Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[N:18](COCC[Si](C)(C)C)[C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:12]2=[N:13][C:14]=1[I:15].CO>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[NH:18][C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:12]2=[N:13][C:14]=1[I:15]
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (70.0 ml, 909 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (14.99 g, 27.1 mmol) in dichloromethane (70 ml). The reaction mixture was an amber solution that was stirred at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure to give an amber oil. Methanol (50 ml) was added and the resulting solution was stirred at room temperature. After about 5 minutes, the product crystallized and precipitated to give a white suspension. Dichloromethane (50 ml) was added to the reaction mixture. The crystalline product was collected from the reaction mixture by vacuum filtration and was dried overnight under vacuum to give the title compound as a crystalline white solid. LC-MS: calculated for C12H11ClIN3O4 422.95 observed m/e: 424.0 (M+H)+ (Rt 0.92/2 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[O:50](C(OC(C)(C)C)=O)[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=O.O>C1COCC1>[C:54]([O:53][C:51](=[O:50])[N:16]([CH2:15][CH2:14][CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:49])[CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCNCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 56 %

Procedure:
The compound obtained in Stage 1 above (2.31 g, 3.3 mmol, 1 eq) is dissolved in 50 mL of THF with stirring. A solution of BOC2O (0.8 g, 3.7 mmol, 1.1 eq) in 10 mL of THF is then added dropwise at room temperature. Stirring is continued for 4 hrs and then the medium is poured into water and extracted with AcOEt (3×100 mL), dried (Na2SO4), filtered, and evaporated. The residue is flash chromatographed with a gradient from pure heptane to pure AcOEt. 1.49 g (Yield 56%) is obtained after evaporation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C@@H:29]([NH2:38])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:24][CH2:23]1)=[O:21])[CH3:18].[CH2:40](Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C@@H:29]([NH:38][C:14]([C:10]2[CH:11]=[C:12]([OH:13])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:9]=2)=[O:16])[CH:30]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH3:40])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(=O)OC(C)(C)C)CC1
Reactant: ClCCCl
Reactant: O=C(O)c1cc(O)n(-c2cccc(F)c2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)C(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.199 g 1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (prepared by standard procedure using 3-fluorophenylhydrazine hydrochloride and sodium diethyl-2-oxosuccinate followed by ester hydrolysis) and 4.743 g 4-((S)-2-amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 26 ml DMF 2.205 g HOBt, 2.5 ml DIPEA and 2.760 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([OH:24])=O)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:51][C@@H:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([N:40]1[CH2:51][C@@H:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[O:24])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](N2CCOCC2)CN1C(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](N2CCOCC2)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and (4S)-1-t-butoxycarbonyl-N-t-butyl-4-morpholino-L-prolinamide (prepared as described in Preparation 6) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 115°-117° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[OH:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[OH:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.84 g, 45%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (1.00 g, 5.54 mmol) and 3-hydroxyphthalic anhydride (1.00 g, 6.09 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH2:28][CH2:29][CH2:30][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CN1CCCNCC1
Reactant: O=C(NCc1cnn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CN1CCCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)cn3)cc2)CC1
Temperature: 85 °C
Yield: 5.2 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.225 mmol), 1-methylhomopiperazine (0.100 mL, 0.81 mmol), ethylene glycol (0.025 mL, 0.45 mmol) and K3PO4 (100 mg, 0.47 mmol) in isopropanol (1 mL) was degassed with Argon before being charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 85° C. overnight. It was then purified by HPLC to give the title compound (5 mg). MS 430.0 and 432.0 (M+H, Cl pattern).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 95.1 %

Procedure:
A solution of 6-benzyloxy-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (5.96 g, 14, mmol) and potassium phthalimide (3.89 g, 21 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[(6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (7.14 g, 95.1%) as crystals.
Reaction SMILES: C1CC=CC=1.C1[CH:10]2[CH:11]3[CH:15]=[CH:14][CH:13]([CH:9]2C=C1)[CH2:12]3.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1.[CH:23]12[CH2:29][CH:26]([CH:27]=[CH:28]1)[CH:25]([C:30]([OH:32])=O)[CH:24]2[C:33]([OH:35])=[O:34].B(F)(F)F.CCOCC>>[C:11]12([C:17]3=[CH:18][C:19]([O:21][C:16]3=[O:22])=[O:20])[CH2:12][CH:13]([CH2:9][CH2:10]1)[CH:14]=[CH:15]2.[CH:26]12[CH2:29][CH:23]([CH2:28][CH2:27]1)[C:24]1[C:33]([O:35][C:30](=[O:32])[C:25]2=1)=[O:34]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)C1C2C=CC(C2)C1C(=O)O
Agent: C1=CCC=C1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1C=C(C23C=CC(CC2)C3)C(=O)O1
Product: O=C1OC(=O)C2=C1C1CCC2C1
Temperature: 100 °C

Procedure:
Mixed polybasic anhydride containing a plurality of 1,2 anhydrides is obtained by distilling, at 200° C., 66.10 gms. (1 mole) of cyclopentadiene directly from dicyclopentadiene into a reactor containing 98.06 gms. (1 mole) of maleic anhydride, heated to a temperature of 55° C. When the transfer is complete, the reaction mixture is heated to 100° C. for 2 hours. The reaction mixture is then stripped of any excess cyclopentadiene at 120° C. at 1 atmosphere. The resulting Diels-Adler adduct of cyclopentadiene and maleic anhydride is the anhydride of cis.-5-norbornene-2,3-dicarboxylic acid. The reaction mixture is cooled to 50° C., and 4.90 gms. (0.03 moles) of boron trifluoride etherate is added slowly with stirring. The reaction mixture exotherms to 65° C. after which it is heated to 125° C., to decompose the BF3OEt and then cooled. The reaction is quenched by mixing with 3 liters of 10% sodium bicarbonate. The mixture is then neutralized with dilute 5% hydrochloric acid. The mixed polybasic anhydride of norbornene-2,3-dicarboxylic acid anhydride is obtained as a fine tan power, Mp. 200° C., and used for foam preparation without further purification.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=C(C3CO3)[CH:18]=[CH:19][C:12]1=2.C(OCC)(=O)C>CS(C)=O>[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:1]([CH:2]([OH:4])[CH2:3][O:9][CH2:8][CH2:7][OH:10])[CH:18]=[CH:19][C:12]1=2
Reactant: OCCO
Reactant: CC(C)(C)[O-]
Reactant: c1cc2cc(C3CO3)ccc2s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCOCC(O)c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.7 g of potassium tert-butoxide and 57 ml of ethylene glycol was heated to 80° C. Thereto was added, in 1.5 hours, a solution of 18 g of 2-(benzo[b]thiophen-5-yl)oxirane dissolved in 30 ml of dimethyl sulfoxide. The resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to a mixture of 120 ml of ice water and 80 ml of ethyl acetate. The organic layer was Separated. The aqueous layer was extracted twice each with 30 ml of ethyl acetate. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant:chloroform/ethanol=20/1) to obtain 9.1 g of 1-(benzo[b]thiophen-5-yl)-2-(2-hydroxyethoxy)ethanol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH3:9][O-:10].[Na+].CCCCCC.O>CO>[CH3:9][O:10][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCCCCBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: COCCCCCCBr
Reaction time: 0.5 h
Yield: 93 %

Procedure:
6-Bromohexyl methyl ether was prepared from 1,6-dibromohexane. To 48.8 g (200 mmol) of 1,6-dibromohexane at 60° C. was added 44 g (200 mmol) of a 25% solution of sodium methoxide in methanol. The reaction mixture was held 0.5 hours, then an additional 4 g of sodium methoxide solution was added, and the reaction mixture was held an additional hour. Hexane and water were added, the organic phase was washed with brine and dried with magnesium sulfate, filtered and stripped. Fractional distillation under vacuum gave 93% pure 6-bromohexyl methyl ether. This bromide was converted to the Grignard reagent, which was converted to 1-(7-methoxyheptyl)-cyclopropene in the same manner that pentylmagnesium bromide was converted to 1-hexylcyclopropene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methoxyaniline (37 mg, 0.193 mmol) similar to Example 13 and isolated as a white solid (10 mg, 14%). 1H NMR (CDCl3): 9.70 (d, J=1.8 Hz, 1H), 8.77-8.74 (m, 2H), 7.86 (s, 1H), 7.67 (s, 1H), 7.48-7.44 (m, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 6.96 (s, 1H), 6.76 (dd, J=3.0, 9.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: COc1cccc(B(O)O)c1
Product: COC(=S)c1cc(Nc2cccc(OC)c2)c(C)s1
Yield: 24.5 %

Procedure:
Using a procedure similar to Example 208, step (a), 73.2 mg (0.35 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 109 mg (2 equiv, 0.70 mmol) of 3-methoxyphenyl boronic acid to give 25.2 mg (23%) of methyl 4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.40 (s, 3H), 3.81 (s, 3H), 3.89 (s, 3H), 6.12 (s, 1H), 6.43-6.63 (m, 2H), 7.20 (m, 1H), 7.78 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C14H15NO3S2, 310.06 (M+H), found 310.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:11](=[O:13])[CH3:12].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[C:11](=[O:13])[CH3:12])[CH2:17][CH2:16]1
Reactant: CC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: CC(=O)c1c(N2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 68.9 %

Procedure:
In a cylindrical quartz tube were placed 1-(2-chloro-6-nitro-phenyl)-ethanone (300 mg, 1.5 mmol) and N-methyl-piperazine (12 ml, 180 mmol). The reaction was heated for 40 hours at 120° C. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (acetone/MeOH 75:25) affording the desired compound (272 mg, 46% yield), as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=O.C([N:26]1[C:38]2[CH:37]=[CH:36]C=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)C1C=CC=CC=1>>[C:1]([C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:38]1[CH:37]=[CH:36][C:16]([C:12]3[S:11][CH:15]=[CH:14][CH:13]=3)=[CH:34][C:33]2=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reactant: O=C(Cl)c1cccs1
Product: CCCCCCCC(=O)c1ccc2[nH]c3ccc(-c4cccs4)cc3c2c1

Procedure:
The reaction as described in example 1b by using octanoyl chloride, 2-thiophenecarbonyl chloride, and 9-benzylcarbazole (which is obtained according to Bulletin of the Chemical Society of Japan (1981), 54(6), 1897-8) as starting materials; affords the product without the benzyl protection on the nitrogen atom, namely 6-octanoyl-3-(2-thienyl)-9H-carbazole. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.88 (t, 3H), 1.22-1.44 (m, 8H), 1.82 (quint, 2H), 3.10 (t, 2H), 7.23 (t, 1H), 7.51 (d, 1H), 7.55 (d, 1H), 7.76 (d, 2H), 8.07 (d, 1H), 8.14 (d, 1H), 8.72 (s, 1H), 8.76 (s, 1H), 9.04 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=O)=[C:15]3[N:14]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[C:31]4[NH:25][C:26](=[O:27])[NH:28][C:29]4=[O:30])=[C:15]3[N:14]=2)=[CH:8][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: CN(C)CCOc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCOc1ccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)cc1
Temperature: 70 °C

Procedure:
To 5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (90 mg, 0.276 mmol) in EtOH was added hydantoin (28 mg, 0.276 mmol) and piperidine (28 μL, 0.276 mmol). The mixture was heated at 70° C. overnight three times. Solvent was removed under reduced pressure and MeOH was added. Insolubilities were filtered off, and the filtrate was purified by HPLC to yield 5-((5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=408)
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].CC(C)([O-])C.[K+].[CH2:20]([O:27][C@@H:28]1[C@@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:32]([CH2:51][O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[O:31]C1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1COCC1.CCCCCC>[CH2:20]([O:27][C@@H:28]1[C@@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@H:33]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C@@H:32]([CH2:51][O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[O:31][C@H:13]1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:1])[C:7]=1[F:6])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccccc1F
Reactant: [Li]CCCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 1.56 M n-hexane solution of n-butyl lithium (3.57 ml) and 2-fluorotoluene (0.66 ml) were added in that order to a suspension of potassium t-butoxide (625 mg) in THF (11 ml) at −78° C. and the mixture was stirred at the same temperature for 1.5 hours. A solution of 2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (3.00 g) in THF (10 ml) was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes. After the addition of a 1 M aqueous solution of hydrochloric acid, the mixture was heated to room temperature. The reaction mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The filtrate was concentrated and dried to be solid. The resulting residue was dissolved in dichloroethane (5 ml) and acetonitrile (25 ml). Triisopropylsilane (2.27 ml) and boron trifluoride-diethyl ether complex (0.85 ml) were added to the solution at −30° C. After stirring at the same temperature for 30 minutes, saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(2-fluoro-3-methylphenyl)-D-glucitol (559 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1Br.[NH2:11][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29])[CH2:13][NH:14]C(=O)OC(C)(C)C.[NH2:32][CH:33](CC1C=CC=CC=1)[CH2:34][CH2:35][NH:36][C:37](=O)OC(C)(C)C>>[NH2:14][CH2:13][CH:12]([NH:11][C:8]([C:4]1[S:5][CH:6]=[C:2]([C:35]2[N:36]([CH3:37])[N:32]=[CH:33][CH:34]=2)[CH:3]=1)=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:29])([F:30])[F:31]
Reactant: CC(C)(C)OC(=O)NCCC(N)Cc1ccccc1
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1C(F)(F)F
Product: Cn1nccc1-c1csc(C(=O)NC(CN)c2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 4,5-dibromo-2-thiophenecarboxylic acid and substituting 1,1-dimethylethyl {2-amino-2-[2-(trifluoromethyl)phenyl]ethyl}carbamate (152 mg, 0.5 mmol) [prepared according to the procedure of Preparation 16] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 395 (M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 3.36-3.39 (m, 1H) 3.46-3.53 (m, 1H) 3.98 (s, 3H) 5.86-5.91 (m, 1H) 6.48 (s, 1H) 7.51 (d, J=2.02 Hz, 1H) 7.60 (s, 1H) 7.76 (s, 1H) 7.83 (d, J=8.08 Hz, 2H) 7.94 (s, 1H) 8.05 (s, 1H).