Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH2:38][C:39](Cl)=[O:40])[CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)([O-:28])=[O:27]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:39](=[O:40])[CH2:38][C:31]3[CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(3,5-Dinitrophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(3,5 -dinitrophenyl)acetyloxy] -2 (1H)-pyrimidinone as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)C>CN(C)C=O>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[O:13])=[CH:26][CH:27]=1
Reactant: O=C1NCCN1c1ccc(F)cc1
Reactant: CC(CCCCCBr)Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2ccc(Br)cc2)CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-imidazolidinone (0.12 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 39.0 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-6-(4-bromophenoxy)heptane (0.22 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 7) as a white solid (0.14 g, 48%).
Reaction SMILES: [CH2:1]([N:13]([C:15]([CH2:17][N:18]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:26]=[N:27][C:28](=[O:37])[N:29]([CH2:31][C:32]([O:34]CC)=[O:33])[CH:30]=2)[C:21](=[O:38])[N:20]=[C:19]1[S:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:16])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([N:13]([C:15]([CH2:17][N:18]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:26]=[N:27][C:28](=[O:37])[N:29]([CH2:31][C:32]([OH:34])=[O:33])[CH:30]=2)[C:21](=[O:38])[N:20]=[C:19]1[S:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:16])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)C(=O)Cn1cc(Cc2cnc(=O)n(CC(=O)OCC)c2)c(=O)nc1SCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCN(C)C(=O)Cn1cc(Cc2cnc(=O)n(CC(=O)O)c2)c(=O)nc1SCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirring solution of 1-(N-(1-dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one in 1,4-dioxan (8 ml) was added 0.5M sodium hydroxide (1.56 ml). After 1 h, water (3 ml) was added. After a further hour, the mixture was diluted with water, extracted with ethyl acetate and acidified to pH 3 with aq. sodium bisulphate. The solid which precipitated was filtered, washed with water and ether, heated briefly with acetone and filtered again to give the product as a white solid, yield 0.28 g. 1H-NMR (d6-DMSO) δ0.85 (3H, t), 1.22 (18H, m), 1.35-1.61 (2H, m,), 2.78, 2.95 (3H, 2xs), 3.20-3.35 (2H, m), 3.58 (2H, s), 4.40 (2H, s), 4.55 (2H, s), 4.83 (2H, m), 7.10 (2H, m), 7.44 (2H, m), 7.54 and 7.57 (1H, 2xs), 8.03 (1H, m), 8.54 (1H, m) 13.10 (1H, br. s); MS (APCI+) found (M+1)=642, C33H44FN5O5S requires 641.
Reaction SMILES: [Na+].[Na+].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([CH3:39])[CH:10]=[CH:11][C:12]=1[S:13]([NH:16][C:17]1[C:26]2[C:25]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:24][C:23]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:22][C:21]=2[C:20]([S:35]([O-:38])(=[O:37])=[O:36])=[CH:19][CH:18]=1)(=[O:15])=[O:14])([O-])=O.[H][H]>[Pd].O>[NH2:4][C:7]1[CH:8]=[C:9]([CH3:39])[CH:10]=[CH:11][C:12]=1[S:13]([NH:16][C:17]1[C:26]2[C:25]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:24][C:23]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:22][C:21]=2[C:20]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:19][CH:18]=1)(=[O:15])=[O:14]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(N)c1
Reaction time: 16 h
Yield: 67.5 %

Procedure:
A mixture of 8.0 g of 8-(3-nitro-p-toluenesulfonamido)-1,3,5-naphthalene trisulfonic acid trisodium salt, 160 ml of water and 800 mg of 10% palladium on carbon catalyst is hydrogenated on a Parr shaker until no additional hydrogen is absorbed. The resulting mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is dissolved in hot water and filtered. The filtrate is triturated with ethanol until cloudiness persists, then is allowed to stand at room temperature for 16 hours. The mixture is filtered and the filtrate evaporated to afford a gummy material which is dissolved in a small amount of water and triturated with ethanol. An additional 200 ml of ethanol is added and the mixture is stirred for one hour to provide a solid. The solid is collected and washed with ethanol and ether to yield 4.6 g of 8-(3-amino-p-toluenesulfonamido)-1,3,5-naphthalenetrisulfonic acid, trisodium salt as a light tan powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:22][OH:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:33][O:34][CH2:35]Cl.Cl.[Cl-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:22][O:23][CH2:33][O:34][CH3:35])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a solution of tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}-5-hydroxypentanoate (15.05 g, 46.5 mmol) in dichloromethane (150 ml) were added under the ice cooling 4-dimethylaminopyridine (120 mg, 1 mmol), diisopropylethylamine (26 ml, 150 mmol) and chloromethyl methyl ether (12 ml, 150 mmol), and the mixture was raised to the room temperature. Ten hours later the mixture was adjusted to pH about 3 with ice water and 1N hydrochloric acid under cooling in an ice bath. After adding a saturated aqueous sodium chloride solution and separating the mixture with a separating funnel, the organic layer was washed once with water and twice with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and the organic solvent was removed under reduced pressure to give tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}-5-(methoxymethoxy)pentanoate (16.87 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:20])=[C:15]([C:16](O)([CH3:18])[CH3:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:20])=[C:15]([C:16]([CH3:18])=[CH2:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(C)(C)O
Agent: Cl
Solvent: CCOC(C)=O
Product: C=C(C)c1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Yield: 50.4 %

Procedure:
A solution of 7-(2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (150 mg) in 4N-hydrogenchloride in ethyl acetate was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from a mixture of diethyl ether and hexane to give 7-(2,6-dichlorobenzoylamino)-2-methyl-3-(1-methylvinyl)benzo[b]furan (72 mg).
Reaction SMILES: C([NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7](CCC)=[C:6](O)[CH:5]=1)C.[C:18]([C:24](OC)=O)#[C:19][C:20]([O:22][CH3:23])=[O:21]>[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>[CH3:23][O:22][C:20]([CH:19]1[CH2:18][CH2:24][C:5]2[C:4](=[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]3=[CH:7][CH:6]=2)[NH:3]1)=[O:21]
Reactant: CCCc1c(O)cc(NCC)c2c1CCCC2
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CCc2ccc3ccccc3c2N1

Procedure:
Benzyltrimethylammonium hydroxide (40% aqueous solution) (3 drops) was added to a stirred solution of 1-ethylamino-3-hydroxy-4-propyl-5,6,7,8-tetrahydronaphthalene (2.33 g) and dimethyl acetylene dicarboxylate (1.42 g) in methanol (10 ml). The mixture was heated at reflux for 8 hours, cooled, filtered and the methanol removed in vacuo. The resulting oil, a mixture of the cis and trans tetrahydronaphthylamino acrylic acid esters, was heated on a steam bath with polyphosphoric acid (10 g) for 2 hours. The mixture was cooled, poured into water and the solution adjusted to pH7 with sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The extracts were dried (magnesium sulphate) and evaporated in vacuo giving crude tetrahydrobenzo quinoline-2-carboxylic acid methyl ester as a sticky solid.
Reaction SMILES: [CH3:1][CH2:2][O:3]CC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[CH:17]=1.C(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:15][C:12]1([CH3:16])[C:11]2[CH:17]=[C:7]([CH:2]([OH:3])[CH3:1])[CH:8]=[CH:9][C:10]=2[O:14][CH2:13]1
Reactant: CCOCC
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)C(C)(C)CO2
Yield: 682 %

Procedure:
A mixture of the precursor ether (0.21 g. 0.9 mmol), Mg turnings (1.0 g 0.041 g at) and dry THF (2 mL) was heated (heat gun) under N2 until the mixture turned cloudy (ca 15 min). Dry THF (15 mL) was added to the mixture which was then heated to reflux. A solution of ether (42) (2.92 g, 12.9 mmol) in dry THF (25 mL) was added dropwise to the vigorously stirred mixture over a period of 0.75 hours. After vigorous stirring at reflux for 2.75 hours, another 0.25 g (0.010 g at) of Mg turnings were added. The new mixture was stirred at reflux for 0.75 hour and with no external heat for 0.5 hours. Upon cooling the mixture to -5° to -10° C. (ice-salt bath), a solution of freshly distilled acetaldehyde (2.0 g, 0.045 mol) in dry THF (20 mL) was added dropwise to the vigorously stirred mixture over a period of 0.7 hours. This reaction mixture was stirred in an ice-salt bath (-5° to -10° C.) for 1.5 hours, after which time a solution of acetaldehyde (0.9 g, 0.020 mol) in dry THF (5 mL) was added dropwise (over a period of about 0.2 h) and the new mixture was stirred 0.3 hours. With continued cooling (-5° to -10° C.), saturated aqueous NH4Cl (3 mL) was added and the excess Mg turnings were removed by filtration. Saturated aqueous NH4Cl (10 mL) and ether rinses (of glassware and Mg turnings, 60 mL) were added to the filtrate. After separating the organic layer, the aqueous phase (pH≥8) was acidified (pH 6.5 to 7) with saturated aqueous NH4Cl (15 mL) and 4% H2SO4 (14 mL). The aqueous solution was extracted with ether (5×40 mL) and ether (90 mL) was added to the combined organics. The organic solution was washed with saturated aqueous NaHCO3 (75 mL) and brine (50 mL). After drying (MgSO4) the solution, the solvent was removed, and the residual oil was chromatographed through a circular silica gel plate (4 mm) spun by a Chromatotron (Model 7924T, Harrison Research, 840 Moana Court, Palo Alto, Calif.). Half of the product was eluted with ether/petroleum ether (bp 50°-110° C.) 20:1, 8:1, then 4:1 and then the same solvent system was used to elute the other half. In both separations, the 4:1 ratio was required to elute the title compound. Concentration of the eluent in the desired fractions gave 1.18 g (44%) of the alcohol as a light yellow, viscous oil. TLC analysis (1:4 ether:petroleum ether, bp 50°-110° C.) indicated the compound was essentially pure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:14][C:24]([NH:23][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:25])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)c1cc2ccccc2n1N
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccccc2n1NC(=S)NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1-Amino-1H-indole-2-carboxylic acid methyl ester (18.56 g, 0.098 mol) was dissolved in tetrahydrofuran (800 mL). Benzoyl isothiocyanate (13.1 mL, 0.098 mol) was added and the reaction was allowed to stir overnight. The solvent was removed in vacuum and the solid residue was triturated with ether. The solid was collected by filtration to yield the 1-(3-benzoyl-thioureido)-1H-indole-2-carboxylic acid methyl ester (24.27 g, 70%), which was used in the next step without further purification. 1H-NMR (CDCl3) δ 12.81 (br s, 1H), 9.29 (br s, 1H), 7.95 (d, J=7.2 Hz, 2H), 7.68 (m, 2H), 7.57 (m, 2H), 7.42 (m, 2H), 7.38 (s, 1H), 7.24 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)=O.[I-:22].[Na+].O>CC(C)=O>[I:22][CH2:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Yield: 86.8 %

Procedure:
1-Methanesulfonyloxy-4,4,5,5,6,6,7,7,7-nonafluoro-heptane (6.7 g, 18.8 mmol) and sodium iodide (8.5 g, 56.4 mmol) were stirred in acetone (400 ml) for 12 hours under heating. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ether. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane (6.33 g, Yield 87%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[N:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]2[N:6]([C:8]([C:11]([NH:51][C:52]3[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=3)=[O:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Reactant: Nc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 2 dram vial was added 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-imidazo[1,2-b]pyridazine-3-carboxylic acid (0.025 g, 0.06 mmol) from (1a), EDCI (0.018 g, 0.09 mmol), HOBT (0.012 g, 0.09 mmol), 4-aminopyridine (8.46 mg, 0.09 mmol), TEA (0.025 ml, 0.18 mmol) and CH3CN (1.0 ml). The reaction was stirred at 25° C. for 48 hours then concentrated to give crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide. To this residue was added trans-1,4-cyclohexyldiamine (0.5 g, 4.3 mmol) and the resulting mixture was allowed to heat at 165° C. for 5 hrs. Upon cooling, the sample was dissolved in methylene chloride, and washed with water. The organics were separated, then dried over Na2SO4, filtered and concentrated in vacuo. To this residue was added a 1:1 mixture of CH2Cl2/TFA (2 ml). The solution was stirred at 25° C. for 3 hours, concentrated, diluted with MeOH and purified by preparative HPLC to provide the titled compound (0.008 g, 22%) as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 8.74 (2H, d, J=7.15 Hz), 8.30 (2H, d, J=7.15 Hz), 8.19 (1H, s), 7.41-7.50 (2H, m), 7.31-7.41 (2H, m), 7.17-7.26 (1H, m), 6.26-6.33 (1H, m), 3.71-3.87 (1H, m), 3.10-3.23 (1H, m), 2.25-2.39 (2H, m), 2.06-2.24 (2H, m), 1.53-1.66 (2H, m), 1.35-1.52 (2H, m). LC/MS, m/z 443 (M+1). HPLC Rt, 2.34 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>CCN(CC)CC.[Cu]I.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[N:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1ccc(C#C[Si](C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (17.4 mmol) in 50 mL of degassed Et3N was added trimethylsilylacetylene (19.1 mmol), CuI, (1.74 mmol) and trans-dichlorobis(triphenylphosphine)palladium (1.74 mmol). The resulting solution was stirred at RT overnight under N2 atmosphere. The black solution was then hydrolyzed with 30 mL of H2O and extracted with Et20 (3×30 mL). Purification of the residue by column chromatography (hexane/Et2O 9/1) provided the desired compound in 81% yield as brown oil. 1H NMR (CDCI3) δ ppm: 0.08 (s, 9H, CH3); 2.30 (s, 3H, CH3); 7.41 (d, 1H, J=7.5 Hz, CHAT), 7.59 (d, 1H, J=7.5 Hz, CHAr); 8.41 (s, 1H, CHAr). 13C NMR (CDCl3) δ ppm: 0.0 (3C, CH3); 18.9 (1C, CH3); 94.0 (1C, C═C); 104.7 (1C, C═C); 126.1 (1C, CHAr); 132 (1C, Cq); 135.2 (1C, CHAr); 141.6 (1C, Cq); 150.7 (1C, CHAr).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1[S:7][C:8]([CH:12]2OCC[O:13]2)=[C:9]([CH3:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl>O1CCCC1>[CH3:11][C:9]1[CH:10]=[C:6]([Sn:5]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:1][CH2:2][CH2:3][CH3:4])[S:7][C:8]=1[CH:12]=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(C2OCCO2)s1
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(C=O)s1

Procedure:
A mixture of tributyl[5-(1,3-dioxolan-2-yl)4-methylthien-2-yl]stannane (intermediate 76, 2.92 g), 1M aqueous hydrochloric acid (3 ml) and tetrahydrofuran (10 ml) was stirred at reflux for 30 minutes. The reaction mixture was cooled, extracted thrice with diethylether. The organic solutions were combined, extracted with saturated sodium bicarbonate and dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (50:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2].Br[C:28]1[CH:33]=C(Br)C=C(Br)C=1.[I-].[Cs+]>>[CH2:16]([O:15][Si:11]([O:12][CH2:13][CH3:14])([O:18][CH2:19][CH3:20])[C:7]1[CH:8]=[C:9]([Si:4]([O:24][CH2:33][CH3:28])([O:21][CH2:22][CH3:23])[O:3][CH2:1][CH3:2])[CH:10]=[C:5]([Si:4]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:3][CH2:1][CH3:2])[CH:6]=1)[CH3:17]
Reactant: CCO[Si](OCC)(OCC)c1cccc([Si](OCC)(OCC)OCC)c1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Cs+]
Agent: [I-]
Product: CCO[Si](OCC)(OCC)c1cc([Si](OCC)(OCC)OCC)cc([Si](OCC)(OCC)OCC)c1

Procedure:
The procedure used for the preparation of 1,3-di(triethoxysilyl)benzene was followed using 1,3,5-tribromobenzene (100.0 g, 0.318 mol) in place of 1,3-dibromobenzene. Two distillations gave a clear, colorless oil (0.1 mmHg, 196-198° C., 23.4 g, 13%). Anal. Calcd for C24H48O9Si3 : C, 51.0: H, 8.56. Found: C, 51.2; H, 8.53. IR (Neat, CsI, cm-1) : 2964 s, 2920 s, 2880 s, 2730 w, 1560 m, 1480 w, 1440 m, 1386 s, 1290 m, 1160 s, 1090 vs, 955 s, 825 s, 775 s, 710 m, 670 m, 487 s. 1H NMR (benzene -d6, 22° C., 300 MHz : δ 1.16 (t, J=7.1 Hz, 18 H, OCH2CH 3), 3.87 (q, J=7.1 Hz, 12 H, OCH2CH3, 8.55 (s, 1H, C6H4). 13C{1H} NMR (benzene-d6, 22° C., 75.5 MHz ): δ 18.43 (OCH2CH3), 58.92 (OCH2CH3), 130.83, 143.60 (C6H4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:9]1[CH2:10][CH2:11][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH:24]N)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:9]1[CH2:10][C:11]1[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:24][C:12]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2CC1CCN2Cc1ccccc1
Reactant: NNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: c1ccc(CN2CCC3CC2Cc2c3[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-benzyl-2-aza-bicyclo[3.3.1]nonan-6-one in acetic acid (0.24 g) is added to a solution of PhNHNH2*HCl (173 mg) in acetic acid (4 mL) heated at reflux temperature. After stirring at this temperature for 2 h, the solution is cooled to room temperature and aqueous K2CO3 solution is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried (Na2SO4), and the solvent is removed. The residue is purified by HPLC on reversed phase (MeCN/water).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[O-]CC.[Na+].CO[CH:23]=[CH:24][C:25](=O)[CH3:26]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:10]([C:11]([OH:13])=[O:12])[C:9]2=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(F)cc1
Reactant: COC=CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a 4-necked 3 L round bottom flask, is added EtOH (1500 mL), ethyl 3-(4-fluorophenylamino)-3-oxopropanoate (139 g, 617 mmol), sodium ethoxide (65.6 g, 925 mmol) and 4-methoxy-3-buten-2-one (103 g, 925 mmol). The mixture is refluxed for 3 hours. After the solution is cooled to RT, the reaction mixture is concentrated under reduced pressure to remove the EtOH. The residue is diluted with DCM (700 mL) and 1 M HCl (1500 mL). The aqueous phase is extracted with DCM (3×500 mL). The combined organic extracts are washed with saturated aqueous sodium chloride (1000 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is triturated with EtOAc (150 mL) at RT (10-15° C.) for 1 hour. After filtration and washing with EtOAc (50 mL), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid is obtained as a yellow solid (85.3 g, 56% yield). MS (m/z): 248 (M+H).