Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10](=O)[CH2:11][CH:12]([CH3:14])[CH3:13]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:10]/[CH2:11][CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isovaleraldehyde (Alfa) (0.43 g, 5 mmol) in CH2Cl2 at room temperature for 18 h to give [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.98 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:32][CH2:31]2)[S:28][CH:29]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 39.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (225 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 117 mg (39.1%) of the desired product as a solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12.[H-].[Na+].Cl[C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:20]4[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]5[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=5[N:21]=4)=[CH:14][CH:15]=3)[C:5]=12
Reactant: Oc1ccc(C2CCCn3ccnc32)cc1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(C3CCCn4ccnc43)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of 4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)phenol (0.13 g) in DMF (10 ml) was added sodium hydride (60% in oil, 0.024 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.17 g) obtained in Example 1, step A), and the mixture was stirred under microwave irradiation at 150° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.19 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7]CCO.[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]S(C)(=O)=O)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:7][CH2:6][CH2:5][O:4][CH3:3])[CH3:12]
Reactant: COCCOCCO
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
NaH (88 mg of a 60% dispersion in oil, 2.2 mmol) was suspended in anhydrous toluene (3 ml) under N2 and chilled to 0° C. Non-polydispersed diethylene glycol monomethyl ether (0.26 ml, 0.26 g, 2.2 mmol) that had been dried via azeotropic distillation with toluene was added. The reaction mixture was allowed to warm to room temperature and stirred for four hours, during which time the cloudy grey suspension became clear and yellow and then turned brown. Mesylate 20 (0.50 g, 1.0 mmol) in 2.5 ml dry toluene was added. After stirring at room temperature over night, the reaction was quenched by the addition of 2 ml of methanol and the resultant solution was filtered through silica gel. The filtrate was concentrated in vacuo and the FAB MS: m/e 499 (M+H), 521 (M+Na). Additional purification by preparatory chromatography (silica gel, 19/3 chloroform/methanol) provided the non-polydispersed product as a clear yellow oil (0.302 g 57%). FAB MS: m/e 527 (M+H), 549 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8](C)(C)[CH2:7][C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.Cl[C:15]([O:17][C:18](Cl)(Cl)Cl)=[O:16].[CH2:22](O)C>>[O:9]1[C:10]2[C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][CH3:22])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)Cc2c(Cl)ccc(N)c2O1
Reactant: CCO
Product: CCOC(=O)Nc1cccc2c1OCC2

Procedure:
Schema 4 illustrates an alternative process for preparing the uracils of this invention in which a 7-amino-2,3-dihydrobenzofurnan, for example, 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran, is successively treated with trichloromethyl chloroformate and then ethanol to give the corresponding ethyl N-(2,3-dihydrobenzofuran-7-yl)carbamate (X). The carbamate is then reacted with sodium hydride and a 3-amino-3-fluoroalkylacrylate, for example, ethyl 3-amino-4,4,4-trifluorocrotonate, and subsequently with an alkyl iodide and potassium carbonate to produce the 3-(2,3-dihydrobenzofuran-7-yl)-1-alkyl-6-haloalkyluracil, for example, 3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil (VI). The 3-(2,3-dihydrobenzofuran-3-on-7-yl)-1-alkyl-6-haloalkyluracils of this invention may be prepared using an analogous method.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:16]>C(O)(C([O-])=O)=O.C(O)(C([O-])=O)=O.O.O=[Ti].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][OH:16])[CH3:2]
Reactant: OCCO
Reactant: CCCCOP(=O)(CC)CCCN
Agent: O=[Ti]
Agent: O=C([O-])C(=O)O
Agent: [K+]
Solvent: O
Product: CCP(=O)(CCCN)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To 414 g (2 mol) of butyl ethyl(3-aminopropyl)phosphinate (produced as in Example 6) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyl oxalate followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuating to leave 374 g (96% of theory) of 2-hydroxyethyl ethyl(3-aminopropyl)phosphinate.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>O1CCCC1.CN(C)C=O.[OH-].[Na+]>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[N:31]=2)[CH:41]=[CH:42][C:43]=1[F:44])=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (100 mg, 0.55 mmol) in tetrahydrofuran (2.0 mL) were added oxalyl chloride (59 μL, 0.69 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in N-methylpyrrolidone (2 mL). N-[6-(3-Amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) was added to the mixture, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (140 mg, 62%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.C1(C=CC(O)=CC=1)O.[CH3:19][O:20][CH:21]=[CH:22][C:23]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH2:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:24][C:23]([O:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[CH:22][CH:21]2[O:20][CH3:19]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: COC1=CC(=O)C=CC1=O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COC1=CC(=O)C2CC(O[Si](C)(C)C)=CC(OC)C2C1=O
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
In a 50 mL round bottom flask, 2-methoxy-1,4-benzoquinone (2.3 g, 16.7 mmol) was suspended in toluene (30 mL). Hydroquinone (95 mg) was added and the resulting suspension was stirred magnetically for 5 min. 1-Methoxy-3-trimethylsilyloxy-1,3-butadiene (Aldrich, used as received, 5.0 g, 4.5 mL, 29.1 mmol) was added in one portion and the reaction was heated under N2 at 60° C. using an oil bath for 18 h. The reaction was removed from the oil bath, allowed to cool to rt and the solvent was removed by evaporation. Crystallization occurred after cooling the mixture to -30° C. for 1 hour. The colorless solid was collected by filtration and washed with hexane (30 mL) giving 4a,5,8,8a-tetrahydro-2,8-dimethoxy-6-trimethylsilyloxynapthalene-1,4-dione ##STR138## as a colorless powder (3.6 g, 11.6 mmol, 70%, >95% pure by 1H NMR, mp 108-110° C.; 1H NMR (CDCl3) δ0.52 (s, 9H), 2.2-2.4 (m, 2H), 3.18 (s, 3H), 3.47 (t, 1H), 3.80 (s, 3H), 3.92 (m, 2H), 5.20 (d, 1H), 6.12 (s, 1H).
Reaction SMILES: [O:1]=[C:2]=[C:3]1[C:13](=[C:14]=[O:15])[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][CH2:8][S:9][NH-])=[CH:4]1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.C[N:23](C=O)C>>[O:1]=[C:2]=[C:3]1[C:13](=[C:14]=[O:15])[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:20]=[C:18]([CH2:17][Cl:16])[N:23]=2)=[CH:4]1
Reactant: CN(C)C=O
Reactant: O=C(CCl)CCl
Reactant: [NH-]SCCCc1ccc(=C=O)c(=C=O)c1
Product: O=C=c1ccc(CCc2nc(CCl)cs2)cc1=C=O
Temperature: 60 °C
Yield: 78 %

Procedure:
19.5 g 2-(3,4-dioxomethylenebenzyl)ethylthioamide (0.1 mol) was dissolved in 100 mL DMF, to which 12.6 g 1,3-dichloroacetone (0.1 mol) was added at room temperature. The reaction solution was heated at 60° C. for 3 hours, and then poured into ice water to isolate a solid. After sucking filtration and drying, 20.8 g off-white solid was obtained. Yield: 78%, MS: 268 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:8].[N:11]1([CH2:10][CH2:9][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of phenol (46.5 g), 1-(2-chloroethyl) piperidine (103.5 g), and potassium carbonate (207 g) in dimethylformamide (900 mL) was heated to reflux. After refluxing for two hours, the reaction mixture was allowed to cool to room temperature. This mixture was filtered, and the solids washed with dimethylformamide (100 mL). The combined filtrates was concentrated in vacuo to a brown oil. This oil was dissolved with ethyl acetate (400 mL), and the resulting solution was washed with water (2×200 mL) and saturated brine (2×200 mL). The ethyl acetate solution was dried over magnesium sulfate, filtered, and concentrated in vacuc to a brown oil. This oil was dissolved in methanol (100 mL), and the resulting solution acidified with 3% methanolic hydrochloric acid (prepared from acetyl chloride and methanol, 500 mL). The resulting solution was evaporated to dryness in vacuo. The residue (74 g) was crystallized from 1-propanol (800 mL) and ethyl acetate (500 mL) to give 59.6 g of the title compound as an off-white crystalline solid. Melting point 179-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH2:12]([O:19][C:20](=[O:25])[CH2:21][C:22](O)=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[CH2:21][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:25])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(O)CC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
3,4-dimethoxyaniline (500 mg, 3.26 mmol), 3-(benzyloxy)-3-oxopropanoic acid (1268 mg, 6.53 mmol), DMAP (798 mg, 6.53 mmol), and EDC (1877 mg, 9.79 mmol) were dissolved in DMF (7 ml). The reaction was stirred at RT for 4 hours to achieve completion. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give benzyl 3-(3,4-dimethoxyphenylamino)-3-oxopropanoate (530 mg, 49.3% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
A mixture of 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (2.95 g, 9.46 mmol), piperazine (10.60 g, 123 mmol) in dioxane (50 mL) is heated overnight at 110° C. Water is added and the reaction mixture is extracted with ethyl acetate. The combined ethyl acetate layers are washed with brine, dried and concentrated. The crude material is purified by chromatography eluting with dichloromethane-5% methanol. Fractions containing product are combined and concentrated to afford 1-(4-tert-butylphenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (2.4 g, 70% yield) as a light cream solid. TLC (silica gel, dichloromethane-10% methanol) Rf 0.27; ESI/MS 362 (M+H), RT 3.27 min; NMR 10.14 (1H, s); 8.12 (1H, d, J=3 Hz); 8.09 (2H, d); 7.68 (2H, d); 7.47 (2H, m); 6.91 (1H, d, J=6 Hz); 3.20 (4H, m); 2.53 (4H, m); 2.25 (1H, br s); 1.36 (9H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].C([Li])CCC.[F:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CCCCCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][F:17]
Reactant: FCCCCCCBr
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: FCCCCCCC#CCCOC1CCCCO1
Yield: 43.9 %

Procedure:
Repetition of the procedure described in Example 3 using 0.7992 g (5.06 mmol) of 3-butyn-1-yl tetrahydropyranyl ether, 3.6 mL (5.06 mmol) of 1.39M n-butyl lithium in hexane and 1.117 g (6.07 mmol, 1.2 eq) of 6-fluoro-1-bromo-hexane followed by purification by flash chromatography affords 10-fluoro-3-decyn-1-yl tetrahydropyranyl ether (570 mg, 44%) as a clear colorless oil: Rf=0.58 hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-2950 (alcane CH); and 1H-NMR (CDCl3) δ1.20-1.95 (m, 14H), 2.15 (m, 2H), 2.45 (m, 2H), 3.65 (m, 4H), 4.42 (dt, J=48 Hz, 6 Hz, 2H), 4.65 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.[CH2:11]([NH:13][CH:14](O)[CH3:15])[CH3:12].[OH-].[K+].[O:19]1C=CC=CN1.C(N(CC)CC)C>C1C=CC=CC=1.C1COCC1>[Cl:9][C:5]1[C:6]([Cl:8])=[N:7][C:2]2[O:19][CH2:12][CH2:11][N:13]([CH2:14][CH3:15])[C:3]=2[N:4]=1
Reactant: C1=CNOC=C1
Reactant: CCNC(C)O
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN1CCOc2nc(Cl)c(Cl)nc21
Yield: 12 %

Procedure:
Tetrachloropyrazine (22 g, 0.1 mol), ethylaminoethanol (9 g, 0.1 mol), and crushed KOH (16.5 g, 85% assay, 0.25 mol) were contacted overnight in 200 ml of refluxing benzene. Work-up gave a mixture of the oxazine (25%) and of the O-adduct (75%). The mixture was dissolved in THF and triethylamine (20 g, 0.2 mol) was added and held at reflux temperature for 6 days. The solid was filtered, the THF rotary evaporated, and the residual oil was partitioned between water and CH2Cl2. The organic layer was dried (MgSO4) and rotary evaporated to leave an oily residue. This was recrystallized from hexane and IPA to give two crops totaling 2.8 g (12% yield), m.p. 108°-10°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)[CH3:20]
Reactant: CNC
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CN(C)C)cs1
Temperature: 50 °C

Procedure:
Dissolved N-(4-chloromethyl-thiazol-2-yl)-acetamide (250 mg, 1.31 mmol) in 5 mL of THF. To this was added Na2CO3 (250 mg). Bubbled dimethyl amine in for 15 min. Sealed the flask and heated at 50° C. for 2 h. LC-MS analysis indicated the desired adduct. Filtered the mixture through diatomaceous earth and washed plug with 2×10 mL of THF. Concentrated to dryness to give 274 mg of N-(4-dimethylaminomethyl-thiazol-2-yl)-acetamide.
Reaction SMILES: C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[C:13]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])([CH3:15])[CH3:14].[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[C:23]=1[CH3:37].CO>C1COCC1>[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[C:23]=1[CH2:37][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:20]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of the lithium bis(trimethylsilylamide) (14 mL) in mL of THF was added t-butylacetate (2 mL). After stirring for 10 min, 4,6-dibromo-2-(2,4-difluorophenyl)-3-methylpyridine (1.0 g) dissolved in 3 mL THF was added dropwise. The mixture stirred at −78° C. for 1.5 h, then warmed to −50° C. The reaction mixture was then recooled to −78° C. and 3 mL of methanol was added. The solution stirred for 24 h at rt. The crude mixture was purified by flash chromatography, eluting with 50% ethyl acetate/hexanes. Mass spectrum m/z (ESI) 478.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (4.91 g, 16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) in methylene chloride (41 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (5.01 g, 28.16 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid solution (400 mL) and then extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, ⅓ hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (4.49 g, 72%) as a white solid: mp 216-217° C.; EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1071.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)NCc1ccc(O)cc1CCC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)NCc1ccc(OCc2ccccc2)cc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[5-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (14.8 mmol) in DMF (100 mL) was added Cs2CO3 (29.6 mmol) and benzyl bromide (16.3 mmol). The reaction mixture was stirred overnight at ambient temperature and diluted with EtOAc (200 mL). The mixture was washed with brine (100 mL) and water (100 mL). The organic layer was dried (Na2SO4) and concentrated to a yellow oil (6.8 g). MS [ES] m/z 428 (M+H)+.