Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC=C)C.O>O1CCOCC1>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: C#Cc1ccc(O)cc1
Reaction time: 5 h

Procedure:
Into a 500 ml four-necked flask purged with nitrogen were charged 25 g of poly (p-vinylphenol) ["VP-5000" manufactured by Nippon Soda K.K.] having a weight average molecular weight (Mw) of 8400 and a dispersion degree (Mw/Mn) of 1.19 (208 mmol as p-vinylphenol unit) and 0.024 g (0.125 mmol) of p-toluenesulfonic acid, and they were dissolved in 250 g of 1,4-dioxane. To this solution was added dropwise 9.0 g (125 mmol) of ethylvinyl ether, and then reaction was carried out for 5 hours at 25° C. This reaction solution was added dropwise into 1500 ml of ion-exchanged water, then separated by filtration to obtain a white wet cake. This wet cake was dissolved again in 200 g of 1,4-dioxane, and the resulting solution was added dropwise into 1500 ml of ion-exchanged water. The resulting mixture was separated by filtration. The wet cake thus obtained was washed by being stirred with 600 g of ion-exchanged water, followed by being filtered to obtain a wet cake. The washing operation with this ion-exchanged water was further repeated twice. The resulting white wet cake was dried under reduced pressure to obtain a resin in which the hydroxyl group of poly (p-vinylphenol) was partially 1-ethoxyethyl etherized. This resin was analyzed by 1H-NMR to find that 40% of the hydroxyl group was protected by a 1-ethoxylethyl group. This resin has a weight average molecular weight of 12300 and a dispersion degree of 1.23.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:19]=1)=[CH:6][C:7]1[C:8]([CH3:18])([CH3:17])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C([Li])CCC.C(N)(C)(C)C.[C:30]([NH:34][Si:35](C1C2C(=CC3C(C)(C)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:37])[CH3:36])([CH3:33])([CH3:32])[CH3:31]>C(OCC)C>[C:30]([NH:34][Si:35]([CH:19]1[C:5]2=[CH:6][C:7]3[C:8]([CH3:18])([CH3:17])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH:3]=[C:2]1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH3:37])[CH3:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC1=Cc2cc3c(cc2C1)-c1ccccc1C3(C)C
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)-c1ccccc1C3(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)(C)N
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)C(C)(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
In a 500 mL round flask, 2,9,9-trimethyl-3,9-dihydrocyclopenta[b]fluorene (15.0 g, 60.9 mmol) was dissolved in 300 mL of diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (2.5M hexane solution, 24.8 mL) was slowly injected thereto, followed by stirring at room temperature for 12 hours. After the volatile materials were removed by vacuum, 350 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (23 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 500 mL round flask, and dissolved in 320 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (16.1 g, 152.2 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of toluene was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, to thereby obtain 21.0 g of a mixture of N-tert-butyl-1-(2,9,9-trimethyl-3,9-dihydrocyclopenta[b]fluoren-3-yl)-1,1-dimethylsilanamine and N-tert-butyl-1-(2,9,9-trimethyl-1,9-dihydrocyclopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (yield: 91.8%), as a viscous material.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:8]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([N:6]2[CH:24]=[CH:22][CH:8]=[C:7]2[C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: N#CC(Nc1ccc(Cl)cc1)c1ccc(S(N)(=O)=O)cc1
Reactant: C=CC=O
Product: NS(=O)(=O)c1ccc(-c2cccn2-c2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-chloroanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a pale yellow powder (yield 38%), melting at 179-181° C.
Reaction SMILES: [CH2:1](O)[CH3:2].[F:4][C:5]([F:11])([F:10])[S:6]([NH2:9])(=[O:8])=[O:7].[C:12]12([C:22]([OH:24])=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:12]12([C:22]([O:24][CH2:1][CH2:2][NH:9][S:6]([C:5]([F:11])([F:10])[F:4])(=[O:8])=[O:7])=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2
Reactant: CCO
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: NS(=O)(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(OCCNS(=O)(=O)C(F)(F)F)C12CC3CC(CC(C3)C1)C2
Yield: 75.8 %

Procedure:
100 g (0.52 mol) of trifluoromethanesulfonamide ethanol, 108.6 g (0.54 mol) of 1-adamantanecarboxylic acid, 0.1 mol of para-toluenesulfonic acid and 500 g of toluene were added to a glass flask equipped with a thermometer and a condenser, followed by dehydration using a dean-stark dehydration apparatus under reflux. After 9 hours of reflux, about 9 ml of water was removed. The resulting reaction solution was dissolved in 500 g of ethyl acetate, and washing was conducted twice with a saturated sodium hydrogencarbonate solution, once with a 1N—HCl and once with a saturated saline solution in this order. Then, the organic phase was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant was subjected to recrystallization in hexane, thereby obtaining 140 g of N-[2-(adamantan-1-ylcarbonyloxy)ethyl]trifluoromethanesulfonamide (yield: 75%, purity: 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl(3-hydroxyphenyl)carbamate (3.02 g, 14.4 mmol) and potassium carbonate (2.99 g, 21.7 mmol) in N,N-dimethylformamide (35 mL) was added 2-chloro-5-nitropyridine (2.52 g, 15.9 mmol), and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 50 mL). The organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl{3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate as a yellow solid. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16](Cl)(Cl)Cl.[CH3:20][CH:21]([CH3:37])[CH2:22][NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(=O)([O-])[O-:39].[K+].[K+]>C(#N)C.O.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:23]([CH2:22][CH:21]([CH3:37])[CH3:20])[C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25]1)=[O:39]
Reactant: CC(C)CN[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Reactant: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccccc21
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 62.7 %

Procedure:
1-(4-Methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (470 mg) and tert-butyl (3S)-3-[(2-methylpropyl)amino]piperidine-1-carboxylate (400 mg) were dissolved in acetonitrile (30 ml) and water (15 ml), potassium carbonate (2.02 g) was added, and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to room temperature and diluted with saturated brine. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (60:40) was concentrated under reduced pressure to give the object product (446 mg).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].[H-].[Na+].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=1)=[CH2:19].C(O)C>CN(C)C=O>[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].[C:1]([O:7][CH2:19][CH2:18][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=1)(=[O:6])[CH2:2][C:3]([O-:5])=[O:4]
Reactant: C=Cc1ccc(C(=O)CCCCCCC)cc1
Reactant: O=C(O)CC(=O)O
Agent: CCC(CC)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
4′-(2-Iodoethyl)octanophenone prepared (5 g) in the step D-3 was dissolved in anhydrous N,N-dimethylformamide (15 ml) to obtain 4′-(2-iodoethyl)octanophenone solution. Diethyl acetamide malonate (9.09 g) was dissolved in anhydrous N,N-dimethylformamide (30 ml) to obtain a solution to which 60% sodium hydride oil dispersion (1.23 g) was added with cooling. The solution was stirred under atmosphere of nitrogen for 1 hour. 4′-(2-Iodoethyl)octanophenone solution was added to the solution, and the solution was stirred under atmosphere of nitrogen at 60° C. for 2 hours. The reaction solution was poured into ice water, and extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0→3:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (3.2 g) and 4′-vinyl octanophenone (1.5 g) in the form of colorless crystal, respectively. The diethyl acetamide malonate (4.25 g) was dissolved in anhydrous N,N-dimethylformamide (30 ml) to obtain a solution, to which 60% sodium hydride oil dispersion (574 mg) was added. The solution was stirred under atmosphere of nitrogen at room temperature for 30 minutes. 4′-Vinyl octanophenone (1.5 g) and anhydrous ethanol (7.5 ml) were added to the solution, and the solution was stirred under atmosphere of nitrogen at 60° C. for 6 hours, and the solution was stirred at room temperature for 2 days. The reaction solution was poured into ice water, extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0→4:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (2.29 g) in the form of colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:35])[C@H:30]([C@@H:32]([CH3:34])[OH:33])[NH2:31])[CH3:27].O.[OH:37][C:38]1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:35])[CH:30]([NH:31][C:38](=[O:37])[C:13]1[CH:14]=[CH:15][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:24])[F:23])[CH:4]=1)[CH:32]([OH:33])[CH3:34])[CH3:27]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-Fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]2)=[C:4](Cl)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]2)=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=2)[N:3]=1
Reactant: NCc1cccc(F)c1
Reactant: O[C@H]1[C@H](O)CS[C@H]1n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCO
Product: O[C@@H]1[C@H](O)CS[C@H]1n1cnc2c(NCc3cccc(F)c3)nc(Cl)nc21
Yield: 80 %

Procedure:
(2R,3S,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophen-3,4-diol (1 equivalent), prepared in Step 2, and 3-fluorobenzylamine (1.5 equivalents) were dissolved in ethanol (5 ml) at room temperature for 2-3 hrs with stirring. The reaction mixture was concentrated in a vacuum and the concentrate was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (20:1, v/v) as an elution solvent to afford the object compound (0.10 g, 80%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.IC.[C:34](=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH3:34])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.8 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 37) (440 mg, 1.00 mmol) in anhydrous dimethylsulphoxide (10 ml) was treated with iodomethane (310 μl, 5.00 mmol) and cesium carbonate (975 mg, 3.00 mmol) and the resulting mixture was heated at 40° under a nitrogen atmosphere for 3 hours then stirred at room temperature for 17 hours. The mixture was diluted with water and extracted with diethyl ether (×3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (2:1) to afford the title compound as a colourless oil (315 mg)
Reaction SMILES: C(S([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][Cl:24])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:25])(=O)=O)(C)C.[OH-].[Na+]>CC(C)=O.O>[NH2:25][C:8]1[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[CH:23][Cl:24])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CCl)c3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Nc1nc2cc(C(=CCl)c3ccccc3)ccc2[nH]1

Procedure:
1-Isopropylsulfonyl-2-amino-6-(α-chloromethylenebenzyl)benzimidazole is reacted with sodium hydroxide in acetone and water by the method of Example 43 to give 2-amino-6-(α-chloromethylenebenzyl)benzimidazole. The latter compound is reacted with phenylsulfonyl chloride and sodium hydroxide in dichloromethane to give 1-phenylsulfonyl-2-amino-6-(α-chloromethylenebenzyl)benzimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[NH2:22][C:23]1([C:26]#[N:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@H:14]([C:15]([NH:22][C:23]2([C:26]#[N:27])[CH2:25][CH2:24]2)=[O:17])[CH2:18][CH2:19][CH3:20])[C:9]([F:10])([F:11])[F:12])=[CH:6][CH:7]=1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid (19.0 g, 53.6 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (12.71 g, 107 mmol, synthesized according to O'Donnell, M. J. et al., Synthesis, 1984, 127-128), and HATU (22.42 g, 59.0 mmol) was dissolved in DMF (200 mL) and cooled to −78° C. Diisopropylethylamine (37.35 mL, 214 mmol) was added and after stirring for 1 hour, the cooling bath was removed. The reaction mixture was allowed to stir for an additional 1 hour, whereupon saturated NaHCO3 (300 mL) was added. The product was extracted with ethyl acetate (500 mL), washed with brine (100 mL), 0.25 M citric acid (200 mL), saturated NaHCO3 (200 mL), brine (200 mL), dried over MgSO4/DARCO, filtered through silica, and evaporated to dryness. After eluting the residue through another short plug of silica with 10% ethyl acetate/dichloromethane as mobile phase, the product was concentrated and recrystallized from ether/hexanes to yield N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30].C(N(CC)CC)C>CN(C)C=O.ClCCl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][Cl:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(N)c2c(n1)c(C#CCCCCl)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a degassed suspension of 5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine (2.768 g, 6.34 mmol), copper (I) iodide (0.242 g, 1.269 mmol), and bis(triphenylphosphine)palladium(II)dichloride (0.445 g, 0.634 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added a solution of 5-chloropent-1-yne (0.781 g, 7.61 mmol) and triethylamine (1.231 mL, 8.88 mmol) in anhydrous N,N-dimethylformamide (20 mL) dropwise over 2 minutes. The reaction was stirred at ambient temperature for 17 hours. The reaction was concentrated in vacuo and the resultant brown oil partitioned between water (500 mL) and ethyl acetate (500 mL). The organic was separated and the aqueous back extracted with ethyl acetate (250 mL). The combined organics were washed with brine (400 mL), dried (MgSO4), filtered and concentrated in vacuo. The sample was dissolved in dichloromethane and purified by chromatography on silica (Si) (2×100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60 minutes. The appropriate fractions were combined and evaporated in vacuo to give a red oil. The sample was dissolved in dichloromethane and purified by chromatography on silica using a 0-100% ethyl acetate-cyclohexane gradient over 80 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid. (1.13 g).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[C:19]1([C:24]([C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:19]1([C:24]([C:26]2[CH:27]=[C:28]([NH:29][C:3]([C:5]3[CH:6]=[CH:7][N:8]4[C:12]=3[CH2:11][S:10][CH:9]4[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:4])[CH:30]=[CH:31][CH:32]=2)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(C(=O)c2cccs2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1)c1cccs1
Temperature: 70 °C
Reaction time: 7 h
Yield: 58.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c] thiazole hydrochloride (6 g) is added, at a temperature between 70° and 82° C., to a solution of 3-(2-thenoyl)aniline (4.1 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 70° C., in the course of 10 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (350 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (10 g) is thereby obtained, which is dissolved in boiling acetonitrile (250 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed twice with acetonitrile (50 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-thenoyl)phenyl]-3-(3-pyridyl)1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (5 g) in the form of cream-coloured crystals m.p. 172° C., is thereby obtained.