Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([NH:11][C:12]([C:14]12[CH2:21][C:18]([C:22]3[NH:30][C:29]4[C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][CH3:38])[C:24]=4[N:23]=3)([CH2:19][CH2:20]1)[CH2:17][CH2:16][CH2:15]2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1>[O:35]=[C:26]1[N:25]([CH2:36][CH2:37][CH3:38])[C:24]2[N:23]=[C:22]([C:18]34[CH2:21][C:14]([C:12]([NH:11][C@H:4]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:3]([OH:39])=[O:2])=[O:13])([CH2:20][CH2:19]3)[CH2:15][CH2:16][CH2:17]4)[NH:30][C:29]=2[C:28](=[O:31])[N:27]1[CH2:32][CH2:33][CH3:34]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)N[C@@H](C(=O)OC)c5ccccc5)(CC3)C4)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)N[C@@H](C(=O)O)c5ccccc5)(CC3)C4)nc2n(CCC)c1=O
Yield: 47.9 %

Procedure:
A solution of (1RS,2R,5SR)-{[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]octane-1-carbonyl]-amino}-phenyl-acetic acid methyl ester (0.022 mmol, 0.012 g) in THF (2 ml) was treated with 1N LiOH (0.22 ml) for 3d. The THF was removed on the rotovap, the aqueous residue acidified (pH 2) with 1N HCl and extracted with EtOAc. The combined organics were washed with H2O, brine and dried (MgSO4). Filtration and evaporation followed by reverse phase HPLC purification provide the desired product (0.0055 g, 48%) as a mixture of diastereomers. HPLC (10% to 90% MeCN (0.1% TFA)/H2O (0.1% TFA), YMC 120 A/S-5 ODS-AM column, 100 mm×4.6 mm, 1.5 ml/min: RT=6.88 min.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:15]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:15][NH:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(CP(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
Dimethyl 4-aminobenzylphosphonate (21.5 g) and then paraformaldehyde (80%, 5.3 g) were added at room temperature to a solution of sodium methoxide in methanol (prepared from 27 g of sodium and 250 ml of methanol). After this mixture was stirred at room temperature for 15 hours, sodium borohydride (3.8 g) was added, and the mixture was heated for 1.5 hours while refluxing. The reaction mixture was concentrated under reduced pressure and then the residue was treated with 1NKOH (500 ml) and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform-methanol (25:25:1, v/v) to yield dimethyl 4-methylaminobenzylphosphonate (2.9 g, 13%) as an oily substance. NMR(δ ppm in CDCl3): 2.55(1H,broad s), 2.82(3H,s), 3.07(2H,d,J=21 Hz), 3.63(3H,s), 3.69(3H,s), 6.57(2H,dd,J=9&1 Hz), 7.11(2H,dd,J =9&3 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH2:10]([OH:13])[CH2:11][OH:12].[C:14]1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:10][O:13][CH2:14][O:12]1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Brc1ccccc1C1COCO1
Yield: 89 %

Procedure:
In a round-bottomed flask equipped with a Dean Stark trap and a condenser, was added a solution of p-Bromobenzaldehyde (5 g, 27 mmol) in toluene (25 mL). To this mixture were then added p-toluenesulfonic acid (50 mg, 0.26 mmol) and etylene glycol (1.84 g, 29.7 mmol). The mixture was heated to reflux under nitrogen atmosphere for 8 h. The progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled down, the solvent was removed under reduced pressure, the residue material was distilled to give an oil (5.49 g, 89%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH:18]2[N:22](CCC3C=CC(OC)=C(OC)C=3)[CH2:21][CH:20](CO)[O:19]2)C=CC=CC=1>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O-:19])(=[O:9])=[O:8].[OH:8][CH2:12][CH:18]1[NH:22][CH2:21][CH2:20][O:19]1
Reactant: COc1ccc(CCN2CC(CO)OC2c2ccccc2)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: OCC1NCCO1

Procedure:
In an operation carried out in a manner similar to that described in Example 1, p-toluenesulfonyl chloride is added portionwise to a cooled to 10° C. solution of 2-phenyl-3-(3,4-dimethoxyphenylethyl)-5-(hydroxymethyl)oxazolidine in pyridine while the temperature is maintained below 25° C. to obtain a tosylate of the 2-hydroxymethyloxazolidine as intermediate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([O:36][CH2:37][C:38](O)=[O:39])=[CH:31][CH:32]=[N:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:38](=[O:39])[CH2:37][O:36][C:30]2[C:29]3[C:34](=[CH:35][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(OCC(=O)O)ccnc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(OCC(=O)NNc3ccc(Cl)nn3)ccnc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (0.372 g, 2.57 mmol), 1-hydroxy-7-aza-benzotriazole (0.350 g, 2.57 mmol), EDC (0.641 g, 3.34 mmol), 2-(7-methoxyquinolin-4-yloxy)acetic acid (0.600 g, 2.57 mmol) and diisopropylethylamine (1.34 ml, 7.72 mmol) in DMF (20 mL) was allowed to stir at 50° C. for 2 h. Concentrated. Reconstituted in MeCN (30 mL). Concentrated with cooling. Product crashed out of solution and was isolated by filtration. Used without further purification. (ESI, pos. ion) m/z: 234.1 (M+H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.CC(C)=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(=O)CC(=O)N1CCCC1
Yield: 97.9 %

Procedure:
9 ml (0.05 mol) of diketene-acetone adduct and a solution of 4.2 ml (0.05 mol) of pyrrolidine in 20 ml of toluene were treated as described in preparation 7. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→1%) yielding 7.6 g of the title compound as a dark oil.
Reaction SMILES: [CH:1]1([C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:1]1([C@@H:4]([OH:11])[C@H:5]([O:10][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)[C@@H](O)[C@H](O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)C1CC1
Reaction time: 72 h
Yield: 79 %

Procedure:
Under argon atmosphere, a solution of 4.22 g of methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropionate in 140 ml of methylene chloride is cooled to -3° C. Then, 4.00 g of triethylamine and 5.17 g of p-toluenesulfonyl chloride are added to the mixture successively. The mixture is stirred for 3 days. Then, the solvent is removed in vacuo. The residue is poured into a mixture of ethyl acetate and water. The organic layer is washed with brine and dried. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=1:3) to give 6.54 g of methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(p-toluenesulfonyloxy)propionate
Reaction SMILES: [CH:1]12[BH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[ClH:10]>CCOCC.CCCCCC>[Cl:10][B:9]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:1]1[CH2:2][CH2:3][CH2:4]2
Reactant: Cl
Reactant: B1C2CCCC1CCC2
Solvent: CCOCC
Solvent: CCCCCC
Product: ClB1C2CCCC1CCC2
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield following the method of Example 1 by treating 9-borabicyclo[3.3.1]nonane (9-BBN, Aldrich Chemical Company, Inc., Milwaukee, Wis.) with anhydrous HCl in ether. 11B NMR δ 79 ppm in hexane, bp 65° C. (0.3 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20](=[N:32][OH:33])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35]=[C:36]=[O:37].C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:11][C:10]([C:20](=[N:32][O:33][C:36]([NH:35][CH3:34])=[O:37])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: ON=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)ON=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
To a solution of 0.75 g (0.0015 mol) of the product obtained from Example 4 dissolved in 15 mL tetrahydrofuran was added 0.097 g (0.0017 mol) of methyl isocyanate and 0.20 g (0.002 mol) of triethylamine. The reaction mixture was stirred at room temperature for 18 hours, poured into cold water (50 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.44 g of a white solid, mp 75° C. to 77° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:11][O:10][CH3:9])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added 4-fluoroaniline (383 μL, 3971 μmol, Aldrich), 2-bromoethyl methyl ether (552 μL, 3971 μmol, Aldrich), sodium carbonate (667 mg, 7943 μmol), DMF (2 mL). The reaction mixture was stirred at 80° C. for overnight (ca 17 h). The mixture was cooled down to RT. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 4-fluoro-N-(2-methoxyethyl)benzenamine. MS (ESI pos. ion) m/z: 170 (M+1).
Reaction SMILES: CN.CO.[CH2:5]([N:7](CC)CC)C.O1CCCC1.Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([S:26][CH3:27])[N:19]=1>O>[CH3:5][NH:7][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([S:26][CH3:27])[N:19]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(SC)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
3 ml of a methylamine-methanol solution, and 246 mg of triethylamine were added to a tetrahydrofuran (10 mL) solution containing 150 mg of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carbonitrile, and the mixture was stirred for 30 minutes at room temperature. After adding water, the solution was extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. After concentration, 134 mg of a white solid was obtained as a subject compound.
Reaction SMILES: N[C:2]1[N:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].ClC(O[CH2:24][CH3:25])=O.[OH2:26]>N1C=CC=CC=1>[O:26]=[C:18]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:24][CH:25]=[CH:17][CH:16]=2)[NH:19]1
Reactant: COc1ccc(CNC(=O)c2cccnc2N)cc1
Reactant: O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)[nH]c3ccccc3c2=O)cc1
Yield: 98 %

Procedure:
(Method 2) 2-Amino-N-(methoxybenzyl)benzamide (23.6 g) was dissolved in pyridine (150 ml) and treated dropwise with ethyl chloroformate (10.6 ml) with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 8 hours, and then heated under reflux for 18.5 hours. After cooling followed by pouring into an iced water followed by the treatment similar to that in Method 1, the title compound (25.5 g, 98%) was obtained as a colorless crystal.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[CH:9][CH:8]=2.[CH2:26]=O.[OH-].[Na+]>C(O)(=O)C.O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH2:26][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:11]=2)[NH:6][C:5]=1[CH3:4])[CH3:3]
Reactant: CNC
Reactant: Cc1cc2cc(/C=C/C(=O)OCc3ccccc3)ccc2[nH]1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1[nH]c2ccc(/C=C/C(=O)OCc3ccccc3)cc2c1CN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethylamine (3.35 ml of 33% solution in methylated spirit) was added to astirred mixture of benzyl (E)-3-(2-methyl-1H-indol-5-yl)-2-propenoate (6.50g) in a mixture of acetic acid (14 ml) and tetrahydrofuran (15 ml) at 0° C., followed by the dropwise addition of formaldehyde (1.75 ml of 40% aqueous solution). The mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate. 2N sodium hydroxide was addeddropwise with stirring until the pH of the aqueous layer was ca.9. The mixture was filtered, and the residue was washed with water followed by ethyl acetate and then dried to give the title compound (6.58 g), m.p. 174°-177° C. Found: C,75.85; H,6.83; N,7.53. C22 H24N2O2 requires: C,75.83; H,6.94; N,8.04%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1>O1CCOCC1>[C:1]([NH:5][S:16]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=1)(=[O:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)cc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: COc1cc(OC)cc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 60 °C

Procedure:
A solution of 7.3 gm (0.1 mol) of tert. butylamine in 20 ml of dioxane was added dropwise to a solution of 10.0 gm (42 mmols) of 3,5-dimethoxy-benzene sulfonic acid chloride in 100 ml dioxane at 40° C. over a period of 15 minutes. After the reaction temperature began to drop the reaction mixture was heated at 45° C. for 1.5 hours and at 60° C. for 2 hours. After cooling and filtering, the filtrate was evaporated in vacuo. The residue was recrystallized from cyclohexane.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[S:8]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]#[N:22])=[CH:17][CH:16]=1)([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].C(O)(=O)C.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])(=O)C.[Na+]>O>[S:8]([C:15]1[CH:16]=[CH:17][C:18]([N:21]=[N:22][C:36]2[CH:37]=[CH:38][C:33]([N:32]([CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH3:39])=[CH:34][CH:35]=2)=[CH:19][CH:20]=1)([C:11]([F:13])([F:14])[F:12])(=[O:10])=[O:9]
Reactant: CN(CCCCO)c1ccccc1
Reactant: N#[N+]c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(CCCCO)c1ccc(N=Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 38.2 g (0.1 mole) of 4-triflylbenzenediazonium hexafluorophosphate in a 50:50 mixture of glacial acetic acid and water at 0° C. is added 17.9 g (0.1 mole) of N-4-hydroxybutyl-N-methylaniline dropwise. The reaction mixture is stirred at 0° C. for 15 minutes, and 12.3 g (0.15 mole) of sodium acetate is added with stirring. The reaction is stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred for 16 hours. Compound C is collected by filtration and purified by recrystallization from ethanol.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:43]2[CH:44]=[N:45][CH:46]=[CH:47][C:42]=2[CH3:41])(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1ccncc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccncc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Yield: 53.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 24 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (161 mg), 15-crown-5 (132 mg) and a solution of crude 4-methylpyridine-3-sulfonyl chloride (125 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a pale-yellow oil (yield 127 mg, 53%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[Br:14][C:15]1[N:16]=[C:17](Br)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1>CC(O)C>[Br:14][C:15]1[N:16]=[C:17]([NH:13][CH:10]2[CH2:12][CH2:11]2)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Brc1cn2ccnc2c(NC2CC2)n1
Reaction time: 4.5 h
Yield: 95.3 %

Procedure:
Diisopropylethylamine (2.4 mL, 13.62 mmol) and cyclopropylamine (943 μL, 13.62 mmol) were added to commercially available (Ark Pharm, Inc.) 6,8-dibromoimidazo[1,2-a]pyrazine (2.51 g, 9.08 mmol) dissolved in 2-propanol (9 mL). The solution was placed in an 80° C. oil bath. After 4.5 h, the volatiles were removed in vacuo. The brown residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was washed further with water (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via a filtration over a short plug of silica gel (40% EtOAc/hexanes) and the filtrate was concentrated in vacuo to afford 6-bromo-N-cyclopropylimidazo[1,2-a]pyrazin-8-amine (2.19 g, 95%) as a light brown solid. 1H NMR (CDCl3, 400 MHz) δ: 7.61 (s, 1H), 7.46 (d, 1H, J=1.2 Hz), 7.44 (d, 1H, J=1.2 Hz), 6.26 (bs, 1H), 3.02 (dddd, 1H, J=7.2, 7.2, 7.2, 3.6 Hz), 0.89-0.95 (m, 2H), 0.64-0.69 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10](=[O:16])[CH2:9][CH2:8]2.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>C1COCC1>[CH2:19]([O:18][C:17]([CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][CH3:3])[CH:6]=2)[C:10]1=[O:16])=[O:21])[CH3:20]
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2C1=O
Yield: 98 %

Procedure:
This compound is prepared according to the procedure disclosed in EP 534859. To a suspension of sodium hydride (50% dispersion in oil, 20 g) in 240 mL of THF, diethyl carbonate was added and the mixture was stirred and refluxed for 90 min. A solution of 5,6-Dimethoxyindan-1-one (40 g) in THF (440 mL) was added, the mixture was heated under reflux for 3 h, then cooled and concentrated. Ethyl acetate (200 mL) was added, the organic layer was washed with water. The organic layer was dried over MgSO4, filtered and the ethyl acetate was removed under reduced pressure. The title product was obtained in 98% yield.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Br:11])C.[Mg:12]>O1CCCC1>[Br-:11].[Mg+2:12].[C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:11]
Reactant: [Mg]
Reactant: CCBr
Agent: O=C1CCCCCN1
Solvent: C1CCOC1
Product: [Br-]
Product: [Mg+2]

Procedure:
The following Examples were prepared by reacting caprolactam, ethylbromide, and magnesium in tetrahydrofuran to form caprolactam magnesium bromide.
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C(N(CC)CC)C.[C:19]([O:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C1COCC1.ClCCl>[CH2:1]([NH:11][C:24](=[O:25])[CH:23]([O:22][C:19](=[O:21])[CH3:20])[CH3:27])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/CN
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)C(=O)NC/C=C(\C)CCC=C(C)C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a cold solution of geranyl amine (7 g) and triethyl amine (6 g) in THF (50 ml) was added dropwise a solution of 2-acetoxypropanoyl chloride (9 g) in dichloromethane (15 ml) at a temperature between 6° C. and 13° C. over a period of 20 minutes. Stirring was continued at room temperature for 2 hrs. The white precipitate (triethylamine HCl salt) was filtered and the filtrate was evaporated. The residue was dissolved in DCM (100 ml), washed twice with 50 ml of aqueous 5% HCl solution and twice with water (2×50 ml) and evaporated to dryness to yield 12.6 g of a colourless oil. The yield was 90%, the purity was 95% according to NMR analysis.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.[OH-:13].[Na+]>CN(C)C=O>[CH2:11]([O:7][CH2:1][CH:6]1[O:13][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: [OH-]
Reactant: Oc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(OCC1CO1)C1CO1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 103.4 %

Procedure:
A mixture of the starting phenol derivative (3.12 g) of the following formula: ##STR47## the same R-(-)-epichlorohydrin (4.627 g) as used in Preparation 3, 50 wt. % aqueous sodium hydroxide (0.88 g) and dimethylformamide (30 ml) is heated with stirring at 60° C. for 2.5 hours. The reaction mixture is cooled and distilled under reduced pressure to remove the solvent. The product is purified by silica gel column chromatography to give S isomer of a glycidyl ether (2.96 g) of the following formula: ##STR48##