Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[CH:17][CH:16]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: CC(c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 4-(1-phenylethyl)benzoic acid (150 mg, 0.66 mol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (303 mg, 0.797 mmol), triethylamine (2 mL) in dichloromethane (25 mL) was stirred at 25° C. for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (101 mg, 0.66 mmol) was added. After stirring at 25° C. for 12 hours, water (15 mL) was added to the reaction mixture. And the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated to give a residue in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenylethyl)benzamide (100 mg, 42%).
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH2:10][C:9](=[O:13])[NH:8]3)[N:3]=[CH:2]1.C(O[CH:19](OC(C)(C)C)[N:20](C)[CH3:21])(C)(C)C.[CH3:28]N(C=O)C>CCOCC>[CH3:19][N:20]([CH3:21])[CH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]3[C:12]=2[S:1](=[CH2:28])[CH:2]=[N:3]3)[NH:8][C:9]1=[O:13]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2c(ccc3ncsc23)N1
Reactant: CN(C)C=O
Solvent: CCOCC
Product: C=S1C=Nc2ccc3c(c21)C(N(C)C)C(=O)N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 1.0 g (5.3 mmol) of 6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one in 7.5 mL of DMF was added 1.38 g (6.80 mmol) of N,N-dimethylformamide-di-t-butyl acetal. The mixture was stirred at ambient temperature for 1 h and diluted with 7.5 mL of Et2O. The resulting precipitate was isolated filtration to afford 8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one as a tan solid (1.0 g, 77%): 1H NMR (DMSO-d6): δ 3.33 (bs, 3H), 3.59 (bs, 3H), 6.97 (d, J=8.4, 1H), 7.33 (s, 1H), 7.62 (d, J=8.4, 1H), 9.13 (s, 1H), 10.29 (s, 1H); APCI-MS: m/z 246 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[H][H].Br[CH:11]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:13]([N:27]([CH3:29])[CH3:28])[O:12]1.Cl>CN(C)C=O.O>[N:1]1([CH:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:13]([N:27]([CH3:29])[CH3:28])[O:12]2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CN(C)C1=C(c2cccc(C(F)(F)F)c2)C(=O)C(Br)O1
Reactant: c1cc[nH]c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1=C(c2cccc(C(F)(F)F)c2)C(=O)C(n2cccc2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In this example, 1.05 g of pyrrole dissolved in 10 ml of dimethylformamide was slowly added to an anhydrous slurry containing 0.76 g of sodium hydride (added as a 50% in oil mixture) in 25 ml of dimethylformamide at room temperature. After the addition was completed and evolution of hydrogen observed to cease a solution containing 5 g of 2-bromo-3-oxo-4-(3-trifluoromethylphenyl)-5-dimethylamino-2,3-dihydrofuran in 25 ml of dimethylformamide was added dropwise. The mixture was then stirred for 48 hours at room temperature. The mixture was then sampled and examined by thin layer chromatography and then heated at 65° C. for one-half hour. The mixture was then poured into water, then acidified to about pH 1 by the addition of aqueous 10 wt.% hydrochloric acid. The mixture was extracted three times with ethyl ether. The combined extracts were washed three times with aqueous saturated sodium chloride solution, dried over magnesium sulfate and then evaporated in vacuo yielding a dark oil. The oil was chromatographed by high-pressure liquid chromatography over silica gel eluting with 1:1 vol. petroleum ether-ethyl acetate yielding the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Cl.[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][NH:35][CH2:34]2)=[O:30].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][N:35]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:34]2)=[O:30]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 20 %

Procedure:
180 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 52 mg of the target compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].Cl>C(OCC)C.O>[CH3:20][CH:19]([CH3:21])[C:18](=[O:22])[CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]
Reactant: CCCCOC(=O)CC(C)=O
Reactant: CC(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCOC(=O)C(C(C)=O)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, to a reactor was added 0.22 mol of potassium tert-butoxide. After evacuating for 2 hrs, 80 ml of THF was added to dissolve the solid with stirring. Then 0.1 mol of butyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath, and the reaction was continued for further 2 hrs. Then under cooled in the ice-water bath, 0.12 mol of isobutyryl chloride was slowly dropped, and the reaction was continued for further 1.5 hrs. Next, under cooled in the ice-water bath, water was added to dissolve resultant solid, and the reaction mixture was neutralized with hydrochloric acid. Diethyl ether was used to extract product, and the collected organic layer was dried over anhydrous sodium sulfate. Removing solvent by using a rotatory evaporator gave the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=NN(C)C=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:18]1[C:22](B(O)O)=CC=[N:19]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:19][N:18]=[CH:22][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Reactant: OB(O)c1ccn[nH]1
Product: COC(=O)c1cc(C)ccc1-c1ccn[nH]1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using (1H-pyrazol-5-yl)boronic acid. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[F:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)c(F)c2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2F)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-fluoro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-2′-fluoro-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Na+]>CO.C1COCC1.O>[C:1]([C:3]1[C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)c1sc2cccc(C)c2c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2sc(C(=O)O)c(C#N)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15.59 g (63.6 mmol) of the 3-cyano-2-ethoxycarbonyl-4-methylbenzo[b]thiophene obtained in Step 3 were dissolved in a mixture of methanol (150 ml), THF (150 ml) and water (150 ml) followed by the addition of 30 ml of 5 M aqueous sodium hydroxide solution and stirring for 2 hours at room temperature. After concentrating the solvent under reduced pressure, the pH was lowered to 4 by addition of 1 M hydrochloric acid and, after extracting with ethyl acetate and washing the organic phase with water, it was dried with magnesium sulfate. The solvent was then concentrated under reduced pressure to obtain 3-cyano-2-carboxy-4-methylbenzo[b]thiophene. This and 1.27 g (20 mmol) of copper powder were added to 18 ml of quinoline followed by stirring for 2 hours at 150° C. After cooling the reaction solution, it was filtered with Celite and the pH of the filtrate was lowered to 3 by addition of hydrochloric acid to transfer the quinoline as the solvent to the aqueous phase followed by extraction with ethyl acetate. After washing the organic phase with water, it was dried with magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 9.10 g (52.6 mmol) of the target compound (yield of the two steps: 83%).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[S:23][C:22]([C:24](OCC)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:29]1([CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[S:23][C:22]([C:24]([N:39]3[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:41][CH2:40]3)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Reactant: C1CCN(CCC2CCNCC2)C1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCC(CCN4CCCC4)CC3)s2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-thiadiazole-2-carboxylate (30 mg, 0.07 mmol), 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (29 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[NH:19]1[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]1[CH2:26][OH:27].C(=O)([O-])O.[Na+]>CC(C)=O.CC(C)=O.O.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:19]2[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]2[CH2:26][OH:27])[N:7]=1
Reactant: OC[C@@H]1CC[C@H](CO)N1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g, 8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water (60 mL). The mixture was treated with a solution of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol) in acetone/water (20 mL, 3:1), followed by a suspension of sodium hydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutes of stirring at 0° C., the mixture was treated with an additional quantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26 g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate (0.35 g) in water (5 mL). The suspension was allowed to stir overnight while regaining room temperature. The title compound was isolated by Büchner filtration, washed with water, and dried under house vacuum. Compound identification by mass spectrometry was achieved via the analysis of the product reaction product of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol with excess morpholine in ethanol. MS (ES+)=417.2 (M+morpholine—CI)+
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:26]([NH:25][C:20]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=3)=[O:27])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: COc1nn(-c2ccc(N)c(C)c2)c(=O)o1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: COc1nn(-c2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)c(C)c2)c(=O)o1

Procedure:
The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of 3,4-dichlorophenyl isocyanate in toluene at 50° C.
Reaction SMILES: ClC(OCC)=O.Br.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1)([OH:10])=[O:9].C(N(CC)CC)C.Br.COC1C=CC(N(S(C2C=CC(CCCCC(O)=O)=CC=2)(=O)=O)C(C2C3C(N=C4C=2C=CC=C4)=CC=CC=3)=O)=CC=1.O[N:94]1[C:98](=[O:99])[CH2:97][CH2:96][C:95]1=[O:100]>O1CCCC1>[C:95]1(=[O:100])[N:94]([O:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[C:18]([C:20]3[C:33]4[C:28]([N:27]=[C:26]5[C:21]=3[CH:22]=[CH:23][CH:24]=[CH:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:19])=[CH:15][CH:16]=2)=[O:10])[C:98](=[O:99])[CH2:97][CH2:96]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)O)cc2)cc1
Agent: Br
Agent: CCOC(=O)Cl
Agent: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCCCC(=O)O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Reaction time: 1 h

Procedure:
0.11 g (1 mmol) of ethyl chloroformate is added, while stirring at -15° C., to a solution of 0.57 g (1 mmol) of N-(4-carboxyphenyl)-N-(4-toluenesulfonyl)acridine-9-carboxamide hydrobromide and 0.21 g (2 mmol) of triethylamine in 25 ml of anhydrous tetrahydrofuran. The mixture is stirred at the same temperature for 1 hour and then 0.12 9 (1 mmol) of N-hydroxysuccinimide is added. After a further hour, the mixture is left to stand at room temperature for 15 hours. It is evaporated in vacuo, the residue is taken up in ethyl acetate, and the solution is washed with water, sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation yields 0.42 g (70.8% of theory) of the desired product.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][N:5]([CH2:18][C:19]#[CH:20])[C:6](=[O:17])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1.ClCCl>[CH3:1][N:2]([CH3:3])[C:6]([N:5]([CH3:4])[CH2:18][C:19]#[CH:20])=[O:17]
Reactant: C#CCN(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCN(C)C(=O)N(C)C
Yield: 46 %

Procedure:
N-Methylpropargylamine (600 mg, 8.70 mmol) and triethylamine (878 mg, 8.68 mmol) in dichloromethane (10 ml) were added dropwise, with ice cooling, to a stirred solution of 4-nitrophenyl chloroformate (1.75 g, 8.68 mmol) in dichloromethane (10 ml). The reaction was stirred at ice temperature for 3 hr. then the resulting solution purified by column chromatography on silica using 25% ethyl acetate in iso-hexane as eluent. Thus was obtained 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (1.80 g, 89%) as a colourless oil. Dimethylamine (3.0 ml of a 2.0M solution in THF, 6.0 mmol) and 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (600 mg, 2.56 mmol), in dichloromethane (7 ml) were stirred at room temperature for 6 days then the reaction solution purified by chromatography on silica using ethyl acetate as eluent to give N,N,N′-trimethyl-N′-prop-2-yn-1-ylurea (164 mg, 46%) as a colourless oil.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[CH3:8]OC(OC)OC.[CH2:15]([NH2:18])[CH2:16][CH3:17]>C(#N)C>[NH2:7][C:6]1[N:18]([CH2:15][CH2:16][CH3:17])[CH:8]=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: N#CC(N)C(N)=O
Reactant: CCCN
Reactant: COC(OC)OC
Solvent: CC#N
Product: CCCn1cnc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 36 h
Yield: 61.1 %

Procedure:
A mixture of 2-amino-2-cyanoacetamide (2.8 g, 0.0282 mol), trimethylorthoformate (3.4 g, 0.0321 mol) and acetonitrile (55 ml) was heated under reflux for 0.75 hour, then allowed to cool. n-Propylamine (1.8 g, 0.0305 mol) was then added dropwise, and the resulting mixture stirred at ambient temperature for 36 hours. The solid which precipitated was collected by filtration and crystallised from methanol to give the title compound as a colourless solid (2.9 g, 61%), m.p. 241°-243° C. Found: C,49.67; H,7.15; N,33.64. C7 H12N4O requires C,49.98; H,7.19; N,33.31%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(F)(F)F)n(C)n1
Yield: 90 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 2-amino-2-methyl-1-propanol, to the title compound (112 mg, 90%) which was obtained as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:18]1OCCOCCOCCOCCOC1.IC>O1CCCC1.CO>[CH3:18][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl (trans-4-hydroxycyclohexyl)carbamate (1.0 g, 4.6 mmol) in tetrahydrofuran (20 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 24 mg, 6.4 mmol) and 15-crown-5 ether (965 μL) for 30 minutes under cooling with ice and then with iodomethane (289 μL) at room temperature for 1 hour. Methanol (2 mL) was added to the reaction mixture, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1 (v/v)) to give the title compound (708 mg, yield 67%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[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][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1.C(Cl)(Cl)[Cl:31].C(=O)([O-])[O-].[Na+].[Na+].[C:40](Cl)([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>O>[C:40]([N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:29])[F:28])[C:19]1[CH:20]=[CH:21][C:22]([C:23]([Cl:31])=[O:25])=[CH:26][CH:27]=1)([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 200 ml. warm chloroform is added a solution of 15 g. of sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time, ultimately to yield 4-[N-carbobenzyloxy-15-(trifluoromethyl)pentadecylamino]benzoyl chloride as a viscous, orange oil.
Reaction SMILES: [C:1]([N:8]([CH3:10])[OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:32]([Si:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:9][N:8]([CH3:10])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:33])([CH3:34])[CH3:35]
Reactant: CN(O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](OCCCCBr)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(OCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Boc-N-methylhydroxylamine (a) (0.74 g, 5 mmol) was dissolved in 10 ml DMF, treated with NaH (200 mg, 60% dispersion in mineral oil, 4.75 mmol), and stirred for 1 h under an argon atmosphere. The mixture was cooled to 0° C., treated with a solution of 4-bromo-butoxy)-tert-butyl-diphenyl-silane (b) (1.56 g, 4 mmol) in DMF (10 mL) and stirred at 0° C. for an additional 3 hours. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc (150 mL) and poured into a separatory funnel. The organic layer was washed with 0.1 M NaOH (5×50 mL), H2O (50 ml), 0.1 M KHSO4, and brine (50 ml) and the dried with MgSO4. After removal of the solvent, the residue was chromatographed on silicagel(Hexane:EtOAc 10:1) to yield 0.588 g (24%). The product was identified by electrospray mass spectrometry (ESI-MS)(MFE calculated 457.26; found 457.8)