Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11](Cl)=[N:10]1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)=[N:10]1
Reactant: N#Cc1nc[nH]n1
Reactant: CCOC(=O)C1=C(C)NC(Cl)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(C)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 49.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-chloro-6-methyl-1,4-dihydropyrimidine-5-carboxylate (3.77 g, 10 mmol) was reacted with 1H-1,2,4-triazole-3-carbonitrile (2.82 g, 30 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a pale yellow solid (2.16 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:35]2[S:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:35]3[S:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[CH2:2][C@H:23]2[N+:24]([O-:26])=[O:25])=[CH:18][CH:17]=1
Reactant: COCCOCOc1ccc(/C=C/[N+](=O)[O-])cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCOCOc1ccc([C@@H]2C[C@H]2[N+](=O)[O-])cc1
Yield: 57.6 %

Procedure:
Trimethylsulfoxonium iodide (0.76 g, 3.44 mmol) was added in small portions to a suspension of NaH 0.14 g (60% in mineral oil), 3.44 mmol] in dry DMSO (5 mL). The mixture was stirred until gas evolution ceased and a clear solution was formed (45 min). Then, a solution of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene (Intermediate J, 0.73 g, 2.86 mmol) in DMSO (5 mL) was transferred via cannula and the reaction was stirred for additional 20 h. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered; after removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (10-20% EtOAc/Hexanes) affording 0.44 g of 1-((2-methoxyethoxy)methoxy)-4-((trans)-2-nitrocyclopropyl)benzene [Rf=0.4 (50% AcOEt/Hexanes), colorless oil, 36% yield].
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][C:18]1([CH3:25])[CH2:21][CH:20]([C:22](Cl)=[O:23])[CH2:19]1.[Cl-]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:22]([CH:20]2[CH2:21][C:18]([CH3:25])([CH3:17])[CH2:19]2)=[O:23])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CC1(C)CC(C(=O)Cl)C1
Agent: Cl
Agent: [Cl-]
Product: CC(C)NCC(=O)c1ccc(OC(=O)C2CC(C)(C)C2)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 3,3-dimethylcyclobutanecarbonyl chloride instead of isovalery chloride, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:19][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g, 0.203 mmol, Example 8D) in acetonitrile (3 mL) at ambient temperature under nitrogen was added cyclopentylamine (0.04 ml, 0.406 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 246 (M+H)+; 1H NMR (300 MHz, DMSO) δ 1.5-2 (8H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[CH3:25][O-:26].[Na+].[ClH:28]>CO.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([O:26][CH3:25])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)(=[O:10])=[O:11].[ClH:28]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2F)CC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)C2CCNCC2)c(F)c1
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
To a suspension of tert-butyl 4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (50 mg, 0.138 mmol) in MeOH (461 μL) was added sodium methoxide (25.6 μL, 0.138 mmol, 5.4 M in MeOH) dropwise. The reaction mixture was allowed to stir at 45° C. for 20 min then concentrated in vacuo. Boc deprotection was carried out by addition of HCl (138 μL, 0.553 mmol, 4 M in dioxane) to the crude reaction mixture in 300 μL dioxane. Stirring at 50° C. for 24 h followed by concentration in vacuo yielded the title compound as its HCl salt (57 mg) as a white solid (10:1 regioisomeric mixture). ESI-MS m/z [M+H]+274.00.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([NH2:22])[CH:3]=1.[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:23](=[O:24])[NH:22][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4,5-Dichloro-2-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D39) (140 mg, 0.4 mmol) was dissolved in 10 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 0.25 ml) and triethylamine (0.2 ml, 1.5 mmol) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous sodium bicarbonate, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, and then further purified by MDAP to yield 5,6-dichloro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 22 mg, which was converted into the hydrochloride salt using 4M HCl in dioxan.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[O:5].[CH:12]([Mg]Br)=[CH2:13]>O1CCCC1>[O:8]1[CH:9]=[CH:10][C:6]([C:4](=[O:5])[CH:12]=[CH2:13])=[N:7]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)c1ccon1
Solvent: C1CCOC1
Product: C=CC(=O)c1ccon1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
The product of step (a) (0.66 g) was dissolved in dry tetrahydrofuran (20 ml), under a nitrogen atmosphere and cooled to −30° C. A solution of vinyl magnesium bromide (1M, 6 ml) was added dropwise over 5 minutes and the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 2 h. The mixture was then poured into ice-cold 2N hydrochloric acid (50 ml) and extracted into ethyl acetate. The extract was washed with water, brine, dried over magnesium sulphate and evaporated to give a dark oil (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1.[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>C(#N)C>[CH2:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1)[CH3:16]
Reactant: CCN=C=S
Reactant: NC(=O)CCCSc1cccc(N)n1
Solvent: CC#N
Product: CCNC(=S)Nc1cccc(SCCCC(N)=O)n1
Yield: 70.8 %

Procedure:
A mixture of 4-(2-aminopyrid-6-ylthio)butyramide (0.25 g.), ethylisothiocyanate (0.2 g.) and acetonitrile (5 ml.) was heated under reflux for 18 hours and then cooled, and the solid which crystallised was collected to give 4-[2-(3-ethylthioureido)pyrid-6-ylthio]butyramide (0.25 g.) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:21]C)=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[O:10][N:9]=2)[CH:7]=1.[Li][CH2:24]CCC.IC.B(Br)(Br)Br>C1COCC1>[OH:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([CH3:24])[C:3]([OH:21])=[CH:4][C:5]=3[OH:19])=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(-c3cc(Br)c(OC)cc3OC)noc2c1
Reactant: [Li]CCCC
Agent: BrB(Br)Br
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(-c2noc3cc(O)ccc23)c(O)cc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 3-(5-bromo-2,4-dimethoxyphenyl)-6-methoxy-1,2-benzisoxazole (200 mg, 0.55 mmol) in THF (6 mL) at −78° C. was added n-BuLi (0.24 mL, 0.60 mmol, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 30 min and then iodomethane (60 μL, 0.96 mmol) was added dropwise. The cooling bath was switched to an ice bath and the solution was stirred at 0° C. for 2 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was conducted in EtOAc (2×30 mL) with water (20 mL). Flash chromatography with silica gel (gradient to 25% EtOAc/hexanes) provided a mixture of the desired methylated product and the protonated side product (both compounds have the same Rf). The above mixture of compounds was treated with BBr3 according to Example 2, Step i, to produce the title compound as a light orange solid (114 mg, 81% yield for two steps): mp 195° C. (dec.); 1H NMR (300 MHz, acetone-d6) δ 2.25 (s, 3H), 6.59 (s, 1H), 7.04 (dd, 1H, J=8.5, 2.1 Hz), 7.09 (d, 1H, J=1.8 Hz), 7.80 (s, 1H), 8.12 (d, 1H, J=8.8 Hz), 8.88 (broad s, 1H), 9.42 (broad s, 1H), 9.52 (s, 1H); MS m/e 258 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCCO)C>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A mixture of 250 mg (1.02 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 210 mg (1.12 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 4 hours then stirred at room temperature for 3 days. The reaction mixture is then heated at reflux temperature for an additional 6 hours, then cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 240 mg (60%) of a beige solid, mp 230-233° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)SC)#[N:2].[CH:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([CH:28]([OH:31])[CH2:29][NH2:30])[CH:22]=1>[N+]([O-])([O-])=O.[Ag+].C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)=[N:30][CH2:29][CH:28]([OH:31])[C:23]1[CH:22]=[CH:21][CH:26]=[C:25]([OH:27])[CH:24]=1)#[N:2]
Reactant: NCC(O)c1cccc(O)c1
Reactant: CSC(=NCCSCc1csc(NC(=N)N)n1)NC#N
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: N#CNC(=NCC(O)c1cccc(O)c1)NCCSCc1csc(NC(=N)N)n1
Yield: 63.2 %

Procedure:
With 15 ml of ethanol were mixed 3.0 g of N-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-S-methylisothiourea, 4.9 g of DL-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amine and 1.97 g of silver nitrate, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. After completion of the reaction, the insolubles were removed by filtration, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=5:1 by volume) and crystallized from methanol to obtain 2.5 g (yield 68%) of N-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]guanidine having a melting point of 162°-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:18][CH:19]=O>CCO>[N:1]1[CH:18]=[CH:19][N:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccn2ccnc2c1
Yield: 72.2 %

Procedure:
To a solution of Methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 mmol, 1.0 equiv) in EtOH (150 ml) was added NaHCO3 (11.1 g, 132 mmol, 2.0 equiv) followed by chloroacetaldehyde (13.0 ml, 99 mmol, 1.5 equiv). The mixture was refluxed for 2 h. Solvents were removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The resulting precipitate was washed with Et2O and recrystallised from MeOH/Et2O to afford 8.4 g of product. 1H NMR (400 MHz, DMSO-d6): 8.66 (1H, d), 8.16 (2H, s), 7.80 (1H, s), 7.33 (1H, d), 3.90 (3H, s). MS: [M+H]+ 177.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][N:12]1[N:16]=[C:15]([CH3:17])[O:14][C:13]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][N:12]([NH:16][C:15](=[O:14])[CH3:17])[C:13](=[O:18])[NH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(CC(=O)COCc2ccccc2)c(=O)o1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NN1CC(COCc2ccccc2)=NNC1=O
Temperature: 75 °C

Procedure:
To a solution of 3-(3-benzyloxy-2-oxo-propyl)-5-methyl-1,3,4-oxadiazol-2-one (36.4 g, 139 mmol) in isopropanol (140 mL) was added hydrazine hydrate (62 wt % in water, 11.8 mL, 152 mmol) in at room temperature in one portion. The mixture was heated to 75° C. for 24 h. The volatiles were removed under reduced pressure, and the remaining brown oil was purified by flash chromatography (7% MeOH/dichloromethane) to furnish the desired product as a yellowish solid. 1H NMR (400 MHz, CDCl3) 2.04 (s, 3H), 4.12 (s, 2H), 4.23 (s, 2H), 4.54 (s, 2H), 7.24-7.44 (m, 5H), 8.25 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(C)C(S(O)(=O)=O)=CC=C[CH:15]=1>C(O)C>[CH2:10]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[CH3:15]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: NCCCCCC(=O)O
Solvent: CCO
Product: CCOC(=O)CCCCCN
Yield: 204.7 %

Procedure:
A mixture of ε-aminocaproic acid (70.0 g, 533.8 mmol), toluenesulfonic acid (111.7 g, 1.1 eq.) and ethanol (1.6 L) was heated to reflux for 20 hours. Thereafter, TLC (CH2Cl2/EtOH/TEA, 85:10:5) revealed complete conversion. The reaction mixture was concentrated until solids started to precipitate. The precipitation was driven to completion by adding diethyl ether (1.5 L). The white solid was filtered, washed with diethyl ether, and dried in vacuo affording 174.0 g (98.3%) of a white powder. 1H NMR: (200 MHz, CDCl3): δ 7.47 (d, 2H, J=8.2 Hz), 7.10 (d, 2H, J=8.2 Hz), 4.02 (q, J=7.0 Hz), 2.79-2.65 (m, 2H), 2.28 (s, 3H), 2.25 (t, 2H, J=7.0 Hz), 1.16 (t, 3H, J=7.0 Hz), 1.49 (dt, 4H, J=7.6, 7.0 Hz), 1.29-1.22 (m, 2H). 13C NMR: 173.4, 145.6, 138.8, 128.9, 126.1, 60.4, 39.4, 33.9, 27.3, 25.9, 24.6, 21.5, 14.8.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=1.O>CS(C)=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: COc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(N2CCC(NC(C)=O)CC2)n1
Temperature: 130 °C
Reaction time: 50 h
Yield: 43 %

Procedure:
A mixture of 0.088 mole of 4-acetamidopiperidine, 15 g of potassium carbonate, 0.088 mole of 2-chloro-6-methoxypyridine in 100 ml of dimethylsulfoxide is heated with stirring to 130° C. for 50 hours, then it is cooled, the mixture is poured into water and the suspension thus obtained is extracted with diethyl ether. The aqueous phase is extracted with methylene chloride, the organic phase is washed with water, it is dried on anhydrous sodium sulfate and evaporated to dryness. 4-acetamido-1-(6-methoxy-2-pyridyl)piperidine is thus obtained which, after crystallisation in 95% ethanol, melts at 125° to 127° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Yield: 82.8 %

Procedure:
To a solution of 2,4,5-tribromoimidazole (3.05 g, 10 mmol) in anhydrous DMF (50 mL) was added powdered K2CO3 (19 g, 137 mmol), and the resulting suspension was stirred vigorously and treated dropwise with SEMCl (2.3 g, 13.8 mmol). The suspension was then stirred vigorously overnight. The solid was filtered off and washed with fresh DMF (20 mL). The combined filtrates were then evaporated under reduced pressure. Methylene chloride (30 mL) was then added and the solution washed with 0.1 N Na2CO3 (3×50 mL), dried (Na2SO4), filtered and evaporated to give a residue, which was passed through a silica gel pad (CH2Cl2) and evaporated to give 3.6 g (83%) of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 0.01 (s, 9H), 0.93 (t, 2H, J=8.0 Hz), 3.60 (t, 2H, J=8.0 Hz), 5.32 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 10.88 g (0.16 mol) of imidazole in 150 ml of dry DMF at 0° C. under argon was added 6.4 g (0.16 mol) of 60% NaH, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. The mixture was cooled to 0° C., and 25 g (0.16 mol) of p-methoxybenzyl chloride was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, concentrated in vacuo to yield 35.6 g of a crude product which was purified by chromatography on silica (methylene chloride/methanol 9:1) to afford 25.3 g (84.2%) of 1-(p-methoxybenzyl)-imidazole.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][N:37]([CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][N:10]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][N:37]([CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1C[C@@](OC)(c2ccc(-c3ccccc3)cc2)CN1
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
A mixture of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (100 mg, 0.287 mmol), (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (145 mg, 0.316 mmol), Hunig's Base (0.176 mL, 1.01 mmol) and HATU (131 mg, 0.345 mmol) in DCM (3 mL) was stirred at rt for 18 h. It was then concentrated in vacuo. The residue was dissolved in EtOAc and washed with dilute HCl, followed by sat.aq. NaHCO3 and water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield 250 mg of the crude product as a brown oil. Purification by Biotage eluting with 60% EtOAc/Hexane gave 188 mg (87%) of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-4-methoxypyrrolidine-2-carboxylate as an off-white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.[OH-].[Na+]>Cl>[CH3:1][N:2]([CH3:19])[C:3]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C1(c2ccccc2)CCC(=O)CC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The residue (N,N-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]decan-8-amine) was taken up in aqueous HCl at pH 1. It was stirred for 1 hour at 65° C. The batch was cooled and brought to pH 4 with NaOH solution. 2-MTHF (52 ml) was then added. The mixture was alkalised with NaOH at 15-25° C. to pH≧12. The organic phase was concentrated at 45° C. and at reduced pressure (<10 mbar). The residue was dissolved at 65° C. in twice the amount of isopropanol/H2O 60/40. The batch was stirred overnight at −10° C. The precipitate was suctioned off, subsequently washed with cold isopropanol/H2O and dried overnight in a drying cupboard (45° C., <100 mbar).