Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25](=[O:27])[NH2:26])([CH3:23])([CH3:22])[CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([O:24][C:25](=[O:27])[NH:26][C:14]1[CH:15]=[C:16]([Cl:17])[C:11]([C:9]2[S:8][C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=3[N:10]=2)=[C:12]([Cl:19])[CH:13]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(N)=O
Reactant: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.40 g, 0.905 mmol), carbamic acid tert-butyl ester (0.159 g, 1.36 mmol), XantPhos (0.053 g, 0.091 mmol) and K3PO4 (0.384 g, 1.81 mmol) in toluene (9 mL) and water (1.5 mL), was degassed with a stream of argon. Pd2(dba)3 (0.041 g, 0.045 mmol) was then added and the reaction mixture was heated at 85° C. for 2 hours using microwave irradiation and then thermally at 100° C. for 18 hours. After cooling to room temperature, the crude residue was partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-10% EtOAc in cyclohexane to afford the title compound as an off-white solid (0.352 g, 90% yield). LCMS (Method D): RT=4.68 min, m/z: 430 [M+H+].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[Si:11]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of N-methylethanolamine (600 mg), in N,N-dimethylformamide were added imidazole (1.13 g) and tert-butyldiphenylsilyl chloride (2.20 g) at ambient temperature with stirring. After 8 hours, the mixture was diluted with water (60 ml) and was extracted with ethyl acetate (20 ml) twice. The organic layer was washed with water three times and brine, dried over magnesium sulfate. The solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane-methanol to give N-(2-tert-butyldiphenylsilyloxyethyl)-N-methylamine (780 mg) as an oil.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])(C)C)[CH:5]=[CH:4][C:3]=1O.C(C1C=CC(O)=[C:19]([N+:24]([O-])=O)C=1)(C)(C)C.Cl.C(C=C)=O.[OH-].[Na+]>C(O)(=O)C.O>[N:24]1[C:7]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:11][CH:19]=1
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: C=CC=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2ncccc2c1
Temperature: 80 °C

Procedure:
Into a 500 mL 3-neck flask fitted with condenser, addition funnel and a thermometer was added 10.0 g of 2-Amino-4-tert-butylphenol (Aldrich) dissolved in 50.0 mL acetic acid. To the solution was added 3.90 g of 4-(t-butyl)-2-nitrophenol (Aldrich) and 100 mL of concentrated HCl. The contents of the flask were heated to 80° C. by means of an oil bath. Acrolein (Aldrich) (6.78 g) was added over 30 min via the addition funnel. After the addition was complete, the solution was heated to 130° C. for 16 hrs. The solution was allowed to cool to room temperature and then poured into 300 mL cold water and neutralized to pH7.0 by addition of a 25% NaOH solution. A tan precipitate formed which was extracted from the aqueous solution (3×200 ml methylene chloride). The combined extracts were dried with MgSO4 and concentrated to an oil. The oil was resuspended in methylene chloride and the insoluble materials (unreacted 2-amino-4-tert-butylphenol) filtered off. The filtrate was concentrated to an oil and purified by chromatography on silica gel column eluting with 1:1 chloroform:hexanes to remove the non-polar impurities followed by chloroform to elute the product. The product containing fractions were combined and concentrated to an oil which solidified upon standing. Yield 1.56 g (13%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CO.C(Cl)Cl>[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([NH:19][CH2:2][C:3]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(N)cccc1Br
Reactant: COC(=O)c1cc(OC)ccc1CBr
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OC)ccc1CNc1cccc(Br)c1C
Temperature: 85 °C
Yield: 17.9 %

Procedure:
Step 2 A mixture of methyl 2-(bromomethyl)-5-methoxybenzoate (1.435 g, 5.54 mmol), 3-bromo-2-methylaniline (1.03 g, 5.54 mmol) and TEA (1.158 mL, 8.31 mmol) in methanol (5 mL) was heated at 85° C. for 2 h. The mixture was diluted with DCM, washed with NaHCO3 (aq), and dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide methyl 2-((3-bromo-2-methylphenylamino)methyl)-5-methoxybenzoate as a yellow oil (361 mg, 18%). Mass spectrum m/z 364, 366 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[NH:23][N:22]=1.N=C=N>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[Cl:20])=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Yield: 6.4 %

Procedure:
The product from Example 3, Step 2 (103 mg, 0.36 mmol, 1.0 equiv) was combined with 3-chloro-1H-indazol-5-amine (91 mg, 0.54 mmol, 1.5 equiv) and PS-carbodiimide resin (0.994 mmol/g loading, 580 mg, 0.54 mmol, 1.5 equiv) in 6 mL of DMF and reacted overnight at room temperature. The reaction mixture was filtered and washed alternately with MeOH and CH2Cl2 (twice), then with diethyl ether. The filtrate was concentrated en vacuo and redissolved in EtOAc. The solution was washed with 0.5 N HCl, 0.5 N NaOH and satd. NaCl. The organic layer was concentrated en vacuo. Following purification by flash chromatography (0-50% EtOAc in CH2Cl2), the solid was triturated with CH2Cl2 to provide 10 mg (6.5%) of the title compound as light pink crystals. MS (ES+) m/e 434 [M+H]+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br.Cl>C(#N)C>[CH3:15][O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: COC(=O)Cc1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1COc1ccccc1C
Reaction time: 0.07 h

Procedure:
5.12 g of o-cresol and 7.2. g of pulverized potash in 30 ml of acetonitrile are preheated to 60° C. and a solution of 11.06 g of 2-(bromomethyl)-phenylacetic acid methyl ester in 35 ml of acetonitrile is added dropwise over a period of 8 minutes. The reaction mixture is then stirred for 4 minutes and immediately poured onto ice-water and weakly acidified with 2N hydrochloric acid. The aqueous solution is extracted exhaustively with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields pure 2-(2-methylphenoxymethyl)-phenylacetic acid methyl ester in the form of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.BrBr.[Cu](C#N)[C:13]#[N:14]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[C:13]#[N:14]
Reactant: COc1cccc(F)c1
Reactant: N#C[Cu]C#N
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(C#N)c(F)c1
Temperature: 60 °C

Procedure:
A stirred solution of 3-fluoroanisole (7.0 g, 50.3 mmol) in 50 mL of chloroform is treated with bromine (2.59 mL, 50.3 mmol) over 30 minutes at room temperature. The reaction is heated to 60° C. for 7 hours and concentrated in vacuo. The resulting material is dissolved in 10 mL of N,N-dimethylformamide and treated with copper cyanide (5.9 g, 65.39 mmol). After refluxing overnight, the reaction is partitioned between ethyl acetate and acidic ferric chloride solution (a mixture of 19.2 g of ferric chloride hexahydrate, 44.8 mL of hydrochloric acid, and 48 mL of water). The organic phase is washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (210 g) with 10% ethyl acetate/hexane as the eluent to afford 2-fluoro-4-methoxy-benzonitrile.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:19])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 1.00 g (4.76 mmol) of 4-acetoxy-3-methoxybenzoic acid (Pfaltz and Bauer, Inc.) in 4 mL of anhyd CH2Cl2 (under a CaSO4 drying tube) was added 4.15 mL (47.6 mmol) of oxalyl chloride followed by 25 μL of anhyd DMF. After stirring for 4 h at room temperature, the mixture was concentrated in vacuo to afford the title compound as light yellow crystals (1.12 g, 103%). 1H-NMR (300 MHz, CDCl3) δ7.81 (dd, 1H, J=8.4, 2.1 Hz), 7.66 (d, 1H, 2.1 Hz), 7.19 (d, 1H, 8.4 Hz), 3.91 (s, 3H), and 2.35 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:20]([OH:22])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:23]([C:27]1[O:31][N:30]=[C:29]([NH2:32])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.CCOC(C)=O>[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:20](=[O:22])[NH:32][C:29]1[CH:28]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:31][N:30]=1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCCCC1C(=O)O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC[C@H]1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (0.88 g, 5.73 mmol) is added drop wise at 0° C. to a solution of perhydro-azepine-1,2-dicarboxylic acid 1-tert-butyl ester (0.93 g, 3.82 mmol) and 5-tert-butyl-isoxazol-3-ylamine (0.54 g, 3.82 mol) in pyridine (10.0 mL). The reaction mixture is slowly warmed up to room temperature and stirred for three hours. The mixture is diluted with EtOAc and washed twice with saturated NH4Cl solution. The organic phase is washed with 1N HCl, and after drying over anhydrous Na2SO4 the solvent is removed under reduced pressure to afford the crude product that is used in the next step without further purification; m/z 366 [M+H+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:10][O:11][CH:12]([O:17][CH3:18])[C:13](OC)=[O:14].C[O-].[Na+].CO.Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:10][O:11][CH:12]([O:17][CH3:18])[C:13](=[O:14])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1ccccn1
Reactant: COC(=O)C(OC)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(OC)C(=O)CC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.3 %

Procedure:
A mixture of 2-acetylpyridine (3.0 g, 24.8 mmol) and methyl dimethoxyacetate (3.32 g, 24.8 mmol) in anhydrous diethyl ether (45 mL) was treated with sodium methoxide 4.37M in methanol (5.67 mL, 24.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 days, and then diluted with ethyl acetate (10 mL). After cooling to 0° C., the reaction mixture was neutralized with 1N hydrochloric acid until pH 6-7 was reached. Water was added (10 mL) and the layers were separated. The organic layer was washed with brine (25 mL), dried over sodium sulfate and concentrated in vacuo to provide 4,4-dimethoxy-1-(pyridin-2-yl)butane-1,3-dione (9a) (5.11 g, 22.9 mmol, 92%) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C1COCC1.[F-].[K+]>O.CCOC(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(OC)c(C=O)cc1Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 60 °C
Yield: 93.7 %

Procedure:
Ex-1A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g, 83 mmol), thiophene-2-boronic acid (11.6 g, 91 mmol) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g, 174 mmol), and Pd(tBu3P)2 (0.424 g, 0.83 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 in Hg) affording 19.32 g (94%) of the desired 2,4-dimethoxy-5-thien-2-ylbenzaldehyde as a light off-white solid, mp 125–126° C. 1H-NMR (300 MHz, CDCl3): 10.34 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J=3.5 and 1.5 Hz), 7.31 (dd, 1 H, J=5.2 and 1.5 Hz), 7.07 (dd, 1 H, J=5.2 and 3.5 Hz), 6.51 (s, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H). HRMS (EI) Calcd. for C13H12O3S: 248.0507 (M+); Found: 248.0504.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccccc1-c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 85.1 %

Procedure:
Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.55 g, 12.9 mmol) with diisopropylethylamine (2.5 g, 19.4 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 provided 4.1 g (85%) of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil Rf=0.64 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C24H23F4NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.95; H, 6.18; N, 3.53. Chiral HPLC separation of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, isopropanol:hexane 1:4) provided two fractions. Fraction 1 (Rt=7.285 min, isopropanol:hexane 1:4); Fraction 2 (Rt=9.361 min, Chiralcel OD, isopropanol:hexane 1:4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(F)c(C)c2[nH]1
Product: CCOC(=O)c1cc2ccc(F)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 6-fluoro7-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. Yellow solid, ISP MS: 379.4 (M+H)+
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Cl[C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[CH:10]=1.Cl>O1CCCC1.O>[C:3]([CH:2]([C:1]#[N:5])[C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[CH:10]=1)#[N:4]
Reactant: N#CCC#N
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(C#N)C#N)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
To a solution of 6.6 g (0.1 mol) of malononitrile in 100 ml of tetrahydrofuran was added 4.0 g (0.1 mol) of 60 wt% sodium hydride under ice-cooling. Seventeen grams (0.1 mol) of 6-chloro-1,3-dimethyluracil were added thereto, followed by stirring at room temperature for 5 hours. A hundred milliliters of water were added to the mixture, and the mixture was neutralized with concentrated hydrochloric acid, followed by extraction with 200 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, followed by filtration to obtain 12.9 g (63%) of 6-dicyanomethyl-1,3-dimethyluracil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=1)=[O:18])[CH3:13])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=1)=[O:18]
Reactant: CN(CCCCNC(=O)OC(C)(C)C)CCNC(=O)c1nc(Cl)c(N)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
[4-({2-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-methyl-amino)-butyl]-carbamic acid tert-butyl ester (0.54 g, 2.2 mmol) in DCM (10 mL) and TFA (2 mL) is stirred at RT for 1 h. The solvent is removed in vacuo and the resulting oil is dissolved in saturated aqueous sodium carbonate solution. The mixture is concentrated in vacuo and the residue is dissolved in MeOH and filtered to remove the sodium carbonate. The filtrate is concentrated in vacuo to afford the title compound. [M+H]+ 316
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C[C:20]([N:22]([CH3:24])[CH3:23])=O>CN(C=O)C>[CH3:20][N:22]([CH3:24])/[CH:23]=[CH:1]/[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of ethyl 5-methyl-2,4-dinitrobenzoate (39 g, 0.15 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water and the precipitated solid was filtered and washed with water to afford (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.[Cl-].[Na+].O.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(C(=O)N(C)OC)c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(C(=O)N(C)OC)c1=O
Yield: 59.9 %

Procedure:
A mixture of 1-(2-fluoro-5-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (500 mg, 1.15 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (264 mg, 1.27 mmol), Na2CO3 (268 mg, 2.53 mmol) and Pd(PPh3)4 (66.4 mg, 0.0575 mmol) in DME (10.1 mL) and water (2.5 mL) was heated to reflux for 14 h under Ar. The mixture was diluted with water, brine and saturated NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 60/40) to yield the title compound (267 mg, 60% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.25 (3H, s), 3.59 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 7.51 (1H, dd, J=10.4, 8.9 Hz), 7.73-7.80 (1H, m), 7.89-7.97 (2H, m), 8.23 (1H, s), 8.58 (1H, s).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: CCO
Solvent: C1CCNC1
Product: CCCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.45 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.53 ml (5 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of pyrrolidine was added at 60° C., followed by refluxing for 19 hours (2.5 hours later, 0.53 ml (5 mmol) of 1-pentanal and 0.05 ml (0.5 mmol) of pyrrolidine were further added). After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/1→1/4), after which the solvent was distilled off, to yield 0.29 g (16.3%, yellow oily substance) of the desired product.