Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.N12CCCNC1CCCC=C2.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>C(#N)C.[Cu]Cl>[CH3:21][C:22]([CH3:23])([O:26][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:24]#[CH:25]
Reactant: COc1ccc(O)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Cu]
Agent: C1=CN2CCCNC2CCC1
Agent: [Cl-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxyphenol (15.0 g, 121 mmol) in acetonitrile (75 mL), 1,8-diazabicyclo[5.4.0]undecene (23.9 g, 157 mmol) was added under ice cooling and the resulting mixture was stirred at 0° C. for 30 minutes (Solution 1). To a solution of 2-methyl-3-butyn-2-ol (11.7 g, 139 mmol) in acetonitrile (75 mL), 1,8-diazabicyclo[5.4.0]undecene (23.9 g, 157 mmol) was added under ice cooling, the resulting mixture was stirred at 0° C. for 30 minutes, then trifluoroacetic anhydride (25.4 g, 121 mmol) was added and the resulting mixture was stirred at 0° C. for 30 minutes (Solution 2). Copper (I) chloride (36 mg, 0.36 mmol) was added to Solution 1, and then Solution 2 was added dropwise thereto over 15 minutes. Upon the conclusion of dropwise addition, the temperature was raised to room temperature, and the mixture was stirred overnight. Upon the completion of the reaction, an aqueous solution of ammonium chloride was added to the reaction solution, and the solvent was distilled off under a reduced pressure. An aqueous solution of 1 mol/L hydrochloric acid was added to the residue, the resulting mixture was extracted with ethyl acetate, the organic phase was washed once with an aqueous solution of 1 mol/L hydrochloric acid, twice with an aqueous solution of saturated sodium hydrogen carbonate and once with saturated sodium chloride solution. Then, the organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was directly used for the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reaction time: 0.17 h

Procedure:
6 g (19.52 mmol) of (8R,9R)-2,3-dimethyl 8 hydroxy-9-phenyl-7,8,9,10-tetra-hydroimidazo-[1,2-h][1,7]naphthyridin-7-one (see >90% Dalcet Chiralcel HPLC) are suspended in 60 ml of methanol and cooled to −5° to 0° C. in a methanol-ice bath. At this temperature, sodium borohydride (0.81 g, 21.47 mmol) is added by spatula during the course of 0.5 h (evolution of gas). After addition is complete, the mixture is stirred for a further 10 min, and then concentrated in a vacuum rotary evaporator at a bath temperature of 40° C. The oily residue obtained is taken up in distilled water and extracted three times with chloroform. The organic phases are combined and washed with a little water, then dried using anhydrous sodium sulfate and filtered. The filtrate is concentrated on a vacuum rotary evaporator and co-evaporated with acetone; the title compound crystallizes out in the course of this. The precipitate is filtered off, washed with acetone and dried to constant weight at 50° C. in a vacuum drying oven. 5.15 g (85.3%, ee>90%, Daicel Chiralcel HPLC) of the title compound are obtained as a colorless crystallize of melting point 206-9° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([CH2:25][NH:26][C:27](=[O:44])[NH:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C.COCCOC.C(O)C.O>[OH:11][C:8]([C:6]1[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:27]([NH:26][CH2:25][C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)=[O:44])=[CH:30][CH:31]=2)[N:7]=1)([CH3:10])[CH3:9]
Reactant: Cn1cc(CNC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cn1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
2-[2-Chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]propan-2-ol (70 mg) was dissolved in an 18% DMF in a mixture of 7:3:2 DME:water:ethanol (4 mL). 3-[(1-Methylpyrazol-4-yl)methyl]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (115 mg) and 2M sodium carbonate (1 mL) were added. Dichlorobis(triphenylphosphine) palladium catalyst (10 mg) was added and the solution heated in a microwave reactor at 100° C. for 0.5 h. The mixture was acidified with concentrated hydrochloric acid and loaded directly onto a SCX-2 column (10 g), column washed with methanol then product eluted with 7N ammonia in methanol, to give the desired material (55 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[N:4]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=2)[C@H:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)cc1C
Temperature: 140 °C
Yield: 90 %

Procedure:
A microwave vial was charged with (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.100 g, 0.523 mmol), methyl 4-bromo-2-methylbenzoate (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.132 g, 0.575 mmol), tribasic potassium phosphate (0.555 g, 2.61 mmol) and dioxane (3.50 mL). The mixture was purged with argon and then copper (I) iodide (0.100 g, 0.523 mmol) and N,N′-dimethylethylenediamine (0.113 mL, 1.046 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 140° C. for 1 hour in a microwave. The reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford an orange brown solid. The solid thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoate (0.159 g, 0.468 mmol, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (s, 3H), 1.63 (s, 3H), 2.43 (s, 3H), 3.75 (s, 3H), 5.52 (s, 1H), 7.03-7.46 (m, 6H), 7.50 (d, J=2.35 Hz, 1H), 7.75 (d, J=8.71 Hz, 1H). m/z (ESI) 340 (M+H)+.
Reaction SMILES: [CH3:1][CH:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:1]
Reactant: CC(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)c1cccc([N+](=O)[O-])c1

Procedure:
A 1,000-milliliter flask equipped with a reflux condenser and a magnetic stirring bar was charged with 24.1 grams (0.13 mole) of α-methyl-3-nitrobenzyl chloride in 400 milliliters of methyl alcohol. To this stirred solution was added 8.1 grams (0.15 mole) of sodium methoxide. The reaction mixture was heated to reflux and maintained at reflux for 26 hours. Since some traces of α-methyl-3-nitrobenzyl chloride were present (as indicated by a thin layer chromatograph test), an additional 5.4 grams (0.1 mole) of sodium methoxide was added and the reaction was again heated to reflux and maintained at reflux for 49 hours. The reaction mixture was then cooled and concentrated on a rotary evaporator at 55° C. The residue was taken up with 200 milliliters of methylene chloride, transferred to a separatory funnel and washed consecutively with 100 milliliter portions each of water, 1 Normal hydrochloric acid, water, 1 Normal sodium hydroxide, and water, respectively. The organic layer was separated, dried over magnesium sulfate and concentrated on a rotary evaporator at 55° C., leaving a dark liquid residue. The dark liquid was charged to a distillation flask and distilled at a pressure of 1.8 millimeters of mercury. A main fraction (14.98 grams) was collected, said fraction having a boiling point of 106° C.-112° C. at 1.8 mm Hg pressure. This main fraction was identified by NMR spectroscopy as 1-(1-methoxyeth-1-yl)-3-nitrobenzene.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=O)=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:34][CH2:33][CH2:35][NH:36][C:28]([C:27]1[C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:32][C:24]=2[S:25][C:26]=1[CH3:31])=[O:30]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCO)c(C)sc5c4)c3s2)C1
Yield: 28.1 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with ethanolamine (84 μL, 1.39 mmole), N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to give a yellow solid (40 mg, 28%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.27 Hz), 8.33 (1H, t, J=5.56 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.86 (1H, d, J=8.85 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.75 (1H, d, J=5.46 Hz), 4.76 (1H, br s), 4.13-3.81 (3H, m), 3.67-3.50 (4H, m), 3.43-3.32 (2H, m), 3.27, 3.24 (3H, s), 2.61 (3H, s), 2.18-1.94 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: OP(O)O
Reactant: O=C(O)Cc1cccnc1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 87.5 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
3-Pyridine acetic acid (25 g) in 500 ml of chlorobenzene added to phosphorous acid (35.5 g). The reaction mixture was heated up to 85-90° C. To the reaction mixture phosphorous trichloride (58.97 g) was added slowly to obtain a yellowish rigid, thick mass. The reaction mass was cooled to ambient temperature. The solvent was decanted. Demineralized water (200 ml) was added to the reaction mass and refluxed azeotropically, to remove residual chlorobenzene. Filtered through hyflo bed while hot, washed with hot demineralized water. The reaction mass was cooled to 0-5° C., stirred for 1.0 hour, filtered the solid and washed to get risedronic acid (30.0 g, yield 58%) having purity of 83.98% by HPLC.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OC(C)C)(=O)C.[Zn]>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CBr
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 7.6 g of zinc powder (115 mmol) in 45 ml of isopropyl acetate. After 1.83 ml of trimethylchlorosilane (14 mmol) had been added, the mixture was heated to 60° C. for 15 min, then allowed to cool to 55° C. and 16.3 g of undiluted methyl bromoacetate (107 mmol) were subsequently added dropwise within 5 min, and the temperature was maintained at 60° C. by external cooling. The mixture was then stirred at 50° C. for 15 min. After cooling to 30° C., 9.4 g of undiluted benzaldehyde (89 mmol) were added, and the temperature was maintained at 40° C. by external cooling. After stirring had been continued at 40° C. for 30 min, the mixture was cooled to 0° C., acidified with 20 ml of 20% hydrochloric acid to a pH of 1 and the mixture was stirred for 30 min, during which excess zinc dissolved. The organic phase was then removed. The organic phase was then stirred with 30 ml of concentrated ammonia solution at 0° C. for 10 min. After the phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure. Methyl 3-hydroxy-3-phenylpropionate was obtained in a yield of 14.3 g (89% of theory) and had a boiling point of 78° C. (0.08 mbar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl[(tert-butoxycarbonyl)amino]acetate (1.01 g, 4.37 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LiHMDS (6.5 mL, 1M solution in THF) was slowly added and allowed to stir for 30 minutes. Methyl 4-(bromomethyl)benzoate (1.98 g, 8.64 mmol) in THF (6 mL) was added to the mixture and allowed to stir overnight, slowly warming to room temperature. The reaction was diluted with ethyl acetate and quenched with saturated ammonium chloride. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. MS: cal'd 379 (MH+), exp 402 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:4]1[CH:5]=[C:6]([O:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(OC(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(OC(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
Acetic acid (2.24 mL, 7.4 mmol) was added to a mixture of acetic acid 4-methoxy-phenyl ester (1.0 g, 6.02 mmol) and sodium acetate (940 mg, 11.46 mmol). A solution of bromine (0.37 mL, 6.02 mmol) in acetic acid (2.1 mL) was added drop-wise and mixture stirred for 18 hr at ambient temperature. A further 0.6 mL of acetic acid was added followed by a further 0.1 mL of bromine. Mixture was stirred for 2 hours, then partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated and organic layer was washed sequentially with sat. aqueous sodium bicarbonate solution (2×150 mL), sat. aqueous sodium thiosulphate solution (100 mL) and sat. aqueous sodium chloride solution (100 mL). Organic phase was dried over sodium sulphate, filtered and filtrate solvents removed in vacuo to afford a oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford title compound (1.2 g, 81%) as a light-brown oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.BrCC1CC1>C1COCC1>[CH:9]1([CH2:10][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:7][CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: [Li]CCCC
Agent: BrCC1CC1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCC1CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75˜110° C. then distillation at 138˜142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>Cl>[CH3:2][CH2:1][O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A solution of ethyl (S)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]benzoate (20 g, 41.6 mmol) in denatured spirit (200 ml) was stirred at 60–65° C. and 1N sodium hydroxide solution (62 ml) was added. After two hours of stirring at 60° C., the reaction mixture was cooled to 35° C. and pH was adjusted to about 5.0 using 1N hydrochloric acid (about 70 ml). The solution was stirred for 30 minutes at 35–40° C., cooled to 0° C. and stirred at 0 to 5° C. for one hour to get a crystalline product. The crystals were separated by filtration and washed with water. The product was dried at 60–65° C. under vacuum to get repaglinide (17.8 g, Yield: 94%, Assay 99.5% by HPLC).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=2)=[C:8]([C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:5]=2)[CH:13]=1
Reactant: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2O)n1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2OCc2ccc(Cl)cc2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a stirred suspension of 2-[2-amino-6-(4-chloro-phenylamino) pyrimidin-4-yl]-4-bromo-phenol (0.059 g, 0.15 mmol), 4-chloro-benzylchloride (0.073 g, 0.45 mmol) and cesium carbonate (0.098 g, 0.30 mmol) in acetonitrile (10 ml) was added potassium iodide (40 mg). The mixture was stirred at 80° C. for 2 hours. Filtration and concentration of the filtrate provided a crude product which was purified by preparative TLC eluting with ethyl acetate-hexane (1:3) to provide the title compound (0.02 g, 26% yield). 1H NMR (CD3OD) δ 5.23 (s, 1H, CH2), 6.41 (s, 1H, Ar), 7.26 (d, 1H, J=9.6 Hz, Ar), 7.38-7.42 (m, 6H, Ar), 7.71-7.74 (m, 4H, Ar).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.Br[C:26]1[CH:27]=[C:28](NS(N(C)C)(=O)=O)[C:29](Cl)=[N:30][CH:31]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].BrC1C=CN2C(I)=CN=C2C=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:17][C:14]1[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[CH:31][N:30]=[CH:29][CH:28]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[CH:16][N:15]=1
Reactant: CN(C)S(=O)(=O)Nc1cc(-c2cnc3cc(Br)ccn23)cnc1Cl
Reactant: CN(C)S(=O)(=O)Nc1cc(Br)cnc1Cl
Agent: [Fe+2]
Agent: Brc1ccn2c(I)cnc2c1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1cc(-c2cnc3cc(-c4ccncc4)ccn23)cnc1Cl
Temperature: 95 °C
Reaction time: 20 h

Procedure:
N-(5-(7-bromoimidazo[1,2-a]pyridin-3-yl)-2-chloropyridin-3-yl)dimethylaminosulfonamide. To a 100 mL round bottom flask was added N-(5-bromo-2-chloropyridin-3-yl)dimethylaminosulfonamide (0.220 g, 0.699 mmol), Bis(pinacolato)diboron (0.266 g, 1.049 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.051 g, 0.070 mmol), potassium acetate (0.069 g, 0.699 mmol) and dioxane (20 mL). The resulting mixture was heated at 95° C. under N2 for 4 h. The reaction mixture was removed from the hot plate followed by the addition of 7-bromo-3-iodoimidazo[1,2-a]pyridine (0.226 g, 0.699 mmol), sodium carbonate (0.874 mL, 1.748 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.051 g, 0.070 mmol). The resulting mixture was then reheated at 95° C. under N2 for 20 h. The reaction was cooled to rt. The solvent was removed. The residue was partitioned between pH 7-buffer (1M TRIS-HCL) and CHCl3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, 40 g SiO2, DCM:EtOAc:MeOH (2M NH3)=80%:17%:3%, Flow=40 mL/min) to afford the desired product as brown foam-like solid (50.0 mg). MS (ESI pos. ion) m/z: 429.8. Calcd exact mass for C14H13BrClN5O2S: 428.9. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.91 (s, 6H) 6.88 (br. s., 1H) 7.04 (d, J=7.89 Hz, 1H) 7.78 (s, 1H) 7.93 (s, 1H) 8.08 (s, 1H) 8.16 (d, J=7.16 Hz, 1H) 8.34 (s, 1H).