Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (25 g, 0.159 mmol) in acetonitrile (500 mL) and methanol (500 mL) was treated with diisopropyl ethylamine (28 mL). The reaction mixture was cooled in an ice-bath and after 30 minutes, trimethylsilyldiazomethane was added dropwise. The mixture was stirred at room temperature for 18 hours then evaporated under vacuum to afford the product as an oil (29.4 g, 100%). MS (+ve ion electrospray) m/z 172 (MH+).
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:22]([OH:25])[CH2:23][OH:24]>N1C=CC=CC=1>[CH2:1]([NH:19][C:20]([O:24][CH2:23][CH2:22][OH:25])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCCO
Reaction time: 8 h
Yield: 79.7 %

Procedure:
In 50 ml of pyridine are dissolved 11.8 g (40 mM) of stearyl isocyanate and 12.4 g (200 mM) of ethylene glycol, and the solution is allowed to stand at room temperature overnight. The reaction mixture is concentrated to dryness under reduced pressure, and the residue is recrystallized from 100 ml of methanol to give 11.38 g (yield 79.5%) of the contemplated product. mp. 81°-82° C.
Reaction SMILES: O1CCOCC1.C(OC([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([CH2:32][C:33]5[CH:34]=[C:35]6[C:40](=[CH:41][C:42]=5[F:43])[N:39]=[CH:38][CH:37]=[CH:36]6)=[CH:30][N:31]=4)[N:28]=3)[CH:20]=[N:19]2)[CH2:15]1)=O)(C)(C)C.Cl>CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH:14]1[CH2:15][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([CH2:32][C:33]5[CH:34]=[C:35]6[C:40](=[CH:41][C:42]=5[F:43])[N:39]=[CH:38][CH:37]=[CH:36]6)=[CH:30][N:31]=4)[N:28]=3)[CH:20]=[N:19]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CNC4)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dioxane (5 mL) was charged in a flask. 3-{4-[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (Stage 146.2, 100 mg, 0.200 mmol) and HCl in dioxane (4 M solution, 500 μL, 2.002 mmol) were then added and the mixture was stirred at rt for 1 h. The RM was diluted with EtOAc/NaHCO3. The organic layer was separated and washed with brine (2×) then dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) and precipitated in Et2O to afford the title compound as a foam (tR 2.87 min (conditions 3), MH+=400.1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH3:28])[C:11]1[C:12]([O:23][CH3:24])=[CH:13][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(N(C)C(=O)OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 34.2 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester and 5.8 g. of sodium hydride (50% dispersion in oil) in 300 ml. of absolute dimethylformamide was stirred at room temperature for 4 hours. The resulting solution was treated with 17 g. of methyl iodide with stirring and ice-cooling. After stirring at room temperature for 1 hour, the dimethylformamide was removed under vacuum at 60° C. Then, 1 liter of water was added to the residue and the emulsion was extracted with two 2 liter portions of ethyl acetate. The organic phases were washed with two 1 liter portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained 2,6-dimethoxy-4-(methoxy-carbonyl)-N-methyl-carbanilic acid benzyl ester having a melting point of 130°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1>CO.Cl.[Fe]>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]1=[O:20]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2[N+](=O)[O-])c1=O
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2N)c1=O
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(4-chloro-2-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1 g) in methanol (20 ml) and conc. hydrochloric acid (10 ml) was added iron (powdered, 0.48 g) unded vigorous stirring. After addition, the mixture was heated at reflux temperature for 1 hr. The oil bath was removed and the solution was allowed to cool to ambient temperature. Ethyl acetate (200 ml) was added, washed with brine (×2) and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:3) as the eluent to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][C:15]1=[O:24].[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:21]2[CH:22]=[CH:23][C:18]3[O:17][CH2:16][C:15](=[O:24])[N:14]([CH3:13])[C:19]=3[CH:20]=2)=[O:11])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1Cl
Reactant: CN1C(=O)COc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CN1C(=O)COc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 1, step 1, (4-bromo-2-chloro-phenyl)-acetic acid was converted to the acid chloride and subsequently reacted with 4-methyl-2H-1,4-benzoxazin-3(4H)-one in the presence of AlCl3 to give the title compound as a light brown solid. MS (m/e, ISP neg. ion)=392.1 [M−H+].
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1c(NCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
2-Methyl-3-nitroaniline (3.40 g, 22.3 mmoles) and benzaldehyde (3.9 mL, 38 mmoles) in dichloroethane (78 mL) were treated with glacial acetic acid (5.1 mL, 89 mmoles). The yellow reaction mixture was stirred for 4 hours at room temperature, treated with sodium triacetoxyborohydride (9.5 g, 44.6 mmoles) and allowed to stir overnight at room temperature. The mixture was poured into saturated aqueous NaHCO3 (400 mL), extracted with diethyl ether (400 mL) and the phases separated. The organic phase was washed with brine (200 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1→4:1 hexanes:ethyl acetate) to provide the title compound as a yellow solid (4.72 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][C:9]#N)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14]>>[F:1][C:2]1[CH:12]=[C:11]2[C:5](=[CH:4][CH:3]=1)[O:6][CH2:7][CH2:8][C:9]2=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#CCCOc1ccc(F)cc1
Product: O=C1CCOc2ccc(F)cc21

Procedure:
In the former pathway, 3-(4-fluorophenoxy)propionitrile having the formula (I) is stirred in polyphosphoric acid at a temperature of more than 140° C., preferably at about 170° C. for about 15 minutes to form 6-fluoro-4-chromanimine having the formula (V) and then the reaction mixture is poured into ice-water to hydrolyze 6-fluoro-4-chromanimine having the formula (V) into 6-fluoro-4-chromanone having the formula (II). Though this pathway comprises a short and simple step, it accompanies the side reaction with coloration. In the latter pathway, 3-(4-fluorophenoxy)propionitrile having the formula (I) is hydrolyzed with acid such as hydrochloric acid, hydrobromic acid and sulfuric acid into 3-(4-fluorophenoxy)propionic acid having the formula (IV). When hydrobromic acid or sulfuric acid is employed in a high concentration in order to increase the rate of hydrolysis reaction, an unfavourable side reaction such as cleavage of the ether bond and sulfonation of the aromatic ring may occur. On the other hand, when hydrochloric acid is employed, such side reaction as mentioned above does not occur. Concentrated hydrochloric acid is preferably used from the view point of the reaction rate and yield and 3-(4-fluorophenoxy)propionitrile having the formula (I) is refluxed in the concentrated hydrochloric acid for 10 hours to give 3-(4-fluorophenoxy)propionic acid having the formula (IV) in a quantitative yield. Cyclization of 3-(4-fluorophenoxy)propionic acid having the formula (IV) into 6-fluoro-4-chromanone having the formula (II) can be carried out in a good yield by known method where the compound (IV) is stirred in polyphosphoric acid at 100° C. for 10 minutes (U.S. Pat. Nos. 4,117,230 and 4,130,714), or by the method where the compound (IV) is treated in concentrated sulfuric acid. If the condition of acid hydrolysis and ring closure reaction is agreed, 6-fluoro-4-chromanone having the formula (II) can be obtained in an almost quantitative yield from 3-(4-fluorophenoxy)propionitrile having the formula (II). When 3-(4-fluorophenoxy)propionitrile having the formula (I) is stirred in 85 to 95% sulfuric acid at 90° C. for 10 hours, hydrolysis reaction and ring closure reaction occur simultaneously and thus 6-fluoro-4-chromanone having the formula (II) can be obtained directly. In this reaction, however, by-product such as 3-(4-fluorophenoxy)propionic acid is formed and the yield is quite low.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH:6]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].O>C(O)(=O)C>[OH:1][C:2]([CH3:28])([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7](=[O:8])[CH2:12][CH2:13]1
Reactant: CCOCCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 6 h
Yield: 106.5 %

Procedure:
Crude 7-{7-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-1,4-dioxaspiro[4,4]non-6-yl}heptanoic acid (0.38 g.), water (8 ml.) and glacial acetic acid (16 ml.) were left to stand at room temperature for 6 hours. The solution was then evaporated in vacuo at a temperature lower than 50° C. Ethyl acetate (150 ml.) was added, and then the solution washed with water (until the pH of the washings was pH 5), dried over sodium sulphate, and evaporated to give 7-[5-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]heptanoic acid (0.36 g.), νmax 980 cm-1, 1700 cm-1, 1730 cm-1.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:52])CC2)CC1>>[OH:52][CH:5]1[CH2:6][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33]3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][CH2:4]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation see Example 22) and amine 21.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[Cl:12][C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([OH:22])[C:16]2=[C:15]([CH3:23])[CH:14]=1>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][C:6]([N:20]1[C:21](=[O:22])[C:16]2[C:17](=[N:18][C:13]([Cl:12])=[CH:14][C:15]=2[CH3:23])[NH:19]1)=[O:7]
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: Cc1ccccc1CN=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
136 μl (0.98 mmol) of 2-methylbenzyl isocyanate were added to 150 mg (0.82 mmol) of 6-chloro-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-ol in 10 ml of THF and 2 ml of DMF at room temperature. The reaction mixture was stirred at room temperature for 2 h and left to stand overnight. Concentration was followed by purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 139 mg (51%), M+H+: 331.18.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]3[CH:16]=[C:17]([C:20]4[CH:21]=[N:22][N:23]([C:25]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:44][C:45]1[S:46][CH:47]=[C:48]([CH3:50])[N:49]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:50][C:48]1[N:49]=[C:45]([NH:44][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[N:15]4[CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([C:25]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:10][C:2]=2[F:1])[S:46][CH:47]=1
Reactant: O=C(O)c1ccc(-c2cnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cn23)cc1F
Reactant: Cc1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2ccc(-c3cnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cn34)cc2F)n1
Yield: 84.9 %

Procedure:
170 mg 2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazo-[1,2-a]pyridin-3-yl]benzoic acid (compound in Example 472) and 34.4 mg 2-amino-4-methyl-1,3-thiazole were allowed to react overnight with 146 mg benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate and 50 μL triethylamine in 6 mL dichloromethane. The reaction solution was purified by an NH silica gel column, to give 169 mg of the title compound as colorless crystals (recrystallization solvent: ethyl acetate).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[Cl:9][C:10]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[Cl:9][C:10]1[CH:19]=[C:18]([N:20]([CH3:3])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
78 μL of iodomethane and 447 mg of Cesium Carbonate were added to 300 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 3 mL of DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate. 295 mg of methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 249 mg of 2-chloro-4-(N-methylmethylsulfonamido)benzoic acid.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:3][CH:2]=1.[CH2:28]([N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][CH3:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[C:8]2[N:41]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:42])=[CH:3][CH:2]=1
Reactant: CNCCCCCN(Cc1ccccc1)Cc1ccccc1
Reactant: COC(=O)C=Cc1ccccc1N=C=Nc1ccc(-c2ccccc2)cc1
Product: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN(Cc2ccccc2)Cc2ccccc2)N1c1ccc(-c2ccccc2)cc1

Procedure:
Compound (11) is reacted with compound (18) in a suitable solvent to give 3-(4-biphenylyl)-2-[N-(5-dibenzylaminopentyl)-N-methylamino]-4-methoxycarbonylmethyl-3,4-dihydroquinazoline (19). Then, this compound (19) is hydrogenated in the presence of Pd(C) and formalin solution to give 2-[N-(5-N′,N′-dimethylaminopentyl)-N-methylamino]-3-(4-biphenylyl)-4-methoxycarbonylmethyl-3,4-dihydroquinazoline (20).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[NH:11][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[NH:11][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][CH:8]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
(S)-tert-Butyl 2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (537 mg, 1.61 mmol) was dissolved into MeOH (20 mL) and then potassium carbonate (22 mg, 0.16 mmol) was added and the reaction was stirred at rt for 3 h. The reaction was concentrated, dissolved into dichcloromethane, loaded onto a SiO2 column and purified by BIOTAGE® Horizon (30-50% EtOAc/hexanes) to yield (S)-tert-butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (346 mg, 1.32 mmol, 82% yield) as an off-white solid. LC-MS retention time 0.878 min; m/z 260.35 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 7.21-7.17 (m, 1H), 4.92-4.87 (m, 1H), 3.43-3.30 (m, 2H), 3.05 (s, 1H), 3.03-2.85 (m, 1H), 2.20-1.88 (m, 3H), 1.60-1.45 (m, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:9]([C:5]1[C:6]([NH2:8])=[CH:7][C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 59.7 %

Procedure:
A 500 mL round bottom flask equipped with a reflux condenser was charged with 2-chloro-5-nitropyridin-4-amine (2.00 g, 11.5 mmol, 1.0 equiv), pyrrolidine (2.86 mL, 34.6 mmol, 3.0 equiv), potassium carbonate (4.78 g, 34.6 mmol, 3.0 equiv) and acetonitrile (50 mL). The mixture was heated at 70° C. overnight under nitrogen then cooled to room temperature. The yellow solids were collected by filtration and washed with acetonitrile, water and hexanes. The solids were dried to obtain the title compound as a bright yellow solid (1.43 g, 1st crop). The solvents from the filtrate were removed and the aqueous was extracted with ethyl acetate. The organic extracts was dried (Na2SO4), filtered and removed in vacuo to obtain additional product as an orange/yellow solid (820 mg, 2nd crop). The 2nd crop of product was triturated with ethyl acetate (3 mL) and then filtered and washed with ethyl acetate (2×1 mL) and diethyl ether (3 mL) to obtain a bright yellow solid (751 mg). The total yield of 5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine obtained was 2.18 g (91%). m/z (ES+) 209.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 7.39 (br s, 2H), 5.63 (s, 1H), 3.40 (br s, 4H), 1.93 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:14](=O)[CH2:15]Br>>[CH3:10][C:11]1[CH:12]=[C:13]([C:14]2[N:1]=[C:2]3[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]3[CH:15]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: COc1ccnc(N)c1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Product: COc1ccn2cc(-c3ccc(C)c(C)c3)nc2c1

Procedure:
The title compound, pale yellow solid, m.p. 175° C. and MS: m/e=252.2 (M+), was prepared in accordance with the general method of example 1 from 2-amino-4-methoxy-pyridine and 3,4-dimethyl-phenacylbromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)Cl.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)c(Br)c1
Product: COC(=O)c1nc(C)sc1-c1ccc(F)c(Br)c1

Procedure:
prepared by reaction of 3-(3-Bromo-4-fluoro-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=330.2.
Reaction SMILES: N.[CH2:2]([C@@H:8]1[C:11](=[O:12])[O:10][C@H:9]1[CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:29]([CH2:28][CH2:27][O:26][C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][C@@H:9]1[O:10][C:11](=[O:12])[C@H:8]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:31])[NH2:33]
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OCCC(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CC#N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OCCC(N)=O
Yield: 81.4 %

Procedure:
Ammonia gas was blown into a solution of 40 mg of 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionic acid (Example L) in 2.5 ml of acetonitrile until the solution is saturated and subsequently 50 mg of HBTU were added. Then, the mixture was filtered and evaporated and the residue was chromato-graphed on silica gel with 5 percent methanol in methylene chloride. There were obtained 32.5 mg of (3S,4S)-4-[(S)-2-(2-carbamoylethoxy)tridecyl]-3-hexyl-2-oxetanone, m.p. 35°.