Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=1.[CH:18](N(C)CCN(C)C)=[O:19].[I:27]I.[BH4-].[Na+]>C1COCC1.COCCOC.O>[Cl:6][C:7]1[N:8]=[C:9]([O:13][CH2:14][O:15][CH2:16][CH3:17])[C:10]([CH2:18][OH:19])=[C:11]([I:27])[CH:12]=1
Reactant: CN(C)CCN(C)C=O
Reactant: II
Reactant: CCOCOc1cccc(Cl)n1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: CCOCOc1nc(Cl)cc(I)c1CO
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 2.5M n-butyllithium (2.2 mL, 5 mmol) in 20 mL of THF at -10° C. was added 0.94 g 2-chloro-6-(ethoxymethoxy)pyridine (5 mmol) dropwise over 2 min. The reaction mixture was stirred for 10 min. at -10° C., then cooled to -23° C. and 0.72% N-formyl-N,N',N'-trimethylethylenediamine) was added. After stirring at -23° C. for 30 min., n-butyllithium (2.5M, 3 mL, 7.5 mmol) was added dropwise and the dark reaction mixture was stirred at -23° C. for 4 hr. The mixture was transferred via a double-tipped meedle to a solution of 1.9 g of iodine (7.5 mmol) in 10 mL of DME and 10 mL of THF at -78° C. After stirring at -78° C. for 30 min., the cooling bath was removed. 0.3 g of solid sodium borohydride (8 mmol) was added to the red mixture. 10 mL of water was added dropwise with vigorous stirring. After 30 min., the mixture was extracted with three 20 -mL portions of EtOAc. The combined organic layers were washed with 20 mL of 10 percent sodium thiosulfate solution, water and brine. After drying over sodium carbonate, the solvents were removed under reduced pressure to yield the 1.3 g of crude product, which was purified by radial PLC (10% EtOAc/hexane) to give 0.7 g (40%) of pure product as a white solid, mp 43°-44° C. 1H NMR (300 MHz, CDCl3) δ 7.43 (s, 1 H), 5.62 (s, 2 H), 4.79 (s, 2 H), 3.78 (q, 2 H, J=7.1 Hz), 2.24 (brd, 1 H), 1.26 (t, 3 H, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ 158.9, 147.8, 127.3, 124.7, 113.5, 92.0, 66.0, 63.2, 15.0. Analysis Calculated for C9H11ClNO3 : C, 31.47; H, 3.23; N, 4.08. Found: C, 31.68; H, 3.28; N, 4.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1.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]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:36]([C:32]2[O:31][CH:35]=[CH:34][CH:33]=2)=[O:37])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccco2)c1
Temperature: 50 °C
Yield: 50 %

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (500 mg, 1 mmol), furan-2-carbonyl chloride (0.12 mL), tris(dibenzylideneacetone)-dipalladium (0) (19 mg) and 2-(di-tert-butylphosphino)biphenyl (35 mg) in THF (6 mL) in a previously degassed, sealed vessel. Flush the mixture with nitrogen and heat the sealed mixture overnight at 50° C. Cool the reaction to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, 0:100 to 38:62 ethyl acetate:hexanes) to give the title compound (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: COCC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc3ccnn23)CC1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
5,7-Dichloro-pyrazolo[1,5-a]pyrimidine (980 mg, 5.2 mmol) and tert-butyl piperazine-1-carboxylate (2.3 g, 12.6 mmol) were dissolved in 1-methoxy-2-propanol (40 ml) and heated under microwave irridation at 110° C. for one hour. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica, pentane/ethylacetate). The raw product was crystallized from ethanol to yield 1.23 g of a crystalline solid (3.65 mmol, 70%). MS (APCI): m/z=338.2 [M+1]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(C[O:46][S:47]([CH3:50])(=O)=[O:48])=CC(C2C=CC(S(C)(=O)=O)=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:47]([CH3:50])(=[O:48])=[O:46])=[CH:23][CH:22]=2)=[N:17]1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: Cc1c(-c2ccc(S(C)(=O)=O)cc2)nn(CC(C)C)c(=O)c1N1CCN(C)CC1
Yield: 88.5 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 88.5%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(#N)C.[C:14](ON1C(=O)CCC1=O)(=[O:25])[C:15]1[C:16](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:17](OC)=[O:18]>O>[OH:4][CH2:3][C@@H:2]([N:1]1[C:17](=[O:18])[C:16]2[C:15](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1C(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)c1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (3 g, 21.87 mmol) in water (26.5 mL), and acetonitrile (46.4 mL) was added 2,5-dioxopyrrolidin-1-yl methyl phthalate (5.76 g, 20.78 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. After acetonitrile was removed in vacuo, the reaction mixture was then extracted with EtOAc. The organic was washed by water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding (S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (2.2 g, 40%). LCMS (m/z): 268 (MH+), 0.79 min.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]([CH3:19])[CH3:18])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]([CH3:19])[CH3:18])[N:4]=1
Reactant: CC(C)c1nccn1-c1nc(Cl)nc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5ccnc5C(C)C)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1

Procedure:
The sodium salt of 2-chloro-6-(2-isopropylimidazol-1-yl)purine (0.132 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2 for 1 h (reaction complete, TLC). Sampling of the reaction mixture at the end of the reaction time showed no α-nucleoside by 1H NMR (500 MHz). The residue was chromatographed (25 g silica gel, EtOAc/hexanes˜1:1) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-isopropylimidazol-1-yl)purine (quantitative). Recrystallization (EtOAc) gave the compound (0.22 g, 70%): UV (MeOH) max 223, 241, 285 nm (∈ 32 100, 35 400, 14 800), min 230, 265 nm (∈ 30 300, 9200); 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J=1.0 Hz, 1H), 8.26 (s, 1H), 7.99 (d, J=7.8 Hz, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.30 (d, J=7.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.11 (d, J=1.0 Hz, 1H), 6.60 (t, J=6.8 Hz, 1H), 5.81 (br s, 1H), 4.78-4.83 (m, 1H), 4.67-4.71 (m, 2H), 4.08 (sept, J=6.8 Hz, 1H), 2.97-3.01 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.99, 156.18, 154.20, 153.21, 148.15, 144.72, 144.40, 142.25, 129.88, 129.55, 129.36, 129.33, 128.82, 126.44, 126.26, 123.00, 120.38, 85.23, 83.59, 74.93, 63.87, 38.63, 28.81, 21.78, 21.61; HRMS 77/z 637.1931 (MNa+[C32H31ClN6O5Na=637.1942]).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[Cl-].[C:16]([SiH:20]([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[C:16]([Si:20]([CH3:22])([CH3:21])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C[SiH](C)C(C)(C)C
Reactant: OC1CCNCC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
7.94 g (78.57 mmoles) of 4-hydroxypiperidine are placed in 175 mL of CH2Cl2 and 35 mL Et3N under nitrogen. At 0° C., a solution of 25 g (165 mmoles) of tert-butyldimethylsilane chloride in 350 mL of CH2Cl2 is added dropwise. The reaction medium is agitated overnight at ambient temperature then 2.36 g (15.7 mmoles) of tert-butyldimethylsilane chloride are added. After agitation for 4 h at ambient temperature, 0.69 g (0.55 mmoles) 4-dimethylaminopyridine and 2.36 g (15.7 mmoles) tert-butyldimethylsilane chloride are added. The reaction medium is agitated overnight at ambient temperature then diluted in water and extracted with CH2Cl2. After drying over MgSO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2-MeOH—NH4OH, gradient 100:0:0 to 90:9:1 in 50 min). 12.71 g of intermediate 5a are thus obtained in the form of yellow oil (yield 75%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH—NH4OH: 90:9:1, Rf=0.47.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:35])[CH3:34])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>ClCCl>[F:25][CH2:24][C@@H:23]1[C@@H:22]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:33])=[O:9])=[CH:30][CH:31]=2)[O:21][C:20]([CH3:35])([CH3:34])[N:19]1[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (14.3 g, 1.2 eq ) in 100 ml of dichloromethane was added drop wise to the solution of 13 (17.3 g) in 150 ml of dichloromethane at −20° C. The temperature was maintained at −20° C. for an additional 40 minutes. A saturated solution of sodium bicarbonate (80 ml) was added and stirred for 30 minutes. The organic layer was separated and washed with brine (50 ml) and dried over sodium sulfate. After purification (via a column) 13.4 g of the desired product (as a heavy oil) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[NH4+:11]>COCCOC.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[N:5]=[C:6]([NH2:11])[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1nc(N)cc(Cl)n1
Temperature: 23 °C
Reaction time: 336 h
Yield: 60 %

Procedure:
A stirred suspension of 4,6-dichloro-2-methylpyrimidine (39.5 g, 244 mmol) in 1,2-dimethoxyethane (50 mL) in a sealable pressure reaction vessel was treated with concentrated aqueous ammonium hydroxide (40 mL). The mixture was vigorously stirred at 23° C. for 14 days in the sealed vessel. The mixture was then diluted with water and filtered. The isolated white solids were rinsed with water and dried in vacuo to afford 6-chloro-2-methyl-4-aminopyrimidine (20.94 g, 146 mmol, 60% yield): mp 191°-192° C.; Rf 0.49 (EtOAc); 1H NMR (DMSO-D6, 200 MHz)δ7.09 (br s, 2H, NH), 6.24 (s, 1H), 2.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:23]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)(=[O:25])[CH3:24]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reaction time: 20 h
Yield: 50.7 %

Procedure:
2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) was dissolved in 2 mL of dry pyridine under nitrogen. Then 4-acetamid obenzene-1-sulfonyl chloride (209 mg, 0.85 mmol) was added drop wise to the reaction mixture. The reaction mixture was allowed to stir for 20 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.5) showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford 85 mg of 2-(3-(4-acetamidophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 51%. MS (ES+APCI) M+1=494.2.
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].O=[C:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:41][CH:40]([CH2:42][O:43][CH3:44])[O:39][C:38]3=[O:45])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.O>O1CCCC1>[CH3:44][O:43][CH2:42][CH:40]1[O:39][C:38](=[O:45])[N:37]([C:34]2[CH:35]=[CH:36][C:31]([CH:28]3[CH2:29][CH2:30][C:25](=[CH2:2])[CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[CH2:41]1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(c2ccc(N3CC(COC)OC3=O)cc2)CC1
Yield: 83.4 %

Procedure:
5.76 g (13.8mmol) of methyltriphenylphosphonium bromide/sodium amide mixture were stirred at room temperature under argon in 170 ml of tetrahydrofuran for 1 hour. Then, a solution of 4.20 g (13.8 mmol) of (RS)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one was added dropwise within 5 minutes. After boiling under reflux overnight the mixture was poured into water and extracted with methylene chloride. After drying with sodium sulfate and concentrating the residue was chromatographed over silica gel with ethyl acetate/n-hexane (1:2). 3.47 g (83%) of a solid were obtained. A small sample was recrystallized from hexane. M.p.: 63°-65°.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:30])[CH2:11][CH2:12][C:13]1[C:14](=[O:29])[N:15](CC2C=CC(OC)=CC=2OC)[CH2:16][CH:17]=1>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10](=[O:30])[CH2:11][CH2:12][C:13]1[C:14](=[O:29])[NH:15][CH2:16][CH:17]=1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(OC)cc2OC)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC1=CCNC1=O
Yield: 47.2 %

Procedure:
0.1 ml of triethylsilane (0.63 mM) was added to the reaction solution containing 200 mg of 3-[1-(2,4-dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (0.63 mM) dissolved in 0.7 ml of trifluoroacetic acid solution at 0° C. After the reaction mixture was heated for 1 hr, the mixture was filtered and concentrated in vacuo to remove solvent. Then the resulting mixture was dissolved in 20 ml of chloroform solution to separate into an organic layer and water layer. The organic layer was washed with 5 ml of saturated NaHCO3 solution and 5 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (19:1) as an eluant to give 50 mg of 3-(2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester (20 (yield: 47%).
Reaction SMILES: O(C(N[C:11]1[CH:21]=[C:20]2[C:14]([C:15](Cl)=[C:16](OCC)OC2=O)=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.O([C:33]([NH:35][C:36]1[CH:46]=[C:45]2[C:39]([C:40]([Cl:56])=[C:41]([O:47][CH2:48][CH2:49][C:50]3C=CC=CC=3)[O:42][C:43]2=[O:44])=[CH:38][CH:37]=1)=[O:34])C1C=CC=CC=1>>[C:33]([NH:35][C:36]1[CH:46]=[C:45]2[C:39]([C:40]([Cl:56])=[C:41]([O:47][CH2:48][CH2:49][CH3:50])[O:42][C:43]2=[O:44])=[CH:38][CH:37]=1)(=[O:34])[CH2:16][CH2:15][C:14]1[CH:20]=[CH:21][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1)Oc1ccccc1
Reactant: CCOc1oc(=O)c2cc(NC(=O)Oc3ccccc3)ccc2c1Cl
Product: CCCOc1oc(=O)c2cc(NC(=O)CCc3ccccc3)ccc2c1Cl

Procedure:
7-phenoxycarbonylamino-4-chloro-3-ethoxyisocoumarin and 7-phenoxycarbonylamino-4-chloro-3-(2-phenylethoxy)isocoumarin can be prepared by the same procedure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:23]([O:22][C:20]([C:19]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[Cl:9])=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(F)cc1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 125.6 %

Procedure:
To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification.
Reaction SMILES: CN(C)CCCN=C=NCC.[CH:12]([NH:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13].[N:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[C:24]=S>O1CCCC1.C(OCC)(=O)C>[CH:12]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]=[C:24]1[NH:23][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Nc1ccccc1N
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc3ccccc3n2C(C)C)cc1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 206 mg, 1.34 mmol) is added to a solution of N1-isopropylbenzene-1,2-diamine (100 mg, 0.67 mmol) and methyl 4-isothiocyanatobenzoate (138 mg, 0.67 mmol) in tetrahydrofuran. The reaction may be heated to reflux for a time period (for example 2 hours) and cooled to room temperature. The mixture may be diluted with ethyl acetate, filtered and concentrated. The residue may be purified by any method, including Biotage column chromatography to give methyl 4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (122 mg)
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Cl[CH:6]([C:10]([CH3:12])=O)[C:7]([O-:9])=[O:8].O1CC[CH2:15][CH2:14]1>>[CH3:2][C:1]1[S:3][C:6]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[C:10]([CH3:12])[N:4]=1
Reactant: CC(N)=S
Reactant: C1CCOC1
Reactant: CC(=O)C(Cl)C(=O)[O-]
Product: CCOC(=O)c1sc(C)nc1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
126 mmol of thioacetamide was dissolved in 378 ml of tetrahydrofuran, then a solution, in which 120 mmol of 2-chloroaceto acetate was dissolved in 36 ml of tetrahydrofuran, was gradually dropped with keeping a temperature at 0 to 10° C. using an ice bath. After the dropping, stirring was continued for 1 hour at a room temperature, then the temperature was heated up to 80° C. and the reaction was continued for 3 hours. The reacted liquid was kept still overnight. A recrystallized solid was filtrated, and dissolved in 50 ml of water. Sodium hydrogen carbonate was added until the pH of the solution reached 8 to 9, the product was extracted and separated into an organic layer using ethyl acetate, then dried under sodium sulfate and the solvent was evaporated out, obtaining ethyl 2,4-dimethyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:45]=[N:46][C:47]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[C:56]([C:59](O)=[O:60])[CH:57]=3)[C:52]([S:62]([CH3:64])=[O:63])=[CH:51]2)=[N:48][CH:49]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[N:48][C:47]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[C:56]([C:59]([N:2]([CH3:3])[CH3:1])=[O:60])[CH:57]=3)[C:52]([S:62]([CH3:64])=[O:63])=[CH:51]2)=[N:46][CH:45]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
HATU (158 mg, 0.41 mmol), diisopropylethylamine (0.32 ml, 0.41 mmol) and dimethylamine (2M in THF) (0.95 mL, 1.89 mmol) were added to an ice-cooled suspension of 51e) (150 mg, 0.38 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated ammonium chloride solution (2×30 mL), saturated sodium hydrogen carbonate solution (2×30 mL), water (30 mL), and brine (30 mL). The organic phase was dried over sodium sulfate and evaporated. The remnant was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 62 mg (38% of theory). LC-MS (method 5): Rt=2.99 min; m/z [M+H]+=423.2