Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:33]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:35][CH2:34]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCCCC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCCCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of tert-butyl 5-chloro-2-fluoro-4-((1-methylcyclohexyl)methoxy)benzoate (1.63 g, 4.6 mmol) in toluene-water (v/v 20:1, 21 mL) was added tribasic potassium phosphate (4.37 g, 20.60 mmol), cyclopropylboronic acid (0.581 g, 6.80 mmol) and tricyclohexylphosphine tetrafluoroborate (0.168 g, 0.46 mmol). The mixture was sonicated for 5 minutes, and then sparged with nitrogen for 10 minutes; palladium acetate (0.053 g, 0.23 mmol) was added and the reaction mixture was heated to 100° C. and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and poured into water. The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in anhydrous dichloromethane (8 mL) and trifluoroacetic acid (4 mL) was added. The mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The crude solid obtained was triturated with hexanes to provide the title compound (0.62 g, 44%): 1H NMR (300 MHz, DMSO-d6) δ 12.80 (br s, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.92 (d, J=13.2 Hz, 1H), 3.79 (s, 2H), 2.06-1.96 (m, 1H), 1.48-1.17 (m, 10H), 1.04 (s, 3H), 0.92-0.86 (m, 2H), 0.61-0.56 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[O:8][C:7]1[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=1.Cl.O1CCOCC1>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:6]3[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=3[O:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]=12
Reactant: Cc1ccn2c1C1(CCN(C(=O)OC(C)(C)C)CC1)Oc1ccccc1-2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccn2c1C1(CCNCC1)Oc1ccccc1-2
Reaction time: 1 h

Procedure:
To tert-butyl 3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (first eluting peak from step 2 (1.0 g, 2.8 mmol) was added hydrogen chloride in 1,4-dioxane (7.0 mL of 4.0 M, 28 mmol) and the mixture stirred 1 h, then filtered and rinsed with 1:1 ether/isopropanol to give 3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a pink solid. ESI-MS m/z calc. 254.3. found 255.3 (M+1)+; Retention time: 1.14 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](I)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>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].O.CCOC(C)=O.CN(C=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)=[O:28])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:19]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)c3ccccc32)cc1
Yield: 59.7 %

Procedure:
Add N-(4-Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (268 mg, 0.0.50 mmol), 2-chlorophenylboronic acid (78.2 mg, 0.50 mmol), PdCl2(dppf).CH2Cl2 (41 mg, 0.05 mmol) and 2M Na2CO3 (0.55 mL, 1.1 mmol) respectively to DMF (15.0 mL) at ambient temperature under N2. Heat the reaction to 100° C. for 16 h. Cool the reaction to ambient temperature and pour into a H2O-EtOAc mixture (200 mL/100 mL). Separate the EtOAc, extract several times with H2O and wash with brine. Dry (MgSO4), filter and evaporate the filtrate. Purify the crude material on silica gel using a gradient hexane-EtOAc system to give 0.155 g (60% yield) of 4-[3-(2-chloro-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide: Mass spectrum (m/e) M−1) 517.0787.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: Cc1c(Br)cccc1CBr
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(Br)cccc1Cn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (250 mg, 0.947 mmol), 1H-benzo[d]imidazole (336 mg, 2.84 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was stirred at rt for 5 h, The mixture was diluted with EtOAc and filtered, and the solid was washed with EtOAc. The filtrate was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 60:40 hexane-EtOAc to EtOAc). to provide 1-(3-bromo-2-methylbenzyl)-1H-benzo[d]imidazole as a white solid (233 mg, 82%). 1H NMR (400 MHz, chloroform-d) δ 8.14 (1 H, s), 7.68-7.78 (1 H, m), 7.56 (1 H, d, J=7.9 Hz), 7.36-7.44 (1 H, m), 7.25-7.34 (2 H, m), 7.03 (1 H, t, J=7.8 Hz), 6.82 (1 H, d, J=7.7 Hz), 5.58 (2 H, s), 2.45 (3 H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: NCCSCc1nccs1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Product: COc1cccc(Cc2nnc(NCCSCc3nccs3)[nH]c2=O)c1
Yield: 47.6 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.18 g) and 2-(2-thiazolylmethylthio)ethylamine (0.87 g) were heated together on an oil bath (160°-70°) for 3/4 hour. The resulting oil, after chromatography and crystallisation from ethanol, gave the title compound as a colourless solid (0.83 g) m.p. 128°-29°.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+].O.CO>O1CCCC1>[CH3:1][C:2]([CH3:17])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCC(C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4,4-dimethyl-5-phenylpentanoate (45.47 g, 194.0 mmol) and sodium hydroxide (15.5 g, 388 mmol), water (200 ml), methanol (200 ml) and tetrahydrofuran (100 ml) was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and diluted with water. After washing with diethyl ether, the mixture was acidified with conc. hydrochloric acid and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give the objective substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>O1CCOCC1.CO>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(-c2ccncc2)cc1
Reaction time: 120 h

Procedure:
Under inert gas atmosphere 181 mg (0.248 mmol) PdCl2(dppf)xCH2Cl2 are added to a mixture of 30.0 g (124 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (1.1), 139 mL (279 mmol) 2N sodium carbonate solution and 16.8 g (136 mmol) pyridine-4-boronic acid in 300 mL 1,4-dioxane and 100 mL methanol. The mixture is stirred for 5 d at reflux. After that time, the residue is poured into water (3 L) and extracted with dichloromethane (3×). The combined organic layers are washed with water and dried over magnesium sulphate. The solvent is evaporated and the residue is triturated with acetone and tert-butyl methyl ether.
Reaction SMILES: [Br-].N[CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Br:22]C(C)[CH2:24][CH2:25][CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O>>[Br-:22].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:6])[CH3:7]
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Agent: [Br-]
Product: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
The title compound is prepared by an analogous procedure to (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) by replacing N-(4-bromoethyl)-phthalimide with N-(4-bromopentyl)-phthalimide.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[N:6]1.[S:23](Cl)([Cl:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[O:15][C:16]([S:23]([Cl:25])=[O:24])=[CH:17][CH:18]=2)=[N:6]1
Reactant: O=S(Cl)Cl
Reactant: Fc1ccccc1Cn1nc(-c2ccco2)c2cccnc21
Product: O=S(Cl)c1ccc(-c2nn(Cc3ccccc3F)c3ncccc23)o1

Procedure:
0.85 g (2.86 mmol) of 1-(2-fluorobenzyl)-3-(2-furyl)pyrazolo[3,4-b]pyridine is stirred with 20 ml of thionyl chloride for 25 min at 70° C. The batch is then evaporated in vacuo and reacted further in crude form.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(OC1C=CC(C(F)(F)F)=CC=1C1[S:31][C:30]([NH:32][C:33](=[O:42])[C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:29][C:28]=1[C:43]([O:45][CH3:46])=[O:44])C=C>>[F:41][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=1[C:33]([NH:32][C:30]1[S:31][C:1]([C:3]2[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[C:28]([C:43]([O:45][CH3:46])=[O:44])[N:29]=1)=[O:42]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: C=CCOc1ccc(C(F)(F)F)cc1-c1sc(NC(=O)c2c(F)cccc2F)nc1C(=O)OC
Product: COC(=O)c1cccc(-c2sc(NC(=O)c3c(F)cccc3F)nc2C(=O)OC)c1

Procedure:
Compound 114 was prepared as from methyl 3-formylbenzoate as described for the preparation of Compound 63.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[Br:9][C:10]1[CH:14]=[CH:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:11]=1
Reactant: Brc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2×100 mL). The solid fiber cake was taken up in methylene chloride and washed separately with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink sold. The crude solid was suspended in hexane and stirred vigorously for 1 hr. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be >94% pure by NMR. This material was used without further purification in Step D.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C@@H:7]([CH3:16])[CH2:8][N:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1.ClCCCl.C(N(CC)C(C)C)(C)C.[CH3:32][NH:33][C:34](Cl)=[O:35]>C(OCC)(=O)C>[Br:1][C:2]1[CH:18]=[N:17][C:5]2[N:6]([C:34](=[O:35])[NH:33][CH3:32])[C@@H:7]([CH3:16])[CH2:8][N:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1
Reactant: CNC(=O)Cl
Reactant: CC(C)OC(=O)N1C[C@H](C)Nc2ncc(Br)cc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C

Procedure:
A reaction vial was charged with (S)-isopropyl 7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.02 mmol), 1,2-dichloroethane (0.10 mL), and N,N-diisopropylethylamine (0.25 mL, 0.14 mmol). Methylcarbamic chloride (1.0 M solution in 1,2-dichloroethane, 0.120 mL, 0.120 mmol) was added, and the reaction was heated at 50° C. overnight. N,N-Diisopropylethylamine (0.25 mL, 0.14 mmol) and methylcarbamic chloride (1.0 M solution in 1,2-dichloroethane, 0.120 mL, 0.120 mmol) were added, and the reaction was heated at 80° C. overnight. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The aqueous layer was separated and extracted with ethyl acetate and the combined organic layers were concentrated under a stream of nitrogen to afford (S)-isopropyl 7-bromo-3-methyl-4-(methylcarbamoyl)-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate which was used in the next step without purification.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:33]1[N:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CN(C=O)C>[N:36]1[CH:35]=[CH:34][CH:33]=[N:38][C:37]=1[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Reactant: Clc1ccncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(c3ncccn3)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (6 mL) were added diisopropylethylamine (366 mg, 2.84 mmol) and 6-chloropyrimidine (128 mg, 1.11 mmol) at ambient temperature and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5/hexane-EtOAc=¼) to give ethyl (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (141 mg, 46%) as an amorphous powder.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si:9]([O:16][CH2:17][C@H:18]1[CH2:22][CH2:21][C:20](=[O:23])[N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C1([Se]Cl)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[Si:9]([O:16][CH2:17][C@H:18]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl[Se]c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
Lithium diisopropylamide (2M solution in heptane/tetrahydrofuran/ethylbenzene) solution (11.98 mL) was added dropwise slowly to a solution of the compound 11 (6.58 g) in tetrahydrofuran (15 mL) and the solution was stirred at 30 minutes. A solution of Benzeneselenenyl chloride (4.59 g) in tetrahydrofuran (30 mL) was added dropwise slowly to the reaction solution, which was stirred at −78° C. for 1 hour. To the reaction solution was added an aqueous saturated ammonium chloride solution at −78° C. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The reaction solution was filtrated through Celite (Brand name) and concentrated. The obtained residue was purified by flush column chromatography (n-hexane:ethyl acetate=20:1). To a solution of the obtained compound (3.87 g) in tetrahydrofuran/ethyl acetate (2:3) (80 mL) were added sodium bicarbonate (1.68 g) and 30% hydrogen peroxide solution (3.2 mL) at 0° C. After 1 hour, to the reaction mixture was added water. The reaction solution was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The reaction solution was filtrated through Celite (Brand name) and concentrated. The obtained residue was purified by flush column chromatography (n-hexane:ethyl acetate=15:1) to give the title compound (1.89 g) having the following physical data.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=2)[N:10]([CH3:19])[C:9]=1[CH3:20])=[O:7])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(Cl)Cl>>[CH2:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[N:10]([CH3:19])[C:9]=1[CH3:20])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCNC(=O)c1c(C)n(C)c2cc(O)ccc12
Yield: 84.3 %

Procedure:
This material was prepared by the reaction of 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid butylamide 62a (0.78 g, 2.84 mmole) with 1.0 M BBr3 in CH2Cl2 (8.53 ml, 8.53 mmole) in a manner as previously described for example 1d to give an off-white solid (0.623 g, 96%). 1H NMR (300 MHz, CD3OD) δ7.40 (1H, d, J=8.5 Hz), 6.64 (1H, d, J=2.1 Hz), 6.59 (1H, dd, J=2.1, 8.5 Hz), 3.50 (3H, s), 3.29 (2H, m), 2.48 (3H, s), 1.54 (2H, m), 1.36 (2H, m), 0.90 (3H, t, J=7.3 Hz); ESIMS (MH+): 261.15.
Reaction SMILES: C([O:4][CH:5]([CH2:45][O:46]C(=O)C)[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH:19](COC(=O)C)[CH2:18]2)[C:13]([I:29])=[C:12]([C:30]([NH:32][CH2:33][CH:34]([O:40]C(=O)C)[CH2:35][O:36]C(=O)C)=[O:31])[C:11]=1[I:44])=[O:9])(=O)C.[CH3:50][O-:51].[Na+].[Na]>CO.O>[OH:40][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:30]([C:12]1[C:13]([I:29])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:50][OH:51])[C:15]([I:16])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([OH:4])[CH2:45][OH:46])=[O:9])[C:11]=1[I:44])=[O:31]
Reactant: C[O-]
Reactant: CC(=O)OCC1CN(c2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)C(=O)CO1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2C(=O)COCC2CO)c1I
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[2-(Acetyloxy)methyl-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (5.15 g, 5 mmol) in anhydroous methanol (100 ml), was added a solution of sodium methoxide, prepared from sodium (25 mg) and anhydrous methanol (5 ml), and the mixture was stirred for 3 hours. The solution was adjusted to pH 7 by a slow addition of Dowex-50 (H+) resin and then filtered. The filtrate was concentrated in vacuo to obtain the crude product (3.85 g) as a white solid. The material was dissolved in water (40 ml) and loaded onto a column of CHP-20 diaion resin. The column was first eluted with water (1 L) and then with a stepwise gradient of ethanol in water (1-8%). The fractions containing the pure product were combined and the solvents removed in vacuo to obtain N,N'-Bis(2,3-dihydroxypropyl)-5-[3-(hydroxymethyl)-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white microcrystalline solid (2.45 g, 60% yield, 99% purity). Recrystallization from ethanol/isopropanol (95/5) afforded the analytical sample as a white solid, m.p. 227°-230°.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[Cl:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:47][C:46]1[CH:45]=[CH:44][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH:41]4[CH3:43])=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(Cl)c(N)c3)ccc2n1
Reactant: CCn1cc(C(=O)O)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2Cl)c(C)n1
Yield: 28.4 %

Procedure:
Using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (181 mg, 1.17 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (102 μL, 1.17 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.84 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (118 mg, 28%) was obtained as a white powder.