Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22]#[N:23])[N:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21]/[C:22](=[N:25]/[OH:26])/[NH2:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N/C(Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)=N\O
Reaction time: 1 h

Procedure:
250 mg (0.66 mmol) of the compound from Example 24A and 92 mg (1.32 mmol) of hydroxylamine hydrochloride were suspended in 3.3 ml of ethanol, and the mixture was heated to the boil. 193 μl (1.39 mmol) of triethylamine were added to the hot solution and heating under reflux was continued for a further 1 h. On cooling of the reaction, a colorless solid crystallized out; this solid was filtered off and washed with a little ethanol. This gave 174 mg (69% of theory) of the target compound as a colorless solid. The mother liquor was concentrated under reduced pressure on a rotary evaporator, and the residue was partitioned between water and ethyl acetate. The organic phase was washed successively with 10 ml of water and 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave a further 69 mg (24% of theory) of the target compound in a purity of 87% as a slightly yellowish solid.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]1=2.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([O:12][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[N:17]=[CH:16][N:15]=3)=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: Oc1cccc2sccc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sccc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (0.104 g, 2.6 mmol, 60% suspension in mineral oil, Aldrich) was added in small portions to a solution of benzo[b]thiophen-4-ol (0.3 g, 2 mmol, prepared according WO 01/68653) in DMF (4 mL) and the mixture was stirred at room temperature for 0.5 h. (4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.776 g, 3 mmol) was then added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under vacuum, the residue was dissolved in EtOAc (50 mL), washed with 1 N NaOH and water, dried over MgSO4, and filtered. The filtrate was evaporated under vacuum and the residue purified by silica gel chromatography (10% EtOAc in hexanes) to give the title compound. Mp: 122.3-122.4° C. MS (ESI, pos. ion) m/z: 373.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19]O>Cl>[CH3:19][O:10][C:9](=[O:11])[CH:8]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
Bis-(4-chloro-phenyl)-acetic acid (4.33 g, 15.4 mmol) was suspended in anhydrous methanol (20 mL) and concentrated hydrochloric acid (5 drops) was added. After 1 day the reaction was quenched by the addition of saturated sodium bicarbonate solution, then the organic solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 50% saturated potassium carbonate solution. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with 10% ethyl acetate/petrol, to afford the title compound as a colourless oil (3.57 g, 78%); LCMS (PS-B3) Rt 3.79 min, No Ionisation. 1H NMR (CDCl3) δ 3.74 (3H, s), 4.96 (1H, s), 7.20-7.23 (4H, m), 7.28-7.32 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 500 parts of toluene is added to a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in a 1,000 parts of water at 50° C. The mixture is stirred mechanically at 50° C for 10 hours. The toluene layer is separated; the water layer is extracted with 500 parts of toluene. The combined toluene layers are dried and evaporated to give 110 parts (85% yield) of p-nitrobenzotribromide, m.p. 74°-81° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:26]4[CH2:27][C:28]5[S:29][CH:30]=[CH:31][C:32]=5[C:25]=4[N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C(Cl)Cl>[Br:8][C:30]1[S:29][C:28]2[CH2:27][C:26]3[C:22]([C:19]4[CH:20]=[CH:21][C:16]([N:13]5[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]5)=[CH:17][CH:18]=4)=[N:23][N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:25]=3[C:32]=2[CH:31]=1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Reaction time: 2 h
Yield: 84 %

Procedure:
NBS (0.18 g, 1.0 mmol) was added to a solution of 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.5 mmol) in CH2Cl2 (5.0 mL). After 2 hr, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.42 mmol) as brown solid in 85% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:12]=1)=[O:9])([CH3:6])[CH3:5].[I-].[CH4:30].O>CN(C)C=O>[CH3:6][C:4]([O:7][C:8]([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:14]=[C:13]([CH:23]([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:12]=1)=[O:9])([CH3:3])[CH3:5]
Reactant: CCOC(=O)Cc1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Reactant: C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
84 mg of sodium hydride are added to a solution of 700 mg of ethyl [4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]acetate in 8 ml of N,N-dimethylformamide under argon. The reaction mixture is then stirred for 15 minutes at 0° C. 0.130 ml of methane iodide is then added and the resulting mixture is stirred at ambient temperature overnight. 0.5 ml of water is added and the reaction mixture is concentrated to dryness under reduced pressure. After purification by silica column chromatography, elution being carried out with a gradient of heptane/ethyl acetate eluent of 0% to 50% and then with ethyl acetate at 100%. 150 mg of ethyl 2-[4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]propanoate are obtained in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:9][C:4]1[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)O)C2)n1
Temperature: 140 °C

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1.397 g, 8.52 mmol), (3S)-3-piperidinecarboxylic acid (1 g, 7.74 mmol) and Hunig's base (2.70 ml, 15.49 mmol) in NMP (10 mL) was heated in the microwave at 140° C. for 90 minutes. LCMS showed mainly desired product. The reaction was cooled down to room temperature, and poured onto water (160 mL). The formed solid was filtered, and the filtered solid was identified as the SM 4,6-dichloro-2-pyrimidinamine. The product stayed in the aqueous solution. 1N HCl was added to adjust the pH=7. Then the aqueous solution was extracted 3× with a mixture of CHCl3 and isopropanol (200:10 mL). The organic layers were combined and evaporated to afford the title compound (1.99 g) as a yellow solid. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1nccs1)C(F)(F)F
Yield: 73.6 %

Procedure:
According to Reference Example 8-2, by use of thiazole-2-carbaldehyde (300 mg, 2.65 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (73 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.470 mL, 3.18 mmol), the mixture was stirred and reacted at room temperature for 1.2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 2,2,2-trifluoro-1-(thiazol-2-yl)ethanol (Compound DM) (357 mg, yield: 74%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](/[CH:15]=[CH:16]/OC(=O)C1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]([C:15]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][CH:16]=1)=[O:14]
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COC(=O)/C=C/OC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a mixture of (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (12.0 g, 77 mmol) and 4-nitro-benzoic-acid (E)-2-methoxycarbonyl-vinyl ester (9.7 g, 39 mmol) in dichloromethane (200 mL) was added triethylamine (20.9 mL, 150 mml) and the resulting solution stirred overnight at room temperature. The mixture was then diluted with dichloromethane (500 mL) and the organic extract removed and washed with water, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (3.1 g, 40%) which was obtained as a light yellow oil. MS: m/e=204.2 [M+H]+
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16]>CO>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]3[CH2:21][CH2:22][N:17]([CH:15]=[O:16])[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=CN1CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Product: O=CN1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1
Yield: 86 %

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-formylpiperazine in 86% yield. mp 106°-107°. FDMS m/e=303 (M+ of free base). α[D]589 =-1.98 (c=1.0, methanol).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@@H:14]1[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:15]1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:9][O:8][C:6]([C:3]1[N:4]=[CH:5][N:1]([C@@H:14]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]2[O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:2]=1)=[O:7]
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: COC(=O)c1nc[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Temperature: 95 °C
Yield: 84.9 %

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (1.27 g, 0.01 mole) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (5.04 g, 0.01 mole) was melted and then 0.095 g of p-toluenesulfonic acid was added thereto. The reaction mixture was reacted for 3 hours, while maintaining the temperature of the reaction mixture at 95±5° C. And then, the reaction mixture was crystallized with 25 ml of methanol to give 4.85 g of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (yield: 85%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Cl.Cl[CH2:15][CH2:16][N:17]([CH:21]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:18][CH2:19]Cl>C(O)C>[CH:1]1([N:7]2[CH2:15][CH2:16][N:17]([CH:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[OH:29])[CH2:18][CH2:19]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Oc1ccccc1CC(c1ccccc1)N(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccccc1CC(c1ccccc1)N1CCN(C2CCCCC2)CC1
Reaction time: 24 h

Procedure:
In ethanol (30 ml) are dissolved in N,N-bis(2-chloroethyl)-1-phenyl-2-(2-hydroxyphenyl)ethylamine hydrochloride (1.9 g) and cyclohexylamine (0.7 g) and thereto is added sodium hydrogen carbonate (1.4 g). The mixture is refluxed with stirring for 24 hours. After the reaction, the solvent is distilled off. To the residue is added a diluted aqueous ammonia and the alkaline solution is extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The crystalline residue (crude free base) is dissolved in a small amount of ethanol and thereto is added a 25% hydrobromic acid-acetic acid solution and the mixture is allowed to cool. The precipitated crystals are recrystallized from ethanol to give the desired compound as dihydrobromide (1.4 g), melting point: 245.5°-247.5° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1.N1C=CC=CC=1>[C:16]([NH:14][C:11]1[CH:12]=[CH:13][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(C(=O)O)cc1C(=O)O
Yield: 94.9 %

Procedure:
Dimethyl-4-amino-isophthalate (9 g) in 60 ml of dioxane and 18 ml of pyridine is treated with hexanoyl chloride (8.8 g) at room temperature for 16 hours. After dilution with water and extraction with ethyl acetate, the solution is washed with 40% citric acid and 5% NaHCO3 and evaporated to dryness, so obtaining dimethyl-4-hexanoylamino-isophthalate (14.8 g) that is dissolved in 75 ml of dioxane and treated with 75 ml of 2 N NaOH at room temperature for 6 hours. After acidification with HCl the precipitate is collected under vacuum and washed until neutral. 4-hexanoylamino-isophthalic acid (11.4 g) is obtained, which is treated with 26 ml of acetic anhydride at reflux for 10'. After cooling, dilute with 30 ml of isopropyl ether and filter. 6-carboxy-2-pentyl-4H-3,1-benzoxazin-4-one (7.3 g; m.p. 185°-190° C.) is obtained, which is treated at room temperature first with 70 ml of 32% ammonium hydroxide for 16 hours and then with 50 ml of 2 N NaOH for 2 hours. After acidification with 2 N HCl, the precipitate is filtered off and crystallized from ethanol, so obtaining 6-carboxy-2-pentyl-3,4-dihydro-4-oxo-quinazoline (6.1 g; m.p. 311°-313° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)(C)C.[CH2:17]([O:29][CH2:30][CH:31]1[O:33][CH2:32]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[ClH:34]>O>[ClH:34].[OH:33][CH:31]([CH2:30][O:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:32][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Yield: 33.1 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride (yield 36.0%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15]C)=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][O-:18].[Na+].[NH4+].[Cl-]>CO>[CH3:17][O:18][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1cc2cccnc2nc1Cl
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cccnc2nc1OC

Procedure:
Ethyl 2-chloro-1,8-naphthyridine-3-carboxylate (104.0 mg, 0.44 mmol) was dissolved in anhydrous MeOH under N2. NaOMe (33.2 mg, 0.62 mmol) was added as a solution in MeOH. The mixture was refluxed for 15 h, and then it was allowed to cool. NH4Cl (sat) was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated to yield 102.0 mg (quant) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][NH:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+:25]>O1CCOCC1.CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][NH:5][CH2:4][C:3]([O-:23])=[O:2])=[O:8])[CH2:10][CH2:11]2)=[CH:21][CH:20]=1.[Na+:25]
Reactant: COC(=O)CNNC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C([O-])CNNC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(1-(4-chlorobenzyl)-piperazine-4-carboxamido) glycine methyl ester (813 mg, 2.50 mmol) in dioxane-CH3OH (3:1, 12 mL) was treated with 4N aqueous NaOH solution (0.63 mL, 1 equiv.). The mixture was stirred at room temperature for 2 hours. Solvent removal afforded the desired material which was used without further purification (885 mg, 100%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)C(C)O
Temperature: 130 °C
Yield: 35.5 %

Procedure:
A 2liter one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 150.0 g (1.67 moles) lactic acid, 293.0 g (2.25 moles) octyl alcohol, 6 ml sulfuric acid and 500 ml toluene. Mixture was heated to 130° C. for 6 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Octyl lactate was distilled under high vacuum to yield 119.9 g (35.6% yield) of clear colorless liquid. According to GC the product is 96.2% pure.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:11]([CH3:12])[CH3:10])(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
Diisopropylethylamine (4.95 mL, 27.8 mmol) was added at 0° C. to a stirred solution of dimethylamine (3.70 mL, 55.6 mmol) in tetrahydrofuran (25 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (3.0 g, 11 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2.90 g (94%) of 4-bromo-3-methyl-N,N-dimethyl-benzenesulfonamide, which was used in subsequent reactions without further purification. MS cald. for C9H12BrNO2S [M+] 278.2, obsd. 280.0.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]([O:10][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2.0 g (10.8 mmol) of ethyl 4,4,4-trifluoroacetoacetate in 10 ml of DMF was added 2.28 g of p-toluenesulfonyl chloride and 4.24 g of cesium carbonate and stirred at room temperature overnight. The reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.27 g of ethyl 4,4,4-trifluoro-3-p-toluenesulfonyloxy-2-butenoate.