)c1
Solvent: c1ccncc1
Product: COc1cccc(C(C)N(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 23.9 g. (0.1 mole) of 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)benzylamine in 100 ml. of dry pyridine is stirred, cooled and treated with a solution of 20.2 g. (0.107 mole) of tosyl chloride in 100 ml. of dry pyridine. The mixture is stirred at 25° C. for three days, poured into 800 ml. of water and extracted with ether. The combined ether extracts are washed with dilute hydrochloric acid and then with water, dried, filtered and evaporated to yield 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)-N-tosyl-benzylamine.
Reaction SMILES: [CH2:1]([C:5]1[N:6](CC2C=CC=CC=2Cl)[C:7](C=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)c1ncc[nH]1

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde and N-bromosuccinimide in carbon tetrachloride is irradiated to give the 2-(1 bromobutyl)imidazole which is dehydrobrominated by treating 1,8-diazabicyclo[4.5.0]undec-1-ene in tetrahydrofuran to give 2-(1-butenyl)-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=3[CH3:24])[CH2:33][CH2:34]2)=[O:16])[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23]
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccc(F)cc3F)CC2)c1

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 521.5 ([M+H]+)
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:15][N:14]=[C:13]([CH2:16][OH:17])[CH:12]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N12CCN(CC1)CC2.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>COC(C)(C)C>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:17][CH2:16][C:13]2[CH:12]=[C:11]([CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])[O:15][N:14]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(CO)no1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)O[Si](C)(C)C(C)(C)C)on2)cc1
Reaction time: 10 h
Yield: 30.6 %

Procedure:
7.35 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methanol was dissolved in 50 ml of methyl-t-butyl ether, and 3.36 g of 1,4-diazabicyclo[2.2.2]octane and 5.72 g of 4-toluenesulfonyl chloride were then added under ice-cooling. The mixture was stirred for 10 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.60 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methyl 4-methylbenzenesulfonate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19](Br)=[CH:18][C:17]([O:21][C:22](=[O:24])[CH3:23])=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.CC1C=CC(C)=CC=1>C(OCC)C>[C:22]([O:21][C:17]1[CH:18]=[C:19]([CH:26]=[CH2:27])[C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([F:25])[CH:7]=3)=[N:15][C:14]=2[CH:16]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccc(C)cc1
Product: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
Dichlorobis(tri-o-tolyphosphine)palladium (II) (46 mg, 0.06 mmol) was added into a mixture 4-[5-(acetyloxy)-7-bromo-1,3-benzoxazol-2-yl]-2-fluorophenyl acetate (0.8 g, 1.98 mmol), tributyl(vinyl)tin (0.9 g, 2.8 mmol) and p-xylene (9 mL). The reaction mixture was stirred at 130° C. for 5 h, cooled to room temperature, diluted with ethyl ether (10 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (0.4 g, 56% yield, m.p. 154–156° C.); MS m/e 356 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C(Cl)Cl.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>[Cl:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccnc(Cl)c1
Yield: 52.5 %

Procedure:
To a solution of 4-bromo-2-chloro-pyridine (1.0 g, 5.2 mmol) in DME/water 10:1 (15 mL) was added (2-methoxyphenyl)boronic acid (0.79 g, 5.2 mmol), Pd(PPh3)2Cl2 (240 mg, 0.34 mmol), and K2CO3 (1.8 g, 13.0 mmol). The mixture was heated with reflux for 6 hours. It was diluted with DCM, washed three times with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM/MeOH 100:0 to 90:10) to give the title compound A1 (0.6 g, 52%). MS (ES) C12H10ClNO requires: 219. found: 220 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[CH:19]=[O:20].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:6]=1[CH2:19][OH:20]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-formylpyridin-2-ylcarbamate (75 mg, 0.2 mmol) in methanol (1 mL) at 0° C. was added sodium borohydride (7.6 mg, 0.20 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with saturated aqueous ammonium chloride solution (1 mL). The reaction was diluted with EtOAc (5 mL) and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (65 mg, 86%) as a white solid which was used without further purification. 1H NMR (CD3OD) δ 8.28 (dd, 1H, J=10.4, 2.8 Hz), 8.22-8.18 (m, 2H), 7.45 (t, 1H, J=8.4 Hz), 6.68 (d, 1H, J=6 Hz), 4.81 (s, 2H), 1.57 (s, 9H); MS(ESI+) m/z 380.27 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2/[C:19](/[C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:20]\[CH:21]2[CH2:29][CH2:28][C:23]3([O:24][CH2:25][CH2:26][O:27]3)[CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCC3(C2)OCCO3)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 82.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-vinyl ester (1 g, 1.72 mmol), 4-(methanesulfonyl)phenylboronic acid (862 mg, 4.31 mmol) and dichlorobis(triphenylphosphine)palladium (II) (121 mg, 0.17 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 2.15 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded (Z)-1-benzenesulfonyl-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (800 mg, 82%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.[Cl-].C(N=C=NCCC[NH+](C)C)C>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][NH:28][C:16](=[O:18])[CH2:15][C:13]2[CH:12]=[CH:11][C:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=3[CH:14]=2)=[O:26])=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Reactant: COc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCC[NH+](C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(CC(=O)NNC(=O)c3ccc(OC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [2-(ethoxycarbonyl)-1-benzothien-6-yl]acetic acid (100 mg, 0.38 mmol) and 4-methoxybenzohydrazide (63 mg, 0.38 mmol) in 2 mL DMF was added 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropan-1-aminium chloride (91 mg, 0.47 mmol). The reaction was stirred at ambient temperature for 12 hours. The reaction mixture was loaded directly onto a reverse phase C18 column for purification to give the title compound as a white solid. LC/MS (EI): cal'd 413.1 (MH+), exp 413.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([CH:20]2[CH2:22][CH2:21]2)=[CH:4][N:3]=1.[CH2:23]([N:25]1[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]1)[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:20]1([C:5]2[C:6]([NH:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:30][C:29]3[N:25]([CH2:23][CH3:24])[N:26]=[C:27]([CH3:31])[CH:28]=3)=[N:3][CH:4]=2)[CH2:22][CH2:21]1
Reactant: CCn1nc(C)cc1N
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)NOC)c(C2CC2)cn1
Reaction time: 0.58 h

Procedure:
To a 10 mL microwave tube were added 2-(2-chloro-5-cyclopropyl-pyridin-4-ylamino)-N-methoxy-benzamide (0.075 g, 0.24 mmol, 1 eq), 2-ethyl-5-methyl-2H-pyrazol-3-ylamine (0.05 g, 0.36 mmol, 1.5 eq), Cs2CO3 (0.23 g, 0.71 mmol, 3 eq), and 1,4-dioxane (3 mL) and the resulting mixture was degassed with N2 for 15 min. To this was added Pd2(dba)3 (0.014 g, 0.014 mmol, 0.06 eq) and xanthphos (0.03 g, 0.06 mmol, 0.25 eq) and this mixture was again degassed with N2 for another 10 min. The resulting mixture was irradiated in a CEM microwave at 120° C., 150 W for 35 min. After the reaction was finished solvent was removed under reduced pressure and crude product was purified by column chromatography over silica gel (100-200 mesh) using 1% MeOH-DCM as the eluant followed by washing with diethyl ether and pentane and DCM to give the title compound as an off white solid (5 mg, 5%). 1H-NMR (400 MHz, DMSO-d6): δ 0.50-0.60(m, 2H), 0.88-1.00 (m, 2H), 1.15-1.27 (m, 3H), 1.55-1.65 (m, 1H), 2.07 (s, 3H), 3.70 (s, 3H), 3.80-3.95 (m, 2H), 5.95 (s, 1H), 6.64 (s, 1H), 6.90-7.10 (m, 1H), 7.40-7.60 (m, 3H), 7.72 (s, 1H), 8.34 (s, 1H), 9.47 (s, 1H), 11.88 (brs, 1H). LC-MS [M+H]+=407.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14](C=C)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: C=Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3,5-diphenyl-1-vinyl-1H-pyrazolo[3,4-c]pyridazine (50 mg, 0.15 mmol) in acetone (5 mL) was added a 2% aqueous solution of potassium permanganate (71 mg, 0.45 mmol, 3.5 mL water) in one portion. The mixture was stirred at room temperature for 2 h, then another portion of potassium permanganate (12 mg, 0.075 mmol), was added and stirring continued for 15 min. The solids were filtered off and the filtrate was partitioned between water and CH2Cl2. The aqueous phase was re-extracted with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (64 mg) was used directly in the following step.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH2:37]C)=[O:35])=[N:31][N:30]=1)[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[N:12]=[C:11]([CH3:27])[N:10]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:27][C:11]1[N:10]=[C:9]([NH:8][CH2:28][C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[N:31][N:30]=2)[CH:14]=[C:13]([O:15][CH2:16][C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[N:12]=1
Reactant: CCOC(=O)c1nnc(CN(C(=O)OC(C)(C)C)c2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nnc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Yield: 45.3 %

Procedure:
The solution of ethyl 5-((tert-butoxycarbonyl(2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-yl)amino)methyl)-1,3,4-thiadiazole-2-carboxylate (S-7) (70 mg, 0.1294 mmol) in TFA (1 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase column (Waters Sunfire Prep C18 OBD, 5-75% methanol in water with 0.1% NH3H2O modifier) to provide product as a white solid (25 mg, 21.4%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.35 (dd, J=7.9, 1.7 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 5.60 (s, 1H), 5.48 (s, 1H), 5.02 (d, J=6.3 Hz, 1H), 4.27 (ddd, J=24.1, 11.1, 7.0 Hz, 2H), 4.03 (s, 3H), 2.48 (d, J=5.8 Hz, 3H), 2.19 (s, 3H), 1.87-1.85 (m, 1H), 1.85-1.80 (m, 1H), 1.32-1.29 (m, 1H), 1.06-1.02 (m, 1H); LRMS (ESI) calculated M+H for C20H23N6O3S: 427.5. Found: 427.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:32])=[C:7]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:16][CH:15]=3)=[C:11]([C:29]#[N:30])[CH:10]=[N:9][N:8]2[CH:31]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:29]([C:11]1[CH:10]=[N:9][N:8]2[CH:31]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([CH3:32])=[C:7]2[C:12]=1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[CH:18][CH:19]=1)#[N:30]
Reactant: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC)cc3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(C(=O)O)c(C)c23)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 430C (1.60 g, 3.73 mmol) and 6N NaOH (5 ml, 30 mmol) in a mixed solvent of MeOH/THF (20 ml, 1/1) was heated at reflux for 2 h, cooled to rt. Removed half of the solvent in vacuo. The residue was treated with H2O (30 ml), washed with CH2Cl2 (3×50 ml). The aqueous layer was acidified to PH=5 and extracted with EtOAc (3×50 ml). The combined organic layers were washed with H2O (2×30 ml) and brine (30 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave 430D (1.47 g, 95%) as a yellow powder. It has retention time of 5.88 min (∠Cl, 8 min. run). MS Found: (M+H)+=415.2.