Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[CH3:15][CH2:16][O:17][C:18](OCC)(OCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:18]([O:17][CH2:16][CH3:15])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccccc1

Procedure:
A solution of 41.9 g 1-acetyl-6-chloro-2-indolinone (educt V.1) and 136 ml triethyl orthobenzoate in 150 ml acetic anhydride is stirred for six hours at 120° C. After cooling the mixture is evaporated down by half, the crystals precipitated are suction filtered and dried at 100° C. in vacuo.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[CH:29].C(N(CC)CC)C>C1COCC1.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.[Cu]I>[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[C:29][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: Ic1cnccc1OCc1nnc2ccc(-c3ccccc3)nn12
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC#Cc1cnccc1OCc1nnc2ccc(-c3ccccc3)nn12
Temperature: 75 °C
Reaction time: 1.25 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.5 μmol) was added to a suspension of 3-((3-iodopyridin-4-yloxy)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (107 mg, 249 μmol) and 1-dimethylamino-2-propyne (80.4 μl, 748 μmol) in THF (0.6 mL) and triethylamine (591 μl, 4238 μmol) at RT. Copper(i) iodide, 99.999% (4.75 mg, 24.9 μmol) was added and the reaction mixture was stirred at 75° C. (oil bath) for ˜75 min. The reaction mixture was cooled at RT, concentrated in vacuo. Purification by MPLC (ISCO, CH2Cl2/MeOH: 100/0 to 90/10) afforded the title compound. MS m/z=385.1 [M+H]+. Calc'd for C22H20N6O: 384.44
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH:17]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24](OC)=[O:25])[CH2:19][CH2:18]1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:25]=[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH:17]1[CH2:19][CH2:18]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCCCC1CC1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CCCCC1CC1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -78°,25.6 g (0.20 mole) methyl 5-cyclopropylvalerate is added dropwise at a rate that keeps the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the cmbined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled to give dimethyl 2-oxo-6-cyclopropylhexylphosphonate.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][C:8](=O)[S:7][C:6]=2[C:11]=1[CH3:12].[CH:15]([O:17][CH2:18][CH3:19])=[CH2:16].C(Br)Br.C(=O)(O)[O-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CS(O)(=O)=O.O>[CH2:15]([O:17][CH:18]([O:1][C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][S:7][C:6]=2[C:11]=1[CH3:12])[CH3:19])[CH3:16]
Reactant: C=COCC
Reactant: Cc1c(O)c(C)c2sc(=O)oc2c1C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: BrCBr
Solvent: O
Product: CCOC(C)Oc1c(C)c(C)c2c(c1C)SCO2
Temperature: -20 °C

Procedure:
A mixture of 7.35 g of 5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-one, 20 ml of ethyl vinyl ether and 20 ml of methylene dibromide was cooled down to -20° C. under a stream of nitrogen, and then 20 mg of methanesulfonic acid were added dropwise, while stirring. After completion of the dropwise addition, the reaction temperature was gradually raised to room temperature, and the mixture was stirred for 3 hours at room temperature. To this reaction mixture were added 30 ml of water, 8.8 g of sodium bicarbonate and 1.0 g of Aliquat 336 (a trade mark for methyltrioctylammonium chloride), and the mixture was heated under reflux for 9 hours, which caused the excess methylene dibromide to vaporize gradually and leave a crude oil. This crude oil was extracted with diethyl ether, and the extract was dried over anhydrous sodium sulfate. The ether was then distilled off, to yield 12 g of an oily substance, which was purified by silica gel column chromatography. From the portion which could be eluted with a 20:1 by volume mixture of petroleum ether and diethyl ether were obtained 5.2 g of the title compound melting at 52°-54° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[CH:18]=[O:19]
Reactant: OCC1CC2CCC1C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CC2CCC1C2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 103.1 %

Procedure:
In a flask under argon was placed dichloromethane (25 mL) and to this was added a 2M solution of oxalyl chloride in dichloromethane (4.0 mL, 8.0 mmol). The mixture was then cooled to −78° C. and then slowly treated with dimethyl sulfoxide (846 μL, 11.92 mmol) and gas evolution occurred. The mixture was stirred at −78° C. for 20 min. After this time, a solution of bicyclo[2.2.1]hept-2-yl-methanol (505 mg, 4.0 mmol) in dichloromethane (15 mL) was added dropwise. The mixture was stirred at −78° C. for another 15 min and then triethylamine (2.2 mL, 15.6 mmol) was added and the reaction was slowly warmed to 0° C. The mixture was then quenched with a 1M aqueous sodium bisulfate solution (50 mL) and extracted with dichloromethane (3×20 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 3% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded slightly impure bicyclo[2.2.1]heptane-2-carbaldehyde (512 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:35][CH2:36][O:37]C(C)=O>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:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:36](=[O:37])[CH3:35])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: CCOC(C)=O
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2Sc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-{4-(4-bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 2 g, 4.38 mmol), (1-ethoxyvinyul)tributyltin (1.7 g, 4.82 mmol), PdCl2(PPh3)2 (67 mg, 0.2 mmol), and 15 mL of toluene under nitrogen was heated at 100° C. overnight. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered. To the filtrate was added KF/Celite (50% wt from Aldrich) which was stirred for 1.5 h. Upon filtration and concentration, the residue was taken up in 20 mL of EtOH and 10 mL of 2 N HCl, stirred at rt for 1 h. The precipitate was collected by filtration, washed with water and a small amount of EtOAc. The solid was further purified by silica gel column chromatography (10-50% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CDCl3): 8.62 (d, 1H), 8.38 (d, 1H), 8.26 (d, 2H), 8.19 (d, 2H), 7.83 (t, 1H), 7.31 (t, 1H), 7.23 (d, 2H), 7.04 (d, 2H), 4.13 (s, 3H), 2.61 (s, 3H). LCMS: m/z 420 (M+H)+.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[Br-:11].C(OC([NH:19][CH2:20][CH2:21][CH2:22][P+:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br-:11].[NH3+:19][CH2:20][CH2:21][CH2:22][P+:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Br-:11]
Reactant: CC(C)(C)OC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [NH3+]CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
The solution of TFA/CH2Cl2 (1:1, 50 ml) containing triisoproylsilane (0.2 ml) was added to (3-((tert-butoxycarbonyl)amino) propyl)triphenylphosphonium bromide (6.15 g, 14.6 mmol). The mixture was stirred for 2 hours. After removal of the solvent, the compound was dried over vacuum and directly used in next step.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3](=[O:29])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:41]1[C:42]2[C:49]([CH3:50])=[CH:48][NH:47][C:43]=2[N:44]=[CH:45][N:46]=1>C(O)(C)C.CCOC(C)=O>[CH3:1][N:2]([CH3:30])[C:3](=[O:29])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH2:16][N:17]([C:41]3[C:42]4[C:49]([CH3:50])=[CH:48][NH:47][C:43]=4[N:44]=[CH:45][N:46]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(COCc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2ncnc(N3CCC(COCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 85 °C
Yield: 37.6 %

Procedure:
To a solution of 3-(4-(benzyloxymethyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (0.2 g, 0.49 mmol) in isopropanol (5 mL) was added N,N-diisopropylethylamine (0.167 mL, 0.98 mmol) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.08 g, 0.49 mmol). The reaction was heated at 85° C. overnight, diluted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (40 g SiO2, 0-80% ethylacetate:hexanes) to give the title compound (0.1 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[Cl:13][C:14]1[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[CH:17]=[CH:16][C:15]=1[NH2:24].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:13][C:14]1[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[CH:17]=[CH:16][C:15]=1[NH:24][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)Cc3ccc(Cl)cc3Cl)ccc2s1
Yield: 34.6 %

Procedure:
Reaction of 2,4-dichlorophenylacetic acid (163 mg, 0.79 mmol) in thionyl chloride (2 mL) then with 4-chloro-2-methyl-benzothiazol-5-ylamine (52 mg, 0.26 mmol) in presence of triethylamine (0.5 mL) in THF (3 mL) according to method B gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(2,4-dichloro-phenyl)-acetamide (33 mg, 0.09 mmol, 35% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[Br:6][C:7]([C:29]([OH:31])=[O:30])=[CH:8][C:9]1[CH:10]=[C:11]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:6][C:7]([C:29]([O:31][CH2:4][CH2:3][O:2][CH3:1])=[O:30])=[CH:8][C:9]1[CH:10]=[C:11]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)O)c2)c1=O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOC(=O)C(Br)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 17 h

Procedure:
0.52 ml of methoxyethyl bromide was added to a solution of 2.27 g of 3-[3-(2-bromo-2-carboxyethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.76 g of potassium carbonate in dimethylformamide, and the resulting solution was stirred for 17 hours. Thereafter, 100 ml of water were added and the aqueous phase was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. After flash chromatography (dichloromethane→9:1 dichloromethane/ethyl acetate), the title compound was obtained as an oil.
Reaction SMILES: [N+]([O-])(O)=O.C(O)C.[C:8](=[O:10])=O.[Cl:11][C:12]1[C:17](C)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>>[Cl:11][C:12]1[C:17]([CH3:16])=[C:8]([OH:10])[CH:15]=[CH:14][C:13]=1[CH3:19]
Reactant: O=C=O
Reactant: Cc1cccc(C)c1Cl
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Cc1ccc(O)c(C)c1Cl
Reaction time: 0.17 h

Procedure:
Nitration of 2-chloro-m-xylene. Nitric acid (90%, 50 mL) was cooled to −35° C. (ethanol-dry ice bath). 2-Chloro-m-xylene (10 mL) was added dropwise over 1 h keeping the temperature between −30° C. and −35° C. The reaction mixture was poured onto ice, stirred for 10 min, precipitate formed was collected by filtration, washed with water, dried. The crude product was purified on SiO2 (50 g), hexane-EtOAc (0 to 2% v/v). The product—yellow solid, 12.8 g, as a mixture of 2-chloro-1,3-dimethyl-4-nitro-benzene and chloro-1,3-dimethyl-5-nitro-benzene (4:1).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]/[N:24]=[C:2](/[CH3:15])\[CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OCC(C)=O)cc1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: COC(=O)c1ccc(OC/C(C)=N\Nc2ccc(F)cc2)cc1
Yield: 51.5 %

Procedure:
Methyl 4-(2-oxopropoxy)benzoate (6.21 g) was added to a solution of 4-fluorophenylhydrazine (2.88 g) in ethanol (50 ml). After 1.5 h the precipitate was collected, washed with ethanol and isohexane and dried to give the sub-title compound (3.72 g).
Reaction SMILES: [Al].C(O[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.Br[CH2:13][C:14]#[CH:15]>CCOCC.[Hg](Cl)Cl>[CH2:10]([O:9][CH:5]([O:6][CH2:7][CH3:8])[CH2:15][C:14]#[CH:13])[CH3:11]
Reactant: CCOC(OCC)OCC
Reactant: C#CCBr
Agent: Cl[Hg]Cl
Agent: [Al]
Solvent: CCOCC
Product: C#CCC(OCC)OCC

Procedure:
To a suspension of aluminum (20.87 g, 773 mmol) and mercury(II) chloride (1.187 g, 4.37 mmol) in ether (40 mL) was added triethoxymethane (49.8 g, 336 mmol) in ether (160 mL) over 60 minutes (internal temperature monitored and addition slowed to keep below 41° C.). The mixture was stirred at reflux for one hour, then brought to −78° C. in a dry ice/acetone bath. 3-bromoprop-1-yne (75 g, 504 mmol) in ether (17 mL) was added dropwise and the suspension was stirred at −78° C. for three additional hours. The reaction was quenched with water (300 mL) followed by 1N NaOH (120 mL). The layers were separated and the aqueous layer washed with additional diethyl ether. The organic extracts were dried over magnesium sulfate and concentrated to yield 4,4-diethoxybut-1-yne.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH3:33][N:34]([CH3:37])[CH:35]=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:2]3[CH:3]=[CH:4][CH:16]=[CH:17][C:18]=3[CH2:35][N:34]([CH3:37])[CH3:33])[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:16]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3ccc(C)nc3)c2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(-c3ccccc3CN(C)C)c2)nc1

Procedure:
In a 5 mL microwave vial, 3-bromo-5-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (15.00 mg, 0.03785 mmol), Unnamed (13.55 mg, 0.07570 mmol), cesium carbonate (61.66 mg, 0.1892 mmol), tetra-n-butylammonium iodide (13.98 mg, 0.03785 mmol), and POPd (1.899 mg, 0.003785 mmol) were dissolved in Water (0.03 mL, 2 mmol) and N,N-dimethylformamide (0.1 mL, 2 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase HPLC (acetonitrile:water gradient) at pH 10. The combined pure fractions were reduced in vacuo to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([OH:39])[C:10]1([OH:43])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.CC(C)=O>[CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([O:39][CH2:5][CH2:6][CH3:7])[C:10]1([O:43][C:1](=[O:8])[CH2:2][CH2:3][CH3:4])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: [H][H]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCOC1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1(CCC)OC(=O)CCC
Yield: 123.1 %

Procedure:
The allyl ether 21 (182 mg, 0.26 mmol) was dissolved in a mixture of 7 mL ethanol and 1 mL acetone and 18 mg Wilkinson catalyst (19 μmol) was added. The mixture was stirred in a hydrogen atmosphere for 3 days, before the solvents were removed under reduced pressure. The residue was chromatographed by preparative HPLC (95% MeOH, 40 mL/min, tRet=35.00 min) to give 26 as a colorless solid(108 mg, 0.16 mmol; 59.2% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:19](=O)[CH:20]([CH3:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3ccccc3c2n1N=CC(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (0.940 g, 3.88 mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with isobutyraldehyde (0.800 mL, 8.81 mmol) and pyridinium p-toluenesulfonate (0.098 g, 0.39 mmol) and the reaction mixture was heated to reflux under an atmosphere of nitrogen. After 48 h, the reaction mixture was concentrated under reduced pressure and dissolved in CHCl3. The organic portion was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown oil which solidified under vacuum to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylideneamine (1.15 g) as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[C:5](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=O)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=O.C([O-])(O)=O.[Na+]>[Pd].CC(O)=O>[O:11]1[C:7]2=[CH:6][C:5]3[CH2:13][CH2:14][C:15](=[O:17])[NH:1][C:4]=3[CH:12]=[C:8]2[O:9][CH2:10]1
Reactant: CCOC(=O)/C=C/c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCc2cc3c(cc2N1)OCO3
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Palladium on carbon (340 mg) was added to a solution of (E)-ethyl 3-(6-nitrobenzo[d][1,3]dioxol-5-yl)acrylate (500 mg, 1.89 mmol) in AcOH (60 ml). Then H2 (g) was introduced at 5 Atm and the reaction was stirred overnight at 70° C. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with ethyl acetate (3×80 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-6-one as a brown solid (316 mg, crude).
Reaction SMILES: Br.[C:2]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O.CC1C=CC(S(NC2C=CC(NC3C=CC=CC=3)=CC=2)(=O)=O)=CC=1>[C:2]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CC(=O)N1CCNCC1
Reactant: C=C(C)C(=O)Cl
Agent: Br
Agent: Cc1ccc(S(=O)(=O)Nc2ccc(Nc3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)N1CCN(C(=O)CC(C)=O)CC1
Reaction time: 20 h
Yield: 56 %

Procedure:
Crude 1-acetoacetylpiperazine hydrobromide (50 g, 0.2 mole) was dissolved in N,N-dimethylformamide (300 ml) with Aranox™ (50 mg) (available from U.S. Rubber Co.). Triethylamine (50 g, 0.5 mole) was added at 0° C., followed immediately by the dropwise addition of methacryloyl chloride (20.8 g, 0.2 mole) at 0° C. The reaction solution was then allowed to reach 20° C. over a 20 hour period. The reaction solution was filtered and the solvent was removed at low vacuum. The residue was distilled to give 4-acetoacetyl-1-methacryloylpiperazine (b.p.=110°-129° C./10-8μ) at a yield of 56%.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=5)[C:59](=[O:68])[CH2:58][O:57][C:56]=4[N:69]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=5)[C:59](=[O:68])[CH2:58][O:57][C:56]=4[N:69]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ccncc3)C(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ccncc3)C(=O)CO4)cc2)CCC1
Yield: 140.5 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-oxo-7-phenyl-1-(pyridin-4-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (21 mg, 0.04 mmol) was reacted to afford the title compound (26 mg, quantitative). LCMS (Method A): RT=3.25 min, M+1=464. 1H NMR (500 MHz, MeOD): 8.57 (2H, s), 7.67 (2H, s), 7.28-7.24 (4H, m), 7.23 (1H, s), 7.14-7.10 (3H, m), 6.96-6.94 (2H, m), 5.37 (2H, s), 5.03 (2H, s), 2.66-2.60 (2H, m), 2.49-2.43 (2H, m), 2.14-2.10 (1H, m), 1.89-1.82 (1H, m).