Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]1[O:15][CH:9]1[CH2:10]2)(=O)C.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C@@H:8]1[CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[OH:4])[CH2:10][C@H:9]1[OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)Oc1cccc2c1CC1OC1C2
Product: Oc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2

Procedure:
A mixture of 5-acetoxy-2,3-epoxy-1,2,3,4-tetrahydronaphthalene (prepared in the manner disclosed in U.S. Pat. No. 4,076,843, 20.4 g) and benzylamine (85 mL) was heated in a bomb at 120° C. for 18 h. After cooling, excess amine was distilled off under high vacuum using a 70° C. bath. The semi-solid residue was triturated with chloroform (70 mL) and filtered. The filtercake was washed with chloroform, then with diethyl ether, and dried under vacuum to provide crude product. The crude product was recrystallized from a mixture of methanol and ethyl acetate to yield the title product (10 g) as a white solid. The regioisomeric product (trans 3-benzylamino-2,8-dihydroxy-1,2,3,4-tetrahydronaphthalene) was largely contained in the chloroform extract and wash.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[ClH:24]>C(OCC)C.CCCCCC.O>[ClH:24].[F:15][C:16]1[CH:17]=[C:18]([C:19](=[NH:3])[NH2:20])[CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1cccc(F)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: N=C(N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of hexamethyldisilazane (13.8 g, 85.6 mmol) in diethyl ether (143 ml) was added dropwise a 1.6 N solution (53.5 ml, 85.6 mmol) of n-butyllithium in hexane under ice-cooling. Thereto 3-fluorobenzonitrile (5.00 g, 41.3 mmol) was added, followed by stirring at room temperature for 2 hours. Thereto 3 N hydrochloric acid (57 ml) was added dropwiseunder ice-cooling, and the reaction mixture was stirred at room temperature for 0.5 hour. Water (200 ml) was added thereto, and the ether layer was removed. The aqueous layer was basified with an aqueous 3 N sodium hydroxide solution, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to the residue, and 4.65 g (64.5%) of the desired product as a solid was collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+:12].[C:13](=[S:15])=[S:14].CCCCCC>C1COCC1>[C:13](=[S:15])([S-:14])[NH2:8].[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=1.[Na+:12]
Reactant: S=C=S
Agent: CNc1cccc(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: NC(=S)[S-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-methoxy-2-methylaminopyridine (25.6 g, 0.185 mol) was dissolved in 120 ml of dehydrated THF, and 60% sodium hydride (7.4 g, 0.185 mol) was added. This was then refluxed for 1 hour, and upon becoming transparent, allowed to cool to room temperature. Carbon disulfide (14.1 g, 0.185 mol) was added dropwise into this solution, which was then stirred for two hours at room temperature. 300 ml of hexane were added and stirring continued until crystals precipitated out. The precipitated crystals were filtered out, then washed with 200 ml of hexane, and dried overnight in a dessicator to obtain 43.6 g (yield 99.7%) of the titled compound in the form of a pale yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([OH:16])=O)[S:11][C:12]=1[CH3:13])[CH3:2].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:31])[N:21]1[CH2:20][C@@H:19]([NH:18][C:14]([C:10]1[S:11][C:12]([CH3:13])=[C:8]([C:7]2[N:6]([CH3:17])[N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:9]=1)=[O:16])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:41])([F:40])[F:42]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (137 mg, 0.55 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (211 mg, 0.55 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.48 ml, 2.74 mmol) in Dichloromethane (5.47 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (281 mg, 0.60 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (262 mg, 0.45 mmol, 82% yield) as a clear oil: LCMS (ES) m/e 581 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12]Br>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12][O:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: OCCCCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of 1,4-dihydroxybutane (4.0 ml, 45.13 mmol) in N,N-dimethylformamide (62 ml) was treated with sodium hydride (1.98 g of a 60% solution, 49.63 mmol), and stirred for about 50 minutes at ambient temperature. The resulting mixture was cooled to 0° C. and treated with 2-fluoro-5-bromobenzyl bromide (3.0 g, 11.28 mmol). The reaction mixture was then stirred for four hours at ambient temperature. The reaction was quenched with water. The aqueous fraction was extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(Br)c1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(Br)c1F

Procedure:
A solution of the 3-bromo-2,4,5-trifluorobenzoic acid (2.5 g) in thionyl chloride (10 ml) was refluxed for 2.5 hours, and then concentrated. The resulting residue was purified by distillation through Widmer fractionating column to give the title compound (2.3 g), bp 98°-102° C./18 mmHg.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:38][CH2:39][C@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:41]>>[OH:41][C@@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:39][NH:38][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:32]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([F:19])([F:36])[F:37])=[O:7])=[O:18]
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccccc2-c2ccccc2C(F)(F)F)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=526.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[N:11]1([CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CO>[CH3:1][O:2][C:3]1[C:7]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]#[C:18][CH2:17][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:6][S:5](=[O:10])[N:4]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: NCCCCC#CCN1CCCCC1
Solvent: CO
Product: COC1=NS(=O)N=C1NCCCCC#CCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (2.0 g) in methanol (100 ml) was cooled to 0° C. 7-(Piperidino)hept-5-ynylamine (2.5 g) in methanol (50 ml) was added dropwise with stirring over 30 minutes maintaining the reaction temprature at 0° C. The reaction mixture was stirred at 0° C. for a further 2 hours to give a solution of 3-methoxy-4-[7-(piperidino)hept-5-ynylamino]-1,2,5-thiadiazole-1-oxide. Ammonia gas was bubbled through this solution for 30 minutes and the mixture allowed to stand for 16 hours. The reaction mixture was evaporated under reduced pressure to give an oil which was taken up in ethyl acetate, triturated and cooled to give the title compound (3.0 g), m.p. 134°-6° C. (recrystallisation from isopropanol-ethyl acetate).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[CH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[C:2]1=[O:27].Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH:33][C:23](=[O:24])[CH:22]([O:21][C:18]1[CH:19]=[CH:20][C:11]([CH:10]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:27])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)[CH3:26]
Reactant: CC(Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Reaction time: 15 h
Yield: 44.1 %

Procedure:
To a solution of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy]propionic acid (100 mg, 0.28 mmol), L-alanine methyl ester hydrochloride (40 mg, 0.29 mmol) and triethylamine (0.4 ml) in THF (10 ml) was added N, N'-dicyclohexylcarbodiimide (60 mg, 0.29 mmol) at room temperature under stirring. The stirring was continued for 15 h, then the mixture was filtered and the filtrate evaporated under vacuum. The residue was chromatographed on silica gel using as eluant ethylacetate methanol (9:1) to give pure title compound in 44.1% yield (55 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2].[CH3:33][NH2:34]>CO>[C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([NH:34][CH3:33])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(OS(=O)(=O)C(F)(F)F)cc(C)nc2n(C)c1=O
Reactant: CN
Solvent: CO
Product: CNc1cc(C)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-trifluoromethanesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.062 mmol), methanol (1 ml), and 40% aqueous methylamine (1 ml) was stirred at room temperature for 10 minutes. Concentration under reduced pressure provided crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N-methylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione which was used immediately in the next step.
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](=[O:11])[CH:10]=1)=O.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[C:16]([OH:19])(=[O:18])[CH3:17].[CH3:1][S:2][CH:4]([OH:18])[C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](=[O:11])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)Cc1cc(=O)c2ccccc2o1
Product: CC(=O)O
Product: CSC(O)c1cc(=O)c2ccccc2o1
Yield: 90 %

Procedure:
A solution of 2-[(methylsulfinyl)methyl]-4H-1-benzopyran-4-one (2.22 g, 0.01 m) in acetic anhydride (15 ml) was refluxed under nitrogen for 5 hours. The solvent was removed under reduced pressure to give a brown gum, which crystallized on standing. Recrystallization from methanol gave off-white crystals (2.36 g, 90%), m.p. 123°-125°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.O[NH:23][C:24](=[NH:42])[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:23]=[C:24]([C:25]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:26]=3[CH2:27][CH2:28][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:42]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=N)NO)C1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848, 737 mg, 3.59 mmol) and oxalyl chloride (360 μl) in DCM (20 mL) was added DMF (20 μl). The solution was stirred at room temperature for 90 min, then concentrated in vacuo, and redissolved in dry DMF (6 mL). Separately, 1,1-dimethylethyl 5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 1, 1.05 g, 3.60 mmol), 4-dimethylaminopyridine (20 mg) and N,N-diisopropylethylamine (1.31 ml, 7.50 mmol) were dissolved in DMF (10 mL). 5 mL of the first DMF solution was added to the second solution, and the yellow solution stirred at room temperature for 1 h and then at 95° C. for 18 h. The reaction was concentrated in vacuo then partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (50 mL). The organics were washed with saturated aqueous NaHCO3 (50 mL), then the combined aqueous extracted with DCM (20 mL). The combined organics were concentrated in vacuo to give a crude brown oil. Flash chromatography (gradient [0.5-4%] MeOH in DCM) and concentration in vacuo gave the title compound as a pale yellow solid (512 mg). 1H NMR (400 MHz, CDCl3) δ 8.42 (1H, d), 8.34 (1H, dd), 7.96 (1H, d), 7.34 (1H, t), 7.29 (1H, d), 7.13 (1H, d), 4.80 (1H, sept), 4.67 (2H, s), 3.68 (2H, t), 3.24 (2H, t), 1.51 (9H, s), 1.48 (6H, d); m/z (ES) 361 [M+H-100]+.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]>>[CH2:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[C:9]([C:7]#[N:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=C1CCCC1
Yield: 69 %

Procedure:
The sub-title compound was prepared in a 69% yield analogously to the method described in Organic Synthesis, 39, 25 (1959) from cyclopentanone and ethyl cyanoacetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[CH:22]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(OCC)(=O)C>C(O)C>[CH:22]1([CH2:28][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)[CH2:3][CH2:2]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Reactant: BrCC1CCCCC1
Solvent: CC(C)NC(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC2CCN(CC3CCCCC3)CC2)nc1
Yield: 75.3 %

Procedure:
A solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg), diisopropylamine (202 mg) and cyclohexylmethyl bromide (212 mg) in ethanol (2 mL) was refluxed for 16 hours. To the reaction solution was added ethyl acetate, and insolubles were filtered off, and then, concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (NH silica gel, hexane:ethyl acetate=4:1) to give the title compound (216 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C(NC1SC(/C=C\C(OCC)=O)=C(CCC2C=CC(NC(OC(C)(C)C)=O)=CC=2)N=1)(=O)C.[H][H]>[Pd].C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: CCOC(=O)/C=C\c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1

Procedure:
A mixture of ethyl (2E)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate and ethyl (2Z)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate (200 mg), THF (7 ml) and 10% Pd/C (392 mg) were combined under nitrogen atmosphere. The mixture was stirred under 3 atm hydrogen atmosphere at 20° C. for 3 h. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give ethyl 3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]propanoate as a colorless amorphous.
Reaction SMILES: [F-:1].[K+].C(=O)=O.[C:6]([C:16](F)=[O:17])([C:9]([C:12]([F:15])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7].[C:19](=[C:22]([C:24]([F:27])([F:26])[F:25])[F:23])([F:21])[F:20]>COCCOCCOC>[F:20][C:19]([F:1])([F:21])[C:22]([F:23])([C:24]([F:27])([F:26])[F:25])[C:16](=[O:17])[C:6]([F:7])([F:8])[C:9]([F:10])([F:11])[C:12]([F:13])([F:14])[F:15]
Reactant: [F-]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=C=O
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(C(F)(F)C(F)(F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 85 °C
Yield: 665.2 %

Procedure:
Into a clean dry 600 mL Parr reactor equipped with stirrer, heater and thermocouple were added 5.8 g (0.10 mol) of anhydrous potassium fluoride and 108 g of anhydrous diglyme. The contents of the reactor were stirred and cooled with dry ice while 232.5 g (1.02 mol) of n-C3F7COF (approximately 95.0 percent purity) was added to the sealed reactor. The reactor and its contents were then heated, and when a temperature of 72° C. had been reached, 141 g (0.94 mol) of CF2═CFCF3 (hexafluoropropylene) was added at a pressure of 85 psig (5150 torr) over a 3.25 hour time period. During the addition of hexafluoropropylene the temperature of the reactor was increased slowly to 85° C. while maintaining the pressure at less than 90 psig (5400 torr). The pressure at the end of the hexafluoropropylene addition was 40 psig (2800 torr) and did not change over an additional 4-hour hold period. The lower phase was fractionally distilled to give 243.5 grams of 1,1,1,2,4,4,5,5,6,6,6-undecafluoro-2-trifluoromethylhexan-3-one, having a boiling point of 72.5° C. and a purity of 99.9% as determined by gas chromatography. The structure was confirmed by gcms.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(OCC)(=O)C>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][CH2:20][NH:19][C:6]1[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of 2.21 g (11.45 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid prepared in step 2.3 (method B) in 20 mL of anhydrous THF is cooled to 2-5°C. on an ice bath. A solution of 4.79 mL (34.35 mmol) of triethylamine and 2 g (11.48 mmol) of tert-butyl (3-aminopropyl)carbamate in 15 mL of anhydrous THF is then added dropwise. The reaction mixture is stirred at room temperature for 30 minutes. Ethyl acetate is added and the organic phase is washed with aqueous 1N HCl and with water. The organic phases are combined, dried over sodium sulfate, filtered and concentrated under vacuum. 3.35 g of the expected product are obtained in the form of a yellow solid. Yield=88.6%.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C@@H:4]([NH:15]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](=[S:31])[NH2:30].C(OCC)C>CC#N>[BrH:1].[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@@H:4]([C:3]2[N:30]=[C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[S:31][CH:2]=2)[NH2:15])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Reactant: NC(=S)c1cccs1
Solvent: CCOCC
Solvent: CC#N
Product: Br
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (7.74 g, 20 mmol), and thiophene-2-carbothioic acid amide (3.14 g, 22 mmol) in CH3CN (200 mL) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 7.14 g (87% yield) of the desired product. ESI+ MS 332 (M+1).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:28])([F:27])[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]2[CH:26]=1.O>CS(C)=O>[F:28][C:10]([F:9])([F:27])[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:4][CH:20]3[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]2[CH:26]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C(F)(F)F)cn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a suspension of 60% sodium hydride (1.24, 28.5 mmol) in dimethyl sulfoxide (50 mL) was added trimethylsulfoxonium iodide (6.26 g, 28.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]acrylate (6.74 g, 23.7 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=33/67) to give the title compound (3.40 g, yield 48%).