Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 104.4 %

Procedure:
Beginning with 1.00 gm (6.6 mMol) 6-chloro-1H-indole and 1.6 mL (13.0 mMol) 1-methyl-4-piperidone, 1.7 gm (100%) of the title compound were recovered as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][CH2:39][CH2:40][C:41]#[CH:42]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:42]#[C:41][CH2:40][CH2:39][OH:38])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CCCO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CCCO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 729 mg, 1.5 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 4-hydroxybutyne (210 mg, 3.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg), and copper(I) iodide (30 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, elution with 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-but-1-ynyl)-pyrazin-2-yl]-propionamide (650 mg, 88.4%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H26ClN3O4S (M+H)+ 476.1406, found 476.1395.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:11]([CH:13]=O)=O.O>C(O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][CH:11]=[CH:13][N:9]=[C:4]2[C:3]=1[CH3:10]
Reactant: O=CC=O
Reactant: Cc1c(Br)cnc(N)c1N
Solvent: O
Solvent: CCO
Product: Cc1c(Br)cnc2nccnc12
Temperature: 25 °C

Procedure:
5-bromo-4-methylpyridine-2,3-diamine (0.21 g, 1 mmol) was dissolved in a mixture of EtOH—H2O; to this was added aqueous glyoxal 40% (0.2 ml, 4 mmol) and the resulting mixture was refluxed for 1 h. Upon cooling to room temperature, water was then added. The product was separated, filtered and washed with excess water yielded 7-bromo-8-methylpyrido[2,3-b]pyrazine as a sufficiently enough pure material (0.21 g) for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].CC(C)=O>C(O)C>[O:25]=[C:24]([CH3:26])[CH2:22][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: C=CC(C)=O
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: CC(=O)CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (5 g) and methyl vinyl ketone (5 ml) in ethanol (100 ml) was stirred at reflux for 3 days. After cooling, the product 3-(γ-oxobutylamino)-4-phenoxy-5-sulfamylbenzoic acid was collected to give 5.05 g (82%) in two crops of colorless solid. An analytical sample from aq. acetone had m.p. 215°-215.5°; ir (Nujol) 3400, 3250, 1710, 1695, 1615, 1590, and 1570 cm-1 ; nmr (CDCl3 /d6 -DMSO/D2O-washed) 2.00 (s, CH3), 2.60 (t, CH2), 3.37 (t, CH2), 6.8-7.4 (m, C6H5), 7.60 (d, J=2, CH), and 7.93 (d, CH); mass spectrum was of decomposition products, 308 (100%).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:22][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].O.C(=O)(O)[O-].[Na+:31].C>O1CCOCC1.[Pd]>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:22][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:31]
Reactant: CC(C)SC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)SC1=C(C(=O)[O-])N2C(=O)C(C(C)O)C2C1
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (25 mg) is dissolved in dioxane (2 ml) and the solution is treated with water (1 ml) containing sodium bicarbonate (6 mg) and 10% palladium on powdered charcoal (25 mg). The resulting mixture is hydrogenated at 40 psi for 1 hr. The catalyst is filtered off and washed with water (3 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), concentrated in vacuo, and lyophilized to afford sodium 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH2:1]([C:4]1([C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>O1CCCC1>[CH2:1]([C:4]1([C:13]([C:16](=[O:18])[NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([CH3:14])[CH3:15])[C:5](=[O:12])[NH:6][C:7](=[O:11])[NH:8][C:9]1=[O:10])[CH:2]=[CH2:3]
Reactant: NCCCN
Reactant: C=CCC1(C(C)(C)C(=O)O)C(=O)NC(=O)NC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCC1(C(C)(C)C(=O)NCCCN)C(=O)NC(=O)NC1=O

Procedure:
5-Allyl-5-[1-(3-aminopropylcarbamoyl)-isopropyl]barbituric acid was prepared from 2.5 g. of 5-allyl-5-(1-carboxy-isopropyl)barbituric acid, 2 g. of 1,1'-carbonyldiimidazole, 100 ml. of tetrahydrofuran and 4 g. of 1,3-diaminopropane by the above procedure. The product melted at 202°-203°.
Reaction SMILES: Cl(O)(=O)(=O)=O.C(OC(NN=[C:13]([CH3:33])[C:14](=[N:30][O:31][CH3:32])[C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16])=O)C.[OH-:34].[Na+]>>[CH3:32][O:31][N:30]=[C:14]([C:13](=[O:34])[CH3:33])[C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: [OH-]
Reactant: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 2 h

Procedure:
70% Perchloric acid (4.1 ml.) was added to a solution of 7-(3-ethoxycarbonylhydrazono-2-methoxyiminobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 4.1 g.) at room temperature and stirred at the same temperature for 2 hours. After adjusting to pH 2.0 with 1N sodium hydroxide aq. acetone was evaporated in vacuo from the resultant solution. Ethyl acetate (100 ml.) and a sodium chloride saturated aqueous solution (50 ml.) to the residue and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml.) and combined with the ethyl acetate layer. The solution was washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration to give 7-(2-methoxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.25 g.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3Cl)[S:17][CH:18]=2)=[CH:10][CH:9]=1.[I-].[Na+]>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Clc1ccc(-c2csc(-c3cnccc3Cl)n2)cc1
Agent: [I-]
Agent: [Na+]
Product: Clc1ccc(-c2csc(-c3cnccc3N3CCOCC3)n2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
Morpholine (5 ml) was added to compound (43) (120 mg, 0.40 mmol) and sodium iodide (156 mg, 0.40 mmol). The reaction mixture was heated to 80° C. and stirred for 6 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate. The extracts were combined, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and crystallized from ethyl acetate-n-hexane to give white crystals (100 mg, 67%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(CC)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 7-(4-ethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (430 mg) in ethanol (20 ml) was added 1N sodium hydroxide (4.0 ml) at room temperature, and the mixture was stirred for 24 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated to give crystals, which were collected by filtration to give 7-(4-ethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (328 mg) as colorless crystals.
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH3:12])[C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:14].Cl[CH2:16][CH2:17][CH2:18][P:19](=[O:22])([CH3:21])[CH3:20]>>[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH3:12])[C:7]=2[C:6](=[O:13])[N:5]([CH2:16][CH2:17][CH2:18][P:19](=[O:22])([CH3:21])[CH3:20])[C:4]1=[O:14]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CP(C)(=O)CCCCl
Agent: [Na]
Product: Cn1cnc2c1c(=O)n(CCCP(C)(C)=O)c(=O)n2C

Procedure:
The title substance was prepared from 10.1 g (0.05 mol) of 3,7-di-methylxanthine sodium salt and 3-chloropropyldimethylphosphine oxide analogously to Example 59 and crystallized from ethyl acetate.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3cncs3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3cncs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1

Procedure:
Racemic benzyl 2-benzamido-7a-thiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.173 g, 2.45 mmol) is purified by chiral HPLC: (Column: Chiralpak AS 8×33 cm; eluent: 100% methanol; flow: 400 mL/min at UV 240 nm), to give the title product as the first eluting isomer with Rt=3.43 minutes, (422 mg, 36%, >99% ee). Analysis column: Chiralpak AS-H 4.6×150 mm; eluent: 99.8% methanol with 0.2% isopropylamine; flow: 1.0 mL/min at UV 225 nm). ES/MS (m/e): 479 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2F)[C:5](=[S:8])[S:6][CH:7]=1.[CH3:18][NH2:19]>C(#N)C.CO>[CH3:18][N:19]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([F:15])[C:11]=2[F:16])[N:4]2[C:5](=[S:8])[S:6][CH:7]=[C:3]2[CH2:2]1
Reactant: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F
Reactant: CN
Solvent: CO
Solvent: CC#N
Product: CN1Cc2csc(=S)n2-c2ccc(F)c(F)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
4-Chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione (2.5 g) is dissolved in acetonitrile (25 ml) and thereto is added 40% solution of methylamine in methanol (3.3 g), and the mixture is stirred at 50° C. for 16 hours. The reaction mixture is evaporated to dryness under reduced pressure, and water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from cyclohexane-ethyl acetate to give the title compound (2.0 g) as yellow crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)CCOCCc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
tert-Butyl 3-[2-(2-naphthyl)ethoxy]propanoate (Example 32a) (4.96 g) was dissolved in DCM (25 ml), and trifluoroacetic acid (25.5 ml) added. The mixture was stirred for 1 hour. The solvents were removed in vacuo, and the residue taken up in ether. The ether was washed with saturated bicarbonate solution (×3) and the aqueous layer was acidified with 2N HCl, then extracted with ether (×3), dried over magnesium sulfate, filtered and evaporated to give the sub-titled compound (3.66 g).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 81.6 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (4.3 g) and 3-pyridinebutanamine (1.51 g) in tetrahydrofuran (20 mL) was stirred for 1.5 hours at room temperature and was worked up in the usual fashion. The crude product was crystallized from ethyl acetate-hexane to provide 3.6 g of (E)-5,5-bis(4-methoxyphenyl)-N-[4-(3-pyridinyl) butyl]-2,4-pentadienamide mp 76°-77° C. Anal. Calculated for C28H30N2O3 : C, 75.99; H, 6.83; N, 6.33 Found: C, 76.36; H, 6.97; N, 6.35.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1>C(N(CC)CC)C.C(#N)C.[Cu](I)I>[Br:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:2]2[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)Cn1cc(I)cn1
Reactant: C#Cc1cccc(Br)c1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)Cn1cc(C#Cc2cccc(Br)c2)cn1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a solution of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.14 g, 15 mmol) in triethylamine (53 mL) is added tetrakis(triphenylphosphine)paddadium (1.20 g, 1.04 mmol), copper iodide (0.28 g, 1.46 mmol) and a solution of 1-bromo-3-ethynylbenzene (2.78 g, 15 mmol) in acetonitrile (15 mL) at room temperature. After heating for 1 hour at 80° C., the reaction mixture is cooled and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:5/95) to give the title compound as a solid (4.91 g, 99%). mp: 107-109° C. MS (+) EI: 328 M+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:33][CH2:32][CH2:31][CH2:30][NH:29][C:26]3[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:34])=[CH:28][CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CN(C)c1ccc(NCCCN)cc1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-(4-dimethylamino-phenylamino)-propylamine analogously to Example 1.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH:35]=O)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:16]([N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH:35]1[O:4][CH2:1][CH2:2][O:3]1)=[O:29])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C1OCCO1

Procedure:
Ethylene glycol (0.3 ml), p-toluenesulphonic acid (1 mg) were added to a solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-al (164 mg) in benzene (3 ml). The mixture was refluxed for 1 hr. The reaction solution was poured into a saturated aq. solution of sodium bicarbonate. The mixture was extracted with benzene. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (CH3OH-EtOAc-CH2Cl2) to give the title compound (79 mg) having the following physical data:
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:8]([CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9][CH2:10][S:22]1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: ClCC[NH2+]CC1CCCC1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CCCC2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[N:10][C:9]([CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].Cl>N1C=CC=CC=1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:3]3[CH:11]=[N:10][C:9]([CH3:12])=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc2ncnc(O)c2cn1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc2ncnc(Nc3cccc(Cl)c3)c2cn1
Yield: 34 %

Procedure:
Utilizing a procedure analogous to that described in Example 16, this product was prepared in 34% yield from 4-hydroxy-7-methyl-pyrido[4,3-d]pyrimidine (1.0 eq) and m-chloroaniline (40.0 eq) in pyridine. The HCl salt was generated from the purified free base according to the procedure given in Example 1. (M.P. 255-256° C.; GC-MS: 270 (MH+); anal. RP18-HPLC RT: 4.05 min.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[OH:35]/[N:34]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:25][N:26]([S:28]([NH2:31])(=[O:29])=[O:30])[CH2:27]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(S(N)(=O)=O)C3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CN(S(N)(=O)=O)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-3-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)azetidine-1-sulfonamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=465.3 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.[C:19]([O:23][C:24](SC1N=C(C)C=C(C)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To an aqueous solution (40 ml) of L-hydroxyproline methyl ester hydrochloride (8.2 g, 45.2 mmol), triethylamine (7.54 ml, 54.2 mmol) was added at room temperature, and then a solution of 2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine (10.8 g, 45 mmol) in dioxane (80 ml) was added thereto. The reaction solution was stirred at room temperature for 1.5 hours, and then dioxane was distilled off under reduced pressure. The residue was extracted with ethyl acetate (250 ml). The organic layer was washed sequentially with a 0.1N sodium hydroxide aqueous solution, dilute hydrochloric acid, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 5% methanol-methylene chloride) to obtain N-tert-butoxycarbonyl-L-hydroxyproline methyl ester (9.3 g, yield: 84%).