Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Sn]Cl.[F:4][C:5]1[C:10]([F:11])=[C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[C:8]([F:23])=[C:7]([F:24])[N:6]=1>CCO>[F:4][C:5]1[C:10]([F:11])=[C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[C:8]([F:23])=[C:7]([F:24])[N:6]=1
Reactant: O=[N+]([O-])c1ccccc1C#Cc1c(F)c(F)nc(F)c1F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1C#Cc1c(F)c(F)nc(F)c1F
Yield: 68 %

Procedure:
SnCl2 (3.26 g, 17.2 mmol) was added to the solution of 2,3,5,6-tetrafluoro-4-((2-nitrophenyl)ethynyl) pyridine, (12c) (1.02 g, 3.44 mmol) in EtOH (100 mL). The reaction mixture was refluxed for 1.5 hours. After basification till pH>9 with NaOH (1.0 N solution), the product was extracted with dichloromethane. Solvent was evaporated and 0.22 g (24%) of the product aniline was purified by recrystallization with benzene. The residue was purified by column chromatography on silica gel using EtOAc:Hexane=1:10 as the eluent to yield the product (0.53 g, 68%): 1H-NMR (300 MHz, acetone-d6) δ 7.39 (d, J=7.5 Hz, 1H), 7.26 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.69 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 5.35 (s, 2H); 13C-NMR (150 MHz, CDCl3) δ 149.3, 143.7 (dm, J=245.3 Hz), 141.4 (dm, J=260.9 Hz), 133.0, 132.6, 118.3, 117.8 (m), 114.8, 104.7, 104.6 (t, J=3.5 Hz), 79.4 (t, J=4.3 Hz); HRMS (ESI+): calcd for C13H7F4N2 [M +H]+ 267.05454, found 267.05454; m.p. 133-134° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])=[CH:11][CH:10]=4)[CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH2:24][CH2:25]1
Reactant: C=CC(=O)Nc1ccc(Sc2ccnc(Cl)n2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: C=CC(=O)Nc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Yield: 53.6 %

Procedure:
In a procedure analogous to Example 8, reaction of N-(4-(2-chloropyrimidin-4-ylthio)phenyl)acrylamide (540 mg, 1.85 mmol) and 4-morpholinoaniline (400 mg, 2.24 mmol) furnished the product (430 mg, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:36])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][O:16][C:17](=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@H:11]([CH2:13][O:14][C:17](=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Compound XIII-1 (280 mg, 54.6%) was obtained in the same manner as that in Reference Example 2, by using trans-3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (156 mg, 0.674 mmol) obtained by using the method described in WO2006/100036 and oleic acid (Tokyo Chemical Industry Co., Ltd.; 419 mg, 1.48 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.C([O-])(=O)C.[Na+].Cl.[NH2:30][OH:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[N:30][OH:31])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: ON=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A 100 mL round bottomed flask charged with 4-(3,4-dichlorophenyl)-5,6-dihydro-1-benzothiophen-7(4H)-one (1.29 g, 4.34 mmol), tetrahydrofuran (11.0 mL) and ethanol (12.5 mL). The mixture was stirred and sodium acetate (1.117 g, 13.62 mmol) and hydroxylamine hydrochloride (0.9242 g, 13.30 mmol) were added. The mixture was stirred for 16 h at 50° C. under an atmosphere of Nitrogen. The reaction was then cooled to rt, giving a pale yellow solution with much white ppt. The reaction was quenched into ˜75 ml saline solution w/stirring and the resulting mixture was transferred to a separatory funnel and extracted with ethyl acetate (2×). the extracts were combined, washed with saline, dried over sodium sulfate, filtered, and evaporated to leave 1.27 g (94% yield) product as pale yellow powder. LCMS: (FA) ES+ 312, 314. 1H NMR indicated that the product was an ˜3:1 mixture of geometric oxime isomers.
Reaction SMILES: [N:1]([C:4]1[N:8]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)=[N+]=[N-]>CO.[C].[Pd]>[NH2:1][C:4]1[N:8]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N=[N+]=[N-])nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
2-Azido-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (100 mg) was dissolved in methanol (2 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent of filtrate was removed under reduced pressure to give the title compound (97 mg).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:21][C:22]([OH:24])=[O:23]>C(O)(=O)C>[N+:8]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH2:12][CH:13]([CH2:21][C:22]([OH:24])=[O:23])[CH2:14]2)([O-:11])=[O:9]
Reactant: O=C(O)CC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.2 %

Procedure:
Acetic anhydride (3.5 mL) was added slowly to a stirred solution of nitric acid (2.1 g, S.G.1.42) in glacial acetic acid (4.2 mL) cooled in an ice-water bath. This nitrating solution was then added dropwise over 5 minutes to a rapidly stirred solution of indan-2-acetic acid (1.65 g) in a mixture of glacial acetic acid (4.2 mL) and acetic anhydride (3.5 mL), whilst keeping the reaction temperature below 5° C. After stirring for a further 20 minutes at room temperature the reaction mixture was poured onto ice-water (60 mL). This mixture was extracted three times with dichloromethane. The combined extracts were washed twice with a little water, then dried over magnesium sulfate and then evaporated to give the title compound (2.22 g) as a red oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1

Procedure:
In a similar manner as described in step 1 of Example 4, the title compound was prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.250 g, 0.665 mmol), prepared in step 2 of Example 2, methyl bromoacetate (0.122 g, 0.797 mmol) and cesium carbonate (1.08 g, 3.33 mmol). The isolated tan amorphous solid (0.298 g, 100%) was used without further purification, mp 101–102° C. Elemental Analysis for C30H25NO3 Calc'd: C, 80.51; H, 5.63; N, 3.13. Found: C, 79.81; H, 5.60; N, 2.83.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]1=[O:37].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)[C:7](=[O:37])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g) and trifluoroacetic acid (5 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (10 mL), and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in 1N aqueous sodium hydroxide solution, washed with chloroform, and adjusted to pH 4 with 1N hydrochloric acid. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.21 g, 93%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][NH:8][C:9](=O)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.N>C1COCC1>[CH3:7][NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: CNC(=O)CC1CCCCN1Cc1ccc(F)cc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCCC1CCCCN1Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a suspension of lithium aluminum hydride (243 mg, 6.40 mmol) in THF (10 ml) was added dropwise under ice-cooling a solution of N-methyl-2-[1-(p-fluorobenzyl)-2-piperidyl]acetamide (1.13 g, 4.26 mmol) in THF (20 ml). The mixture was stirred for 20 minutes and then heated under reflux for 1.5 hours. To the reaction mixture was added dropwise under ice-cooling aqueous ammonia (20 ml) and the mixture was stirred at room temperature for 3 hours. Then, it was filtered with Celite and the aqueous layer was extracted with chloroform (50 ml×3). The combined organic layer was washed with saturated aqueous sodium chloride (20 ml), dried over potassium carbonate and the solvent was distilled off under reduced pressure to give crude 2-(2-methylaminoethyl)-1-(p-fluorobenzyl)piperidine (860 mg). Yield=76%. This compound was used for the subsequent reaction without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)[CH:13]=[N:12]1
Reactant: OCc1ccc(Cl)nc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(CO)cn2)cn1
Temperature: 140 °C

Procedure:
In a microwave vial containing (6-chloropyridin-3-yl)methanol (H1) (0.25 g, 1.7 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (63 mg, 0.30 mmol), Pd2(dba)3 (16 mg, 0.02 mmol), and tricyclohexylphosphine (12 mg, 0.04 mmol) was added 7.0 mL of dioxane and 2.3 mL 1.7 M aqueous tribasic potassium phosphate. The reaction was heated to 140° C. in a microwave reactor for 1.5 h. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-15% methanol in methylene chloride to afford [6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]methanol (H2) that gave a mass ion (ES+) of 190.2 for M+H+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl ethyl (6-nitropyridin-3-yl)propanedioate (1.4 g, 4.5 mmol) in a mixed solution of TFA/DCM (10 mL/10 mL) was stirred for 5 hours at room temperature. The mixture was concentrated under reduce pressure. The residue was dissolved with DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated to give ethyl (6-nitropyridin-3-yl)acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-fluorophenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 397.2 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20]>>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: CN(C)C=CC(=O)c1ccsc1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccsc3)n2)c1

Procedure:
In accordance with the general procedure described in Example 1, reaction of 10 g (0.055 mol) of 3-dimethylamino-(3-thienyl)-2-propen-1-one [described in EP-A-0 233 461] and 15 g (0.060 mol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(3-thienyl)-2-pyrimidine-amine; FAB-MS:370 (M+ +1), m.p. 110°-111°, Rf =0.8 (ethyl acetate:hexane=1:1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17](/[CH:19]=[C:6]1/[CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:2]/1=[O:1])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 105 °C

Procedure:
tert-Butyl 3-oxopyrrolidine-1-carboxylate (40 g, 216 mmol) was treated with N,N-dimethylformamide dimethyl acetal (267 g, 2241 mmol) and heated at 105° C. for 40 min. The solution was cooled and evaporated under reduced pressure and the resulting orange solid was treated with hexane (200 mL) and cooled in the refrigerator for 64 h. The resulting brownish-yellow solid obtained as such was collected by filtration, dried and used in the next step without further purification. LC/MS: 241.1 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](O)=[O:34]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (24.3 mg, 69.4%), MS (ISP) m/z=430 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and tetrahydrofuran-2-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].[CH2:20]([SH:22])[CH3:21].C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:22][CH2:20][CH3:21])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCS
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O

Procedure:
5.02 g (20 mmols) of 3,5-dinitrophthalic acid N-methylimide, 2.73 g (44 mmols) of ethylmercaptan, 8.2 g (100 mmols) of anhydrous sodium acetate and 50 ml of ethyl acetate are kept at 25° C. overnight and then kept under reflux, again overnight. The reaction mixture is evaporated, the residue is taken up in methylene chloride/water, the extracts are washed with saturated NaHCO3 solution, dried over sodium sulfate and evaporated and the residue is chromatographed with methylene chloride over 20 g of silica gel. After recrystallisation from methylene chloride/n-pentane, 2.40 g (45% of theory) of 3-ethylthio-5-nitrophthalic acid N-methylimide, with a melting point of 193°-4° C., are obtained.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:27][C:21]3=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:27][C:21]3=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 62.2 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine (240 mg, 0.63 mmol) and 10% palladium on activated carbon (100 mg) in methanol (50 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine as a white solid (150 mg, 100%): LC/MS m/e calcd for C22H26N2O2S [M+H]+ 383.53, observed 382.9; 1H NMR (400 MHz, CD3OD) δ ppm 8.21 (s, 1H), 8.06 (s, 1H), 7.87-7.91 (m, J=8.1 Hz, 2H), 7.56-7.61 (m, J=8.3 Hz, 2H), 6.61 (s, 1H), 4.34 (t, J=7.8 Hz, 1H), 2.99-3.10 (m, 3H), 2.48 (s, 3H), 2.22-2.30 (m, 1H), 2.10-2.18 (m, 1H), 1.58-1.86 (m, 5H), 1.43-1.54 (m, 2H), 1.16-1.30 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1.[Cl:31]Cl>C(O)(=O)C.[Zn]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]3)=[CH:7][C:6]=2[Cl:31])=[C:2]([F:1])[CH:27]=1
Reactant: CCOC(=O)C1=Cc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2OC1C(F)(F)F
Reactant: ClCl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(N)cc3F)cc2OC1C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of the ester from Step 1 (0.5 g, 1.17 mmole) in acetic acid was stirred at 10° C. The pre-prepared solution of Cl2 (gas) in acetic acid (10 mL, 4.0 mmole was added to the above solution. The mixture was stirred for 2 hour. After Cl2 (gas) was blown away, Zn powder (5 eq) was added to the mixture and stirred for 30 min. The Zn salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by normal phase silica chromatography with 20% ethyl acetate in hexane to give the ester as a yellow oil, which solidified upon standing (0.43 g, 85%): LCMS m/z 431.75 (M+H). 1NMR (CDCl3/400 MHz) 7.61 (s, 1H), 7.27 (s, 1H), 6.95 (dd, 1H, J=8.4 Hz), 6.50 (dd, 1H, J=12, 2.4 Hz ), 6.42 (m, 1H), 5.61 (q, 1H, J=6.8 Hz), 4.30 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:18][NH2:19])=[O:17])[CH3:15])=[O:12])[CH3:10].CN1CCOCC1.C(Cl)Cl>CN(C=O)C>[NH:8]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:18][NH:19][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:17])[CH3:15])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)NN
Reactant: CCOC(=O)CBr
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CNNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Ethyl bromoacetate (1.1 eq) was added dropwise to a stirred solution of Cbz-Ala-Ala-NHNH2 (1 eq) and NMM (1.1 eq) in DMF that was cooled to −10° C. The resulting solution was stirred for 30 min at −10° C., after which the mixture was allowed to react at room temperature for 36 hours. The DMF was evaporated, and the residue was purified on a silica gel column using 1:9 MeOH:CH2Cl2 as the eluting solvent system to afford 4a as a white solid (yield=36%). 1H NMR (DMSO-d6): 1.18 (t, 9H, CH3), 3.5 (d, 2H, NCH2COOEt), 4.0-4.15 (m, 3H, α-H and OCH2CH3), 4.2 (m, 1H), α-H), 5.03 (m, 2H, Cbz), 5.18 (m, 1H, NH), 7.22-7.40 (m, 5H, Ph), 7.4-7.5 (d, 1H, NH), 7.9 (m, 1H, NH), 9.35 (m, 1H, NH). MS (FAB) m/z 395 [(M+1)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][CH:20]([SH:22])[CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[S:22][CH:20]([CH3:21])[CH3:19]
Reactant: CC(C)S
Reactant: COC(=O)c1ccc(C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)nc1SC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
2-Chloro-6-methyl-nicotinic acid methyl ester (1.39 g, 7.44 mmol) obtained in Step A was dissolved in DMF (15 mL). Cs2CO3(4.88 g, 14.99 mmol) and propane-2-thiol (1.39 mL, 14.99 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. The reactant was concentrated under reduced pressure to remove the solvent. The residue was added with water and then extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex=1/5) to obtain the title compound (1.17 g, 69%).