Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[CH:30]=[C:31](I)[S:32][C:25]=34)=[C:19]([F:34])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:35]1([C:41]([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[CH:30]=[C:31]([C:46]5[CH:45]=[CH:44][C:43]([C:41]([N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[O:42])=[CH:48][CH:47]=5)[S:32][C:25]=34)=[C:19]([F:34])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(NCc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(NCc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(-c5ccc(C(=O)N6CCOCC6)cc5)sc34)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(benzylamino)-5-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one (0.0157 g, 0.0269 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.008 g, 0.032 mmol), Pd(PPh3)4 (0.002 g, 0.002 mmol) and lithium chloride (0.005 g, 0.107 mmol) in dioxane (0.5 mL) and 2M aqueous Na2CO3 (0.5 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (11.4 mg; 66%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, 1H), 7.99 (s, 1H), 7.84-7.78 (m, 3H), 7.66 (dd, 1H), 7.55-7.45 (m 3H), 7.43-7.32 (m, 5H), 7.32-7.24 (m, 2H), 658 (d, 1H), 4.72 (d, 2H), 3.96-3.60 (m, 8H), 3.50 (s, 3H). LRMS (APCI pos) m/e 648 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16](=[O:19])[CH:15]=[C:14]2[CH3:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+].CCCCCC.C(OCC)(=O)C>CC#N>[C:24]([C:23]1[O:21][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([O:17][C:16](=[O:19])[CH:15]=[C:14]3[CH3:20])=[C:9]2[C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(=O)oc2c(C(=O)c3ccccc3)c(O)ccc12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(=O)oc2c1ccc1oc(C(=O)c3ccccc3)c(-c3ccccc3)c12
Yield: 71 %

Procedure:
A mixture of 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (30 mg, 0.1 mmol), 2-bromoacetophenone (22 mg, 0.11 mmol), and K2CO3 (143 mg, 1.03 mmol) in CH3CN (5 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 then hexane/ethyl acetate=1/1, Rf=0.33 hexane/ethyl acetate=1/1) to provide 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one as a yellow solid (71% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:22]([NH:24][CH3:25])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 64.3 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (125 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.293 mmol, 64.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.50 (m, 4 H) 2.75 (d, J=4.29 Hz, 3 H) 2.96-3.14 (m, 4 H) 3.35-3.45 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.05 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.04 (t, J=8.59 Hz, 1 H) 7.51-7.67 (m, 3 H) 8.27-8.38 (m, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C23H27FN6O2, 439; found, 439.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]4[N:31]=[N:32][NH:33][N:34]=4)=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]4[N:31]=[N:32][NH:33][N:34]=4)=[CH:29][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nn[nH]n4)ccc3n2C2CCCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc3cc(-c4nn[nH]n4)ccc3n2C2CCCCC2)cc1
Reaction time: 66 h
Yield: 210.2 %

Procedure:
Compound 31 (2.65 g, 3.3 mmol) was added to tetrabutylammonium fluoride (17.5 mL of a 1.0 N solution in THF, 17.5 mmol) at rt. The suspension was shaken for 66 h and was filtered. The resin was washed and dried as described in the preceding experiment to afford resin bound 2-[4-hydroxyphenyl]-1-cyclohexyl-5-(2H-tetrazol-5-yl)-1H-benzimidazole (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH:1][C:2]2[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]3[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=3[CH:12]=2)=[CH:23][CH:22]=1)[CH3:18]
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 86.8 %

Procedure:
Following general procedure E and using 5-amino-7-t-butyl-3,3-dimethyl-2,3-dihydrobenzofuran (Compound 14, 0.14 g, 0.47 mmol), ethyl-4-iodo-benzoate (0.0.13 g, 0.57 mmol), cesium carbonate (0.22 g, 0.66 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.040 g, 0.064 mmol) in 4 mL of anhydrous toluene, the title compound (0.15 g, 86%) was obtained. 1H NMR (300 MHz, CDCl3): δ 7.92 (d, 2H, J=8.8 Hz), 6.91(d, 1H, J=2.2 Hz), 6.84(d, 1H, J=2.2 Hz), 6.82(d, 1H, J=8.7 Hz), 6.04 (br s, 1H), 4.34 (q, 2H, J=7.1 Hz), 4.26 (s, 2H), 1.36 (s, 9H), 1.33 (s, 6H), 1.29-1.34(buried t, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=NC=CC=1)([O-])=O.[CH3:29][C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1.[CH3:39][N:40]([CH:42](OC)OC)[CH3:41]>[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.C1(C)C=CC=CC=1.CO.N1C=CC=CC=1>[CH3:39][N:40]([CH3:42])[CH:41]=[CH:29][C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[N+]([O-])c1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: CN(C)C=Cc1ncccc1[N+](=O)[O-]
Yield: 84 %

Procedure:
Particularly key to an efficient synthesis of 3-AP or 3-AMP is the high-yield introduction of a methyl or vinyl group, preferably vinyl, at the 2 position of the pyridine moiety utilizing a Heck or Stille vinylation reaction or a methylation reaction under Suzuki conditions. These reactions proceed at the 2-position of a pyridine moiety in high yield (generally, greater than 50% and in most instances, greater than 70%). The advantage of the vinylation reaction is that the 2-vinyl group may be readily converted to a 2-carboxaldehyde group for further conversion to the 2-thiosemicarbazone using a high yield ozonolysis reaction conducted in a polar solvent, such as methanol. The preferred vinylation reaction is a Heck or Stille vinylation reaction performed utilizing a reagent selected from among the following: Bu3SnCH=CHR3, (OH)2B--CH=CHR3, ClZnCH=CHR3 and XMgCH=CHR3. The vinylation reaction takes place in the presence of triphenylphosphine (PPh3) and/or tetrakis(triphenylphosphine) palladium [Pd(PPh3)4 ] usually in a solvent such as toluene in the presence of heat. The advantages of the methylation reaction under Suzuki conditions over the two step methylation of the prior art include a greatly improved yield, reduction in the number of steps and therefore handling required and ease in scaling the synthesis up for commercial production. Alternatively, to introduce a vinyl group at the 2-position of 3-nitropyridine, one may advantageously react 2-methyl-3-nitropyridine with dimethylforamamidedimethylacetal (DMFDMA) to produce 2-dimethylamino vinyl-3-nitropyridine compound 3a, followed by oxidation with sodium periodate (NaIO4) to produce carboxaldehyde 4 in an unexpectedly high 84% yield.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:17]2[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[N:11]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:17]2[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[N:11]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 3-[2-{2-(ethoxycarbonylmethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.80 g) in ethanol (8 ml) was added a solution of sodium hydroxide (0.15 g) in water (4 ml) and the mixture was stirred for 0.5 hour at room temperature. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated, neutralized with 1N hydrochloric acid to give the precipitate, which was collected and purified by recrystallization from 50% aqueous ethanol to give 3-[2-{2-(carboxymethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.50 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cnc(OC)nc4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12m and 4-bromoanisole
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[S:22][C:23]([C:26]#[C:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:24][CH:25]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[S:22][C:23]([CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:24][CH:25]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(C#Cc4ccccc4)s3)C2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(CCc4ccccc4)s3)C2)CC1
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a solution of compound 348 (30 mg) in EtOH (20 mL) was added 10% Pd/C (10 mg) and the mixture was subjected to hydrogenation (45 psi H2) for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 349 (30 mg). MS m/z (M+H+) 460.6.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:21](Cl)[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:18]([OH:20])=[O:19])[N:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[CH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[C:18]([OH:20])=[O:19])[N:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCC(Cl)=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Agent: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCC=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 118.8 %

Procedure:
To a solution of diester (4) (3.03 g) in tetrahydrofuran (30 ml) are added benzenethiol (0.70 ml) and triethylamine (0.79 ml). The mixture is stirred at room temperature for 3.5 hours, concentrated, and purified by silica gel chromatography (eluting with benzene-ethyl acetate (9:1 to 8:2) mixture) to give phenylthiopropionate (5) (3.36 g). Yield: 92%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (10.31 mmol, 2 g) and cyclopentylamine (10.31 mmol, 1.02 mL) were dissolved in THF (60 mL) and cooled to −78° C. N,N-diisopropylethylamine (10.31 mmol, 1.8 mL) was added dropwise. The reaction mixture was stirred at −78° C. for about 45 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for about 16 hours. After removal of the solvent the residue was redissolved in EtOAc and washed with water and brine. The organic phase was dried over MgSO4 and the solvent evaporated. The residue was purified using column chromatography (SiO2, 9:1 n-hexanes/ethyl acetate) to give the desired product (2.11 g, 84% yield). ES-MS: 242 (M+1). When the hydrochloride salt of an amine is used in place of the cyclopentylamine described above, 2 to 3 equivalents of N,N-diisopropylethylamine and dichloromethane are used as solvent.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[N:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14][CH3:15])=[O:6])[CH2:2][CH3:3].[Cl:20]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[C:10]([Cl:20])[S:9][C:8]=1[N:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14][CH3:15])=[O:6])[CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC(=Nc1sccc1C(=O)NCCC)OC
Solvent: c1ccncc1
Product: CCCCC(=Nc1sc(Cl)cc1C(=O)NCCC)OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a sulfonation flask 0.85 g 2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide are added with stirring to 10 ml absolute pyridine. The internal temperature is then raised to 60° C. and 0.5 g of N-chlorosuccinimide (NCS) are added in two portions. After stirring for 1 hour at 60° C., the pyridine is removed in a water jet vacuum. The residue is taken up in ethylacetate and the organic phase is washed twice with water. After drylng of the organic phase, the solvent is removed in a water jet vacuum and the raw material purified by column chromatography over silica gel (eluant:hexane/ethylacetate=3:1). Yield: 0.6 g 5-Chloro-2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide in the form of brownish crystalls; m.p. 110-112° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](B(O)O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(#N)C.O>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:27]3[CH:26]=[C:25]4[C:21](=[CH:20][CH:19]=3)[CH2:22][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]4)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(B(O)O)n2n1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)n2n1
Temperature: 145 °C
Yield: 65.9 %

Procedure:
To a mixture of (6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)boronic acid (47 mg, 0.2 mmol), tert-butyl 5-bromoisoindoline-2-carboxylate (47 mg, 0.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol) and tripotassium phosphate (41 mg, 0.3 mmol) was added 3:1 acetonitrile/water (3 mL). The resulting mixture was heated at 145° C. (microwave) for 800 s. The reaction was then filtered and concentrated. The residue was dissolved in methanol, and then filtered again. The filtration was finally purified by preparative HPLC (neutral) to afford tert-butyl 5-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)isoindoline-2-carboxylate (43 mg, 66% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.15 (d, J=10.9 Hz, 1H), 8.00-8.08 (m, 1H), 7.75 (s, 1H), 7.59 (d, J=9.6 Hz, 1H), 7.35 (t, J=9.1 Hz, 1H), 6.68 (d, J=9.9 Hz, 1H), 4.69 (br. s., 4H), 3.37 (d, J=7.3 Hz, 2H), 1.65-1.78 (m, 2H), 1.56 (s, 9H), 1.45-1.53 (m, 2H), 1.02 (td, J=7.3, 2.3 Hz, 3H); LRMS (ESI) m/e 408.3 [(M+H)+, calcd for C23H30N5O2 408.2].
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([N+:16]([O-])=O)[C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([O-])=O.[H][H].C(O)(=O)C(O)=O>[Pt](=O)=O.C(O)C>[NH2:1][C:4]1[CH:15]=[C:14]([NH2:16])[C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3
Reactant: [H][H]
Reactant: O=C1c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2OC12CC2
Agent: O=[Pt]=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: Nc1cc(N)c2c(c1)C(=O)C1(CC1)O2

Procedure:
250 mg. of 5,7-Dinitrospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one, 50 mg. of platinum dioxide and 20 ml. of ethanol were stirred in a stream of hydrogen for 1.25 hour under atmospheric pressure. To the reaction mixture was added oxalic acid, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure until its volume became above 3 ml. Ether was added to the concentrate, and the resulting powder was collected by filtration. The powder was dissolved in ethanol. To the ethanolic solution was added activated charcoal for decoloration, followed by addition of ether. The precipitating powder was collected by filtration to obtain 5,7-diaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]3-one.1/2 oxalate.monohydrate as yellowish brown powder.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O-:18].[Na+].Cl>CO>[Cl:8][C:6]1[N:7]=[C:2]([O:18][CH3:17])[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)nc(Cl)cn1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3,5-dichloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (13.0 g, 50.2 mmol; prepared according to the general methods described by M. Tutonda, et al., Tetrahedron, 1990, 46, 5715) dissolved in absolute methanol (100 mL) was treated with NaOMe (6.78 g, 125 mmol). The reaction mixture was stirred at room temp for 1 hour, neutralized with 2N HCl (Et2O solution), and evaporated the solvent under reduced pressure. The residue was treated with EtOAc, washed with 0.5N HCl solution, dried over MgSO4, and concentrated under reduced pressure to give the desired product (12.8 g, 100%). LRMS (ESI pos) m/e 254.9, 256.9 (M+1, Cl pattern). 1H-NMR (400 MHz, CDCl3) δ 7.39 (m, 2H), 7.20 (t, 2H), 6.95 (s, 1H), 4.05 (s, 3H); 19F-NMR (376 MHz, CDCl3) δ −111.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11]([Cl:10])(=[O:13])=[O:12])=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(Br)c1
Product: COc1cc(Br)ccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To chlorosulfonic acid (20 ml) at 0° C. was added dropwise 3-bromoanisole (18.7 g, 0.1 mol) at such a rate that the internal temperature remained below 5° C. The mixture was stirred at 0° C. for 1 hour and added dropwise to crushed ice. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:25 ethyl acetate:pentane) to afford the title compound; 4-bromo-2-(methyloxy)benzenesulfonyl chloride (D30) 1H-NMR (CDCl3) δ 7.81 (1H, d, J 8 Hz), 7.28 (1H, d, J 2 Hz), 7.26 (1H, dd, J 8, 2 Hz), 4.07 (3H, s) and an isomer; 2-bromo-4-(methyloxy)benzenesulfonyl chloride 1H-NMR (CDCl3) δ 8.12 (1H, d), 7.33 (1H, d), 6.97 (1H, dd), 3.92 (3H, s).