Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:38]=[C:37]([C:39]2([O:43][CH3:44])[CH2:42][O:41][CH2:40]2)[CH:36]=[C:35]([F:45])[C:34]=1B1OC(C)(C)C(C)(C)O1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:45])=[CH:36][C:37]([C:39]4([O:43][CH3:44])[CH2:40][O:41][CH2:42]4)=[CH:38][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COC1(c2cc(F)c(B3OC(C)(C)C(C)(C)O3)c(F)c2)COC1
Product: COC1(c2cc(F)c(-c3nc(C(=O)Nc4cnn(C)c4[C@@H]4CC[C@@H](N)[C@H](F)CO4)cs3)c(F)c2)COC1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-(2,6-difluoro-4-(3-methoxyoxetan-3-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US2012/225062) gave 339. 1H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.65 (s, 1H), 7.88 (s, 1H), 7.46-7.44 (m, 2H), 4.82-4.79 (m, 5H), 4.37-3.93 (m, 3H), 3.78 (s, 3H), 3.24-3.17 (m, 1H), 3.12 (s, 3H), 2.07-1.67 (m, 4H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1.CO>ClCCl.C(OCC)(=O)C>[CH3:16][CH:14]([CH3:15])[CH2:13][C@H:12]([NH:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1)=[O:19])[C:10](=[O:11])[NH:9][CH:8]1[CH2:7][CH2:6][CH2:5][N:4]([S:42]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH2:3][CH:2]1[OH:1]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCNCC1O
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2cccnc2)CC1O
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a solution of benzofuran-2-carboxylic acid [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.3 g) in dichloromethane was added triethylamine (0.17 mL) followed by 3-pyridinesulfonyl chloride (0.25 g). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (5% methanol:ethyl acetate) provided 0.32 g of the title compound: MS(EI) 528 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([OH:12])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].O>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([OH:12])(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc(CS(=O)(=O)O)cc1
Yield: 90.3 %

Procedure:
A 250 ml of Par hydrogenation bottle was charged 4-Nitrobenzyl Sulfonic Acid (6.80 g, 31.34 mmol), 10% Pd/C (0.4 g), CH3OH (150 ml) with few drop of water, and purged with hydrogen. The reaction mixture was shaken with 20 psi H2 over night. The catalyst was removed by filtration through celite and the solvent was evaporated. The crude compound was co-evaporated three times with 3×50 ml of water and crystallized with water/THF/EtAc/Toluene (1:10:10:100) to give 5.3 g (91%) of the title compound. 1H NMR (D2O), 7.28 (dd, 2H, J=2.2, 4.3 Hz), 6.95 (dd, 2H, J=2.2, 4.3 Hz), 4.10 (s, 2H); 13C NMR 134.30, 127.10, 121.04, 120.42, 59.14; MS m/z−186.35 (M−H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14](=[O:22])/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[CH3:23][Si:24]([CH3:26])([CH3:25])[O:22][C:14](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH2:13]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCC/C=C/C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C=C(/C=C/CCCCC)O[Si](C)(C)C
Yield: 73.3 %

Procedure:
Pursuant to Dienylester Formation Protocol I, diisopropylamine (7.0 mL, 50.0 mmol, 1.4 eq) and n-butyllithium (32.4 mL, 46.5 mmol, 1.3 eq, 1.44 M in hexane) in THF (33 mL) were reacted with a solution of (E)-non-3-en-2-one (5.9 mL, 35.6 mmol, 1.0 eq) in THF (10 mL) and trimethylsilylchloride (8.0 mL, 62.6 mmol, 1.8 eq) in THF (30 mL). For the silylenolether, no aqueous workup was undertaken. n-Hexane (100 mL) was added to the reaction mixture, the residue filtered off and the solvent evaporated. The raw product was purified by distillation to yield 5.54 g (26.1 mmol, 74%) of (E)-trimethyl(nona-1,3-dien-2-yloxy)silane as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C)(=O)=O.[Si](O[C@@H]1[C@@](COS(C)(=O)=O)(CO)O[C@@H]([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])C1)(C(C)(C)C)(C)C>C(Cl)Cl>[NH:34]1[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]1=[O:36]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO)(COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: 24 °C

Procedure:
To a solution of 3'-O-β-butyldimethylsilyl-4'-hydroxymethyl-β-D-erythro-pentofuranosylthymine (1.2 g, 3.1 mM), prepared, e.g., as described in Preparation 4, in CH2Cl2 (20 ml), triethylamine (0.6 g. 6 mM) was added followed by the dropwise addition of mesyl chloride (0.340 g, 3 mM), while the solution was stirred at 24° C. The solution was concentrated by the removal of the solvent by evaporation. The residue was flash chromatographed on silica gel eluting by CH2Cl2 with 5% methanol, to give a mixture of the 4'-α and 4'-β isomers of 3'-O-t-butyldimethylsilyl-4'-methanesulfonyloxymethylthymidine (1.1 g, 2.4 mM). Calcd. for C18H32N2O8Si: C, 46.53; H, 6.94; N, 6.05. Found: C, 46.90; H, 7.02; N, 5.78.
Reaction SMILES: Cl[C:2](=[Ti:4]([CH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)Cl.[CH3:15][Al:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.CCCCCC>C1(C)C=CC=CC=1>[CH2:2]=[Ti:4]([CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9]1)[CH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[CH3:15][Al:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: ClC(Cl)=[Ti](C1C=CC=C1)C1C=CC=C1
Agent: C[Al]1CCCCO1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C=[Ti](C1C=CC=C1)C1C=CC=C1
Temperature: -78 °C
Yield: 71 %

Procedure:
97.2 mg (0.372 mmol) of dichloromethylenebis(cyclopentadienyl)titanium was weighed out. Thereto 20 ml of dry toluene was added, and the mixture was cooled to a temperature of -78° C. 2.98 mmol of methylalumoxane (16-mer ) in toluene was added thereto dropwise with stirring, and the mixture was allowed to react at 50° C. for 6 hours. Then 20 ml of hexane was added to deposit a reddish brown solid. The solid was collected by filtration, recrystallized from toluene/hexane, and dried. The intended product was obtained in a yield of 71%.
Reaction SMILES: ClC1C=CN=C(/C=N/[S@](C(C)(C)C)=O)C=1F.C([Mg]Br)C=C.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C@@H:29]([NH:33][S@:34]([C:36]([CH3:39])([CH3:38])[CH3:37])=[O:35])[CH2:30][CH:31]=[CH2:32])[C:24]=1[F:40]>C1COCC1.C(O)(C)C.CCCCCCC>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C@H:29]([NH:33][S@:34]([C:36]([CH3:39])([CH3:38])[CH3:37])=[O:35])[CH2:30][CH:31]=[CH2:32])[C:24]=1[F:40]
Reactant: C=CC[C@H](N[S@@](=O)C(C)(C)C)c1nccc(Cl)c1F
Agent: C=CC[Mg]Br
Agent: CC(C)(C)[S@](=O)/N=C/c1nccc(Cl)c1F
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C=CC[C@@H](N[S@@](=O)C(C)(C)C)c1nccc(Cl)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a solution of (S,E)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.03 g, 3.92 mmol) in THF (100 mL) was added allyl magnesium bromide (1 M in ether) (4.70 mL, 4.70 mmol) dropwise and the resulting solution was stirred for 1 h at −78° C. The reaction mixture was then warmed to rt and then quenched with saturated NH4Cl solution. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were concentrated in vacuo, and the residue was then subjected to silica gel purification to provide a mixture of the S and R isomers. MS (ESI) m/z: 305.1 (M+H)+. Chiral separation: AD column eluting with 30% isopropanol in heptane provided peak 1 as the desired (S)—N—((S)-1-(4-Chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (0.710 g, 59%) and peak 2 as (S)—N—((R)-1-(4-chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (0.081 g, 7% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:18]=1)([O-])=O>CO.[Pd]>[N:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccncc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 2 h
Yield: 28.1 %

Procedure:
To a solution of 2.03 g (0.00842 mole) of 5-nitro-2-pyridin-4-yl-benzooxazole (R. D. Haugwitz, et al., J. Med. Chem., 1982, 25, 969-74.) in methanol (150 mL) was added 0.2 g of 10% palladium on carbon catalyst. The mixture was hydrogenated on a Parr hydrogenator at 50 psi for 2 hours. The catalyst was filtered off and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-80:20), to give 0.5 g of 2-pyridin-4-yl-benzooxazol-5-ylamine. HRMS (ES+) m/z Calcd for C12H9N3O+H [(M+H)+]: 212.0819. Found: 212.0818.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:24]([O:26][CH3:27])=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13](=[O:16])[C:14]=2[CH:15]=1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:31].O>CN(C)C=O.C(OCC)(=O)C>[CH3:31][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[C:8]([C:24]([O:26][CH3:27])=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13](=[O:16])[C:14]=2[CH:15]=1
Reactant: CI
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(NS(C)(=O)=O)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(N(C)S(C)(=O)=O)cc2C1=O
Reaction time: 2 h

Procedure:
1.4 g of methyl 7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is dissolved under an inert atmosphere in 18 cm3 of dimethylformamide at a temperature close to 20° C. This solution is cooled to a temperature close to 0° C., then 141 mg of sodium hydride (60% in oil) are added in 2 lots. The reaction mixture is stirred for 2 h at a temperature close to 0° C. 0.264 cm3 of iodomethane is introduced then the stirring is continued for 20 h while gradually allowing it to climb back up to a temperature close to 20° C. 20 cm3 of iced water and 50 cm3 of ethyl acetate are added to the reaction mixture. After decanting, the organic phase is washed with 20 cm3 of a 2M aqueous solution of hydrochloric acid, 3 lots of 20 cm3 of water then 30 cm3 of a saturated aqueous solution of sodium chloride. It is then dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). 1.187 g of methyl 7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained in the form of beige crystals.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:41])[CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40].[Cl-].[NH4+]>C1COCC1>[CH2:3]([O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][OH:41])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
Sodium hydride (35 mg, 0.872 mmol) and benzyl bromide (52 μl, 0.436 mmol) were added to 5 mL of a solution of commercially available decaethylene glycol (200 mg, 0.436 mmol) in THF, and the mixture was stirred at room temperature for 16 hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 168 mg of crude decaethylene glycol monobenzyl ether as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])c(Cl)c1

Procedure:
Prepared analogously to Example 4.1.a. from 3-chloro-4-nitrophenol and (2-chloroethyl)diethylamine hydrochloride. Yield: 1.25 g (79.5% of theory); C12H17ClN2O3 (M=272.73); calc.: molecular ion peak (M+H)+: 273/275; found: molecular ion peak (M+H)+: 273/275; Rf value: 0.44 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[CH2:2].[C:25]([OH:28])(=[S:27])[CH3:26].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:25]([S:27][CH2:2][CH2:1][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:28])[CH3:26]
Reactant: C=Cc1cccc(OCc2ccc(C(=O)OC)cc2)c1C(=O)OC
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1ccc(COc2cccc(CCSC(C)=O)c2C(=O)OC)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 2-ethenyl-6-[4-(methoxycarbonyl)phenyl]methoxy-benzoic acid, methyl ester (0.71 g, 2.18 mmol) in benzene (10 mL) was added thioacetic acid (1.80 mL, 25.2 mmol) followed by AIBN (37 mg, 0.23 mmol). After nitrogen was bubbled through the solution for 30 min, the solution was heated at reflux for 4 h. The reaction was allowed to cool to rt and saturated NaHCO3 (20 mL) was added. The mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (1:10 EtOAc/hexanes) to give 2-[2-(acetylthio)ethyl]-6-[4-(methoxycarbonyl)phenyl]methoxy-benzoic acid, methyl ester (0.50 g, 60%) as a clear oil: 1H NMR (CDCl3) δ2.34 (s, 3H), 2.85-2.82 (m, 2H), 3.07-3.10 (m, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 5.16 (s, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 7.28 (t, J=8.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 8.04 (d, J=8.3 Hz, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)O1.Cl[C:22]1[C:31]([N:32]([CH3:36])[CH:33]([CH3:35])[CH3:34])=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:37]([O:39][CH3:40])=[O:38])[CH:28]=2)[N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH3:36][N:32]([CH:33]([CH3:35])[CH3:34])[C:31]1[C:22]([C:9]2[O:10][C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][C:27]([C:37]([O:39][CH3:40])=[O:38])=[CH:26][CH:25]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)o2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(-c4ccccc4)o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(5-phenylfuran-2-yl)-1,3,2-dioxaborolane (553 mg, 2.05 mmol) in dioxane (5.5 mL) and water (3 drops) was methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (200 mg, 0.68 mmol), K3PO4 (430 mg, 2.03 mmol) and Pd(PPh3)4 (39.3 mg, 0.03 mmol) with stirring for 1 h at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylate as light yellow solid (150 mg, 55%).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[C:26]1([CH3:33])[CH:27]=[C:28]([CH3:32])[CH:29]=[C:30]([CH3:31])[C:25]=1[N:22]1[C:16]2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=[C:14]([O:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])[C:15]=2[CH:24]=[CH:23]1
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: CCC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-phenyl-1-propanol (0.061 ml, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 49.4 mg (82%) of the title compound as an oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[C:11]([Mg]Br)#[CH:12]>O1CCCC1>[OH:2][CH:1]([C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]#[CH:12]
Reactant: CCOC(=O)C1CC1C=O
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of ethyl 2-formyl-1-cyclopropanecarboxylate (predominately trans, 331 μL, 2.5 mmol) in tetrahydrofuran (5 mL) was cooled down to −70° C. Ethynylmagnesium bromide (0.5 M in tetrahydrofuran, 5 mL, 2.5 mmol) was added to the above solution under an atmosphere of nitrogen dropwise, and stirred at −70° C. for 1 h. The reaction was quenched with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to get 419 mg of the title compound (yield 100%, unpurified) as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH2:22])[N:21]=2)[N:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C>[CH:1]1([CH2:4][C:5]([NH:22][C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([I:12])=[N:18][N:17]3[CH:19]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(CC1CC1)Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of cyclopropylacetic acid (441 mg, 4.4 mmol) in tetrahydrofuran (8.0 mL) were added N,N-dimethylformamide (1 drop) and thionyl chloride (0.32 mL, 4.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and dissolved in N,N-dimethylacetamide (2.0 mL). To a solution of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.04 g, 4.0 mmol) in N,N-dimethylacetamide (6.0 mL) was added dropwise the above-mentioned solution under ice-cooling. The mixture was stirred at room temperature for 2 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=80/20→100/0), and recrystallized from ethyl acetate to give the title compound (982 mg, 72%) as pale-green crystals.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]([C:11]2[N:12]3[CH2:18][CH2:17][N:16]=[C:13]3[S:14][CH:15]=2)=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[S:6]1[C:10]([C:11]2[N:12]3[CH2:18][CH2:17][N:16]=[C:13]3[S:14][C:15]=2[CH:25]=[O:26])=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2
Reactant: C1=C(c2cc3ccccc3s2)N2CCN=C2S1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=CC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
n-Butyllithium (1.6 M solution in hexanes; 6.25 ml) was added dropwise under nitrogen at −70° C. to a stirred solution of 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole (2.58 g) in tetrahydrofuran (40 ml), then the mixture was stirred at −70° C. for 10 minutes and at 0° C. for 35 minutes. Dimethylformamide (0.85 ml) was added, the mixture was stirred at 0° C. for 1.5 hours, then it was poured into saturated aqueous ammonium chloride solution (200 ml). The product was extracted into ethyl acetate (2×200 ml), then the combined extracts were washed with water (2×100 ml) and saturated aqueous sodium chloride solution (2×100 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to give 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.73 g) as a yellow solid which was used without further purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1cccc(Cl)c1)c1ccccc1

Procedure:
A sodium hydroxide solution (7.5 ml., 20%) is added to a solution of p-chlorobenzaldehyde (17.86 g., 0.127 mole) and 3-phenyl-6-(m-chlorophenyl)-5-hexen-2-one (36.11 g., 0.127 mole) in ethanol (360 ml.) with stirring. The gum that separates on continued stirring is chromatographed (benzene) through a silica gel column to obtain the product as a very viscous oil (opaque).